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  • 151.
    Kinsman, John
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Stöven, Svenja
    Umeå University, Faculty of Science and Technology, European CBRNE Center.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Murillo, Pilar
    Umeå University, Faculty of Science and Technology, European CBRNE Center.
    Sulzner, Michael
    Good practices and challenges in addressing poliomyelitis and measles in the European Union2018In: European Journal of Public Health, ISSN 1101-1262, E-ISSN 1464-360X, Vol. 28, no 4, p. 730-734Article in journal (Refereed)
    Abstract [en]

    Background: All European Union (EU) and European Economic Area (EEA) Member States have pledged to ensure political commitment towards sustaining the region's poliomyelitis-free status and eliminating measles. However, there remain significant gaps between policy and practice in many countries. This article reports on an assessment conducted for the European Commission that aimed to support improvements in preparedness and response to poliomyelitis and measles in Europe.

    Methods: A documentary review was complemented by qualitative interviews with professionals working in International and EU agencies, and in at-risk or recently affected EU/EEA Member States (six each for poliomyelitis and measles). Twenty-six interviews were conducted on poliomyelitis and 24 on measles; the data were subjected to thematic analysis. Preliminary findings were then discussed at a Consensus Workshop with 22 of the interviewees and eight other experts.

    Results: Generic or disease-specific plans exist in the participating countries and cross-border communications during outbreaks were generally reported as satisfactory. However, surveillance systems are of uneven quality, and clinical expertise for the two diseases is limited by a lack of experience. Serious breaches of protocol have recently been reported from companies producing poliomyelitis vaccines, and vaccine coverage rates for both diseases were also sub-optimal. A set of suggested good practices to address these and other challenges is presented.

    Conclusions: Poliomyelitis and measles should be brought fully onto the policy agendas of all EU/EEA Member States, and adequate resources provided to address them. Each country must abide by the relevant commitments that they have already made.

  • 152. Kittayapong, Pattamaporn
    et al.
    Olanratmanee, Phanthip
    Maskhao, Pongsri
    Byass, Peter
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Logan, James
    Tozan, Yesim
    Louis, Valérie
    Gubler, Duane J
    Wilder-Smith, Annelies
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. London School of Hygiene and Tropical Medicine, London, United Kingdom; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; Institute of Public Health, University of Heidelberg, Heidelberg, Germany.
    Mitigating Diseases Transmitted by Aedes Mosquitoes: A Cluster-Randomised Trial of Permethrin-Impregnated School Uniforms2017In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 11, no 1, article id e0005197Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Viral diseases transmitted via Aedes mosquitoes are on the rise, such as Zika, dengue, and chikungunya. Novel tools to mitigate Aedes mosquitoes-transmitted diseases are urgently needed. We tested whether commercially insecticide-impregnated school uniforms can reduce dengue incidence in school children.

    METHODS: We designed a cluster-randomised controlled trial in Thailand. The primary endpoint was laboratory-confirmed dengue infections. Secondary endpoints were school absenteeism; and impregnated uniforms' 1-hour knock-down and 24 hour mosquito mortality as measured by standardised WHOPES bioassay cone tests at baseline and after repeated washing. Furthermore, entomological assessments inside classrooms and in outside areas of schools were conducted.

    RESULTS: We enrolled 1,811 pupils aged 6-17 from 5 intervention and 5 control schools. Paired serum samples were obtained from 1,655 pupils. In the control schools, 24/641 (3.7%) and in the intervention schools 33/1,014 (3.3%) students had evidence of new dengue infections during one school term (5 months). There was no significant difference in proportions of students having incident dengue infections between the intervention and control schools, with adjustment for clustering by school. WHOPES cone tests showed a 100% knock down and mortality of Aedes aegypti mosquitoes exposed to impregnated clothing at baseline and up to 4 washes, but this efficacy rapidly declined to below 20% after 20 washes, corresponding to a weekly reduction in knock-down and mosquito mortality by 4.7% and 4.4% respectively. Results of the entomological assessments showed that the mean number of Aedes aegypti mosquitoes caught inside the classrooms of the intervention schools was significantly reduced in the month following the introduction of the impregnated uniforms, compared to those collected in classrooms of the control schools (p = 0.04).

    CONCLUSIONS: Entomological assessments showed that the intervention had some impact on the number of Aedes mosquitoes inside treatment schools immediately after impregnation and before insecticidal activity declined. However, there was no serological evidence of protection against dengue infections over the five months school term, best explained by the rapid washing-out of permethrin after 4 washes. If rapid washing-out of permethrin could be overcome by novel technological approaches, insecticide-treated clothes might become a potentially cost-effective and scalable intervention to protect against diseases transmitted by Aedes mosquitoes such as dengue, Zika, and chikungunya.

    TRIAL REGISTRATION: ClinicalTrials.gov NCT01563640.

  • 153. Klingspor, Lena
    et al.
    Ullberg, Mans
    Rydberg, Johan
    Kondori, Nahid
    Serrander, Lena
    Swanberg, Jonas
    Nilsson, Kenneth
    Jendle Bengten, Cecilia
    Johansson, Marcus
    Granlund, Margareta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Tornqvist, Eva
    Nyberg, Anders
    Kindlund, Karin
    Ygge, Minna
    Kartout-Boukdir, Dalila
    Toepfer, Michael
    Halldin, Eva
    Kahlmeter, Gunnar
    Ozenci, Volkan
    Epidemiology of fungaemia in Sweden: a nationwide retrospective observational survey2018In: Mycoses (Berlin), ISSN 0933-7407, E-ISSN 1439-0507, Vol. 61, no 10, p. 777-785Article in journal (Refereed)
    Abstract [en]

    Objectives:

    To identify the epidemiology and antifungal susceptibilities of Candida spp. among blood culture isolates to identify the epidemiology and antifungal susceptibilities of Candida spp. among blood culture isolates in Sweden.

    Methods: The study was a retrospective, observational nationwide laboratory-based surveillance for fungaemia and fungal meningitis and was conducted from September 2015 to August 2016.

    Results: In total, 488 Candida blood culture isolates were obtained from 471 patients (58% males). Compared to our previous study, the incidence of candidaemia has increased from 4.2/100000 (2005-2006) to 4.7/100000 population/year (2015-2016). The three most common Candida spp. isolated from blood cultures were Candida albicans (54.7%), Candida glabrata (19.7%) and species in the Candida parapsilosis complex (9.4%). Candida resistance to fluconazole was 2% in C.albicans and between 0% and 100%, in non-albicans species other than C.glabrata and C.krusei. Resistance to voriconazole was rare, except for C.glabrata, C.krusei and C.tropicalis. Resistance to anidulafungin was 3.8% while no Candida isolate was resistant to amphotericin B.

    Conclusions: We report an overall increase in candidaemia but a minor decrease of C.albicans while C.glabrata and C.parapsilosis remain constant over this 10-year period.

  • 154. Klingstrom, J.
    et al.
    Smed-Sörensen, A.
    Maleki, K. T.
    Sola-Riera, C.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Björkström, N. K.
    Ljunggren, H. G.
    Innate and adaptive immune responses against human Puumala virus infection: immunopathogenesis and suggestions for novel treatment strategies for severe hantavirus-associated syndromes2019In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 285, no 5, p. 510-523Article in journal (Refereed)
    Abstract [en]

    Two related hyperinflammatory syndromes are distinguished following infection of humans with hantaviruses: haemorrhagic fever with renal syndrome (HFRS) seen in Eurasia and hantavirus pulmonary syndrome (HPS) seen in the Americas. Fatality rates are high, up to 10% for HFRS and around 35%-40% for HPS. Puumala virus (PUUV) is the most common HFRS-causing hantavirus in Europe. Here, we describe recent insights into the generation of innate and adaptive cell-mediated immune responses following clinical infection with PUUV. First described are studies demonstrating a marked redistribution of peripheral blood mononuclear phagocytes (MNP) to the airways, a process that may underlie local immune activation at the site of primary infection. We then describe observations of an excessive natural killer (NK) cell activation and the persistence of highly elevated numbers of NK cells in peripheral blood following PUUV infection. A similar vigorous CD8 Tcell response is also described, though Tcell responses decline with viraemia. Like MNPs, many NK cells and CD8 T cells also localize to the lung upon acute PUUV infection. Following this, findings demonstrating the ability of hantaviruses, including PUUV, to cause apoptosis resistance in infected target cells, are described. These observations, and associated inflammatory cytokine responses, may provide new insights into HFRS and HPS disease pathogenesis. Based on similarities between inflammatory responses in severe hantavirus infections and other hyperinflammatory disease syndromes, we speculate whether some therapeutic interventions that have been successful in the latter conditions may also be applicable in severe hantavirus infections.

  • 155.
    Klingström, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Lindgren, Therese
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Sex-dependent differences in plasma cytokine responses to hantavirus infection2008In: Clinical and Vaccine Immunology, ISSN 1556-6811, E-ISSN 1556-679X, Vol. 15, no 5, p. 885-887Article in journal (Refereed)
    Abstract [en]

    There are often sex differences in susceptibility to infectious diseases and in level of mortality after infection. These differences probably stem from sex-related abilities to mount proper or unwanted immune responses against an infectious agent. We report that hantavirus-infected female patients show significantly higher plasma levels of interleukin-9 (IL-9), fibroblast growth factor 2, and granulocyte-macrophage colony-stimulating factor and lower levels of IL-8 and gamma interferon-induced protein 10 than male patients. The results demonstrate that a virus infection can induce sex-dependent differences in acute immune responses in humans. This finding may, at least partly, explain the observed sex differences in susceptibility to infectious diseases and in mortality following infection.

  • 156.
    Kuoppa, Yvonne
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Boman, Jens
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Scott, Lena
    Kumlin, Urban
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Eriksson, Iréne
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Allard, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Quantitative detection of respiratory Chlamydia pneumoniae infection by real-time PCR2002In: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 40, no 6, p. 2273-2274Article in journal (Refereed)
    Abstract [en]

    Real-time PCR was evaluated as a quantitative diagnostic method for Chlamydia pneumoniae infection using different respiratory samples. Real-time PCR had efficiency equal to or better than that of nested touchdown PCR. This study confirmed sputum as the best sampling material to detect an ongoing C. pneumoniae infection.

  • 157.
    Kurhade, Chaitanya
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Schreier, Sarah
    Lee, Yi-Ping
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. National Cheng Kung University, Tainan, Taiwan..
    Zegenhagen, Loreen
    Hjertqvist, Marika
    Dobler, Gerhard
    Kroeger, Andrea
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Correlation of Severity of Human Tick-Borne Encephalitis Virus Disease and Pathogenicity in Mice2018In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 24, no 9, p. 1709-1712Article in journal (Refereed)
    Abstract [en]

    We compared 2 tick-borne encephalitis virus strains isolated from 2 different foci that cause different symptoms in tick-borne encephalitis patients, from neurologic to mild gastrointestinal symptoms. We compared neuroinvasiveness, neurovirulence, and proinflammatory cytokine response in mice and found unique differences that contribute to our understanding of pathogenesis.

  • 158. Kusmierek, Maria
    et al.
    Hossmann, Joern
    Witte, Rebekka
    Opitz, Wiebke
    Vollmer, Ines
    Volk, Marcel
    Heroven, Ann Kathrin
    Wolf-Watz, Hans
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Dersch, Petra
    A bacterial secreted translocator hijacks riboregulators to control type III secretion in response to host cell contact2019In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 15, no 6, article id e1007813Article in journal (Refereed)
    Abstract [en]

    Numerous Gram-negative pathogens use a Type III Secretion System (T3SS) to promote virulence by injecting effector proteins into targeted host cells, which subvert host cell processes. Expression of T3SS and the effectors is triggered upon host cell contact, but the underlying mechanism is poorly understood. Here, we report a novel strategy of Yersinia pseudotuberculosis in which this pathogen uses a secreted T3SS translocator protein (YopD) to control global RNA regulators. Secretion of the YopD translocator upon host cell contact increases the ratio of post-transcriptional regulator CsrA to its antagonistic small RNAs CsrB and CsrC and reduces the degradosome components PNPase and RNase E levels. This substantially elevates the amount of the common transcriptional activator (LcrF) of T3SS/Yop effector genes and triggers the synthesis of associated virulence-relevant traits. The observed hijacking of global riboregulators allows the pathogen to coordinate virulence factor expression and also readjusts its physiological response upon host cell contact. Author summary Many bacterial pathogens sense contact to host cells and respond by inducing expression of crucial virulence factors. This includes the type III secretion systems (T3SSs) and their substrates, which manipulate different host cell functions to promote colonization and survival of the pathogen within its host. In this study, we used enteropathogenic Yersinia pseudotuberculosis to elucidate the molecular mechanism of how cell contact is transmitted and translated to trigger this process. We found that multiple global riboregulators control the decay and/or translation of the major transcriptional activator of the T3SS. In the absence of cell contact, these important RNA regulators are coopted by one of the substrate proteins of the T3SS to repress expression of the secretion machinery. Translocation of the substrate protein upon cell contact relieves riboregulator-mediated repression. This leads to a strong induction of the master regulator of T3SS/effector gene expression promoting an increase of the virulence potential and provokes a fast adaptation of the pathogen's fitness, e.g. to compensate for the imposed energetic burden.

  • 159. Kwiecinski, Jakub
    et al.
    Jacobsson, Gunnar
    Karlsson, Maria
    Zhu, Xuefeng
    Wang, Wanzhong
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Bremell, Tomas
    Josefsson, Elisabet
    Jin, Tao
    Staphylokinase Promotes the Establishment of Staphylococcus aureus Skin Infections While Decreasing Disease Severity2013In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 208, no 6, p. 990-999Article in journal (Refereed)
    Abstract [en]

    Skin infections are frequently caused by Staphylococcus aureus and can lead to a fatal sepsis. The microbial mechanisms controlling the initiation and progression from mild skin infection to a severe disseminated infection remain poorly understood. Using a combination of clinical data and in vitro and ex vivo assays, we show that staphylokinase, secreted by S. aureus, promoted the establishment of skin infections in humans and increased bacterial penetration through skin barriers by activating plasminogen. However, when infection was established, the interaction between staphylokinase and plasminogen did not promote systemic dissemination but induced the opening and draining of abscesses and decreased disease severity in neutropenic mice. Also, increased staphylokinase production was associated with noninvasive S. aureus infections in patients. Our results point out the dual roles of staphylokinase in S. aureus skin infections as promoting the establishment of infections while decreasing disease severity.

  • 160.
    Larsson, Christer
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Andersson, Marie
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Current issues in relapsing fever2009In: Current Opinion in Infectious Diseases, ISSN 0951-7375, E-ISSN 1473-6527, Vol. 22, no 5, p. 443-449Article, review/survey (Refereed)
    Abstract [en]

    PURPOSE OF REVIEW: Relapsing fever has the highest incidence of any bacterial disease in Africa and a massive epidemic potential due to current political turmoil in the Horn of Africa. This review focuses on recent advances in diagnostics, molecular biology and host-pathogen interactions. RECENT FINDINGS: Complete relapsing fever genomes have recently been published, and the first site-specific genetic knockout complementation has been performed. Relapsing fever has gone from being a neglected disease to garnering interest in aspects such as tissue invasion, membrane biochemistry and complement evasion. Relapsing fever symptoms are variable, and the disease is commonly misdiagnosed as, for example, malaria. Although relapsing fever is considered a transient disease, it persists as a residual infection in the brain, which can be reactivated on immunosuppression. Therefore, single-dose antibiotic treatment should be avoided. Instead, treatment should cover a longer period, similar to the recommended regime for Lyme disease. Relapsing fever is a common cause of pregnancy complications such as intrauterine growth retardation and placental damage with spirochaetes crossing the maternal-foetal barrier, resulting in congenital infection. SUMMARY: Although relapsing fever remains a big problem, recently described host-pathogen interactions, diagnostics and molecular biology advances such as completed genome sequences and the dawn of genetic tools have brought relapsing fever research into the 21st century.

  • 161.
    Larsson, Christer
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Andersson, Marie
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Guo, Betty P
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Nordstrand, Annika
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hägerstrand, Inga
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Carlsson, Sara
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Complications of pregnancy and transplacental transmission of relapsing-fever borreliosis2006In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 194, no 10, p. 1367-1374Article in journal (Refereed)
    Abstract [en]

    Relapsing-fever borreliosis caused by Borrelia duttonii is a common cause of complications of pregnancy, miscarriage, and neonatal death in sub-Saharan Africa. We established a murine model of gestational relapsing fever infection for the study of the pathological development of these complications. We demonstrate that B. duttonii infection during pregnancy results in intrauterine growth retardation, as well as placental damage and inflammation, impaired fetal circulation, and decreased maternal hemoglobin levels. We show that spirochetes frequently cross the maternal-fetal barrier, resulting in congenital infection. Furthermore, we compared the severity of infection in pregnant and nonpregnant mice and show that pregnancy has a protective effect. This model closely parallels the consequences of human gestational infection, and our results provide insight into the mechanisms behind the complications of pregnancy that have been reported in human relapsing-fever infection.

  • 162.
    Larsson, Christer
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Andersson, Marie
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Pelkonen, Jenni
    Guo, Betty
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Nordstrand, Annika
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Persistent brain infection and disease reactivation in relapsing fever borreliosis2006In: Microbes and infection, ISSN 1286-4579, E-ISSN 1769-714X, Vol. 8, no 8, p. 2213-2219Article in journal (Refereed)
    Abstract [en]

    Relapsing fever, an infection caused by Borrelia spirochetes, is generally considered a transient, self-limiting disease in humans. The present study reveals that murine infection by Borrelia duttonii can be reactivated after an extended time as a silent infection in the brain, with no bacteria appearing in the blood and spirochete load comparable to the numbers in an infected tick. The host cerebral gene expression pattern is indistinguishable from that of uninfected animals, indicating that persistent bacteria are not recognized by the immune system nor cause noticeable tissue damage. Silent infection can be reactivated by immunosuppression, inducing spirochetemia comparable to that of initial densities. B. duttonii has never been found in any host except man and the tick vector. We therefore propose the brain to be a possible natural reservoir of the spirochete. The view of relapsing fever as an acute disease should be extended to include in some cases prolonged persistence, a feature characteristic of the related spirochetal infections Lyme disease and syphilis.

  • 163.
    Larsson, Christer
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    A novel and simple method for laboratory diagnosis of relapsing Fever borreliosis.2008In: Open Microbiology Journal, ISSN 1874-2858, E-ISSN 1874-2858, Vol. 2, p. 10-2Article in journal (Refereed)
    Abstract [en]

    Relapsing fever caused by Borrelia bacteria is often obscured by malaria and incorrectly treated. Here a novel method for diagnosis is presented. The method is cheap, simple and requires minimal laboratory material. Despite its simplicity, the method shows surprisingly high sensitivity, detecting concentrations less than 10 bacteria/ml blood.

  • 164.
    Larsson, Christer
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Comstedt, Pär
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Olsen, Björn
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    First record of Lyme disease Borrelia in the Arctic2007In: Vector Borne and Zoonotic Diseases, ISSN 1530-3667, E-ISSN 1557-7759, Vol. 7, no 3, p. 453-456Article in journal (Refereed)
    Abstract [en]

    The epidemiology and ecology of Lyme disease is very complex, and its reported geographical distribution is constantly increasing. Furthermore, the involvement of birds in long distance dispersal and their role as reservoir hosts is now well established. In this study, we have shown that sea birds in the Arctic region of Norway carry Ixodes uriae ticks infected with Lyme disease Borrelia garinii spirochetes. Interestingly, DNA sequencing showed that these isolates are closely related to B. garinii previously isolated from birds, as well as from clinical specimens in northern Europe.

  • 165.
    Larsson, Christer
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Lundqvist, Jenny
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Residual brain infection in murine relapsing fever borreliosis can be successfully treated with ceftriaxone2008In: Microbial Pathogenesis, ISSN 0882-4010, E-ISSN 1096-1208, Vol. 44, no 3, p. 262-264Article in journal (Refereed)
    Abstract [en]

    Like several other spirochetes, relapsing fever Borrelia can cause persistent infection of the central nervous system (CNS). By treating mice harboring residual Borrelia duttonii brain infection with the bacteriocidal, cell wall inhibiting antibiotic ceftriaxone, bacteria were cleared from the brain. This shows that the residual infection is not latent but actively growing.

  • 166.
    Larsson, Christer
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Lundqvist, Jenny
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    van Rooijen, Nico
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    A novel animal model of Borrelia recurrentis louse-borne relapsing fever borreliosis using immunodeficient mice2009In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 3, no 9, p. e522-Article in journal (Refereed)
    Abstract [en]

    Louse-borne relapsing fever (LBRF) borreliosis is caused by Borrelia recurrentis, and it is a deadly although treatable disease that is endemic in the Horn of Africa but has epidemic potential. Research on LBRF has been severely hampered because successful infection with B. recurrentis has been achieved only in primates (i.e., not in other laboratory or domestic animals). Here, we present the first non-primate animal model of LBRF, using SCID (-B, -T cells) and SCID BEIGE (-B, -T, -NK cells) immunocompromised mice. These animals were infected with B. recurrentis A11 or A17, or with B. duttonii 1120K3 as controls. B. recurrentis caused a relatively mild but persistent infection in SCID and SCID BEIGE mice, but did not proliferate in NUDE (-T) and BALB/c (wild-type) mice. B. duttonii was infectious but not lethal in all animals. These findings demonstrate that the immune response can limit relapsing fever even in the absence of humoral defense mechanisms. To study the significance of phagocytic cells in this context, we induced systemic depletion of such cells in the experimental mice by injecting them with clodronate liposomes, which resulted in uncontrolled B. duttonii growth and a one-hundred-fold increase in B. recurrentis titers in blood. This observation highlights the role of macrophages and other phagocytes in controlling relapsing fever infection. B. recurrentis evolved from B. duttonii to become a primate-specific pathogen that has lost the ability to infect immunocompetent rodents, probably through genetic degeneration. Here, we describe a novel animal model of B. recurrentis based on B- and T-cell-deficient mice, which we believe will be very valuable in future research on LBRF. Our study also reveals the importance of B-cells and phagocytes in controlling relapsing fever infection.

  • 167. Larsson, D. G. Joakim
    et al.
    Andremont, Antoine
    Bengtsson-Palme, Johan
    Brandt, Kristian Koefoed
    Husman, Ana Maria de Roda
    Fagerstedt, Patriq
    Fick, Jerker
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Flach, Carl-Fredrik
    Gaze, William H.
    Kuroda, Makoto
    Kvint, Kristian
    Laxminarayan, Ramanan
    Manaia, Celia M.
    Nielsen, Kaare Magne
    Plant, Laura
    Ploy, Marie-Cécile
    Segovia, Carlos
    Simonet, Pascal
    Smalla, Kornelia
    Snape, Jason
    Topp, Edward
    van Hengel, Arjon J.
    Verner-Jeffreys, David W.
    Virta, Marko P. J.
    Wellington, Elizabeth M.
    Wernersson, Ann-Sofie
    Critical knowledge gaps and research needs related to the environmental dimensions of antibiotic resistance2018In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 117, p. 132-138Article, review/survey (Refereed)
    Abstract [en]

    There is growing understanding that the environment plays an important role both in the transmission of antibiotic resistant pathogens and in their evolution. Accordingly, researchers and stakeholders world-wide seek to further explore the mechanisms and drivers involved, quantify risks and identify suitable interventions. There is a clear value in establishing research needs and coordinating efforts within and across nations in order to best tackle this global challenge. At an international workshop in late September 2017, scientists from 14 countries with expertise on the environmental dimensions of antibiotic resistance gathered to define critical knowledge gaps. Four key areas were identified where research is urgently needed: 1) the relative contributions of different sources of antibiotics and antibiotic resistant bacteria into the environment; 2) the role of the environment, and particularly anthropogenic inputs, in the evolution of resistance; 3) the overall human and animal health impacts caused by exposure to environmental resistant bacteria; and 4) the efficacy and feasibility of different technological, social, economic and behavioral interventions to mitigate environmental antibiotic resistance.

  • 168. Leonhard, Sonja Emily
    et al.
    Lant, Suzannah
    Jacobs, Bart C.
    Wilder-Smith, Annelies
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Ferreira, Maria Lucia Brito
    Solomon, Tom
    Willison, Hugh John
    Zika virus infection in the returning traveller: what every neurologist should know2018In: Practical Neurology, ISSN 1474-7758, E-ISSN 1474-7766, Vol. 18, no 4, p. 271-277Article in journal (Refereed)
    Abstract [en]

    Zika virus has been associated with a wide range of neurological complications. Neurologists in areas without current active transmission of the virus may be confronted with Zika-associated neurological disease, as a large number of returning travellers with Zika virus infection have been reported and the virus continues to spread to previously unaffected regions. This review provides an overview of Zika virus-associated neurological disease and aims to support neurologists who may encounter patients returning from endemic areas.

  • 169.
    Lilja, Mikael
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Widerström, Micael
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Lindh, Johan
    Persisting post-infection symptoms 2 years after a large waterborne outbreak of Cryptosporidium hominis in northern Sweden2018In: BMC Research Notes, ISSN 1756-0500, E-ISSN 1756-0500, Vol. 11, no 1, article id 625Article in journal (Refereed)
    Abstract [en]

    Objectives: In 2010–2011, a large waterborne outbreak of Cryptosporidium hominis affected the city of Östersund in Sweden. Previous findings had suggested that gastrointestinal symptoms can persist for up to 11 months after the initial infection. Here we investigated whether the parasite could cause sequelae in infected individuals up to 28 months after the outbreak. We compared cases linked to the outbreak and the previous follow-up study with non-cases regarding symptoms present up to 28 months after the initial infection. We investigated whether cases were more likely to report a list of symptoms at follow-up compared to non-cases, calculating odds ratio and 95% confidence interval obtained through logistic regression.

    Results: A total of 559 individuals (215 cases) were included in the study. Forty-eight percent of the outbreak cases reported symptoms at follow-up. Compared to non-cases, cases were more likely to report watery diarrhea, diarrhea, abdominal pain, fatigue, nausea, headache, or joint stiffness/pain/discomfort at follow-up after adjusting for age and sex. Our findings suggest that gastrointestinal symptoms and joint pain can persist several years after the initial Cryptosporidium infection and should be regarded as a potential cause of unexplained gastrointestinal symptoms or joint pain in people who have had this infection.

  • 170.
    Lindgren, Helena
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Honn, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Golovlev, Igor
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Kadzhaev, Konstantin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Conlan, Wayne
    NRC Canada.
    Sjöstedt, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    The 58-kilodalton major virulence factor of Francisella tularensis is required for efficient utilization of iron2009In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 77, no 10, p. 4429-4436Article in journal (Refereed)
    Abstract [en]

    We investigated the role of the 58-kDa FTT0918 protein in the iron metabolism of Francisella tularensis. The phenotypes of SCHU S4, a prototypic strain of F. tularensis subsp. tularensis, and the Delta FTT0918 and Delta fslA isogenic mutants were analyzed. The gene product missing in the Delta fslA mutant is responsible for synthesis of a siderophore. When grown in broth with various iron concentrations, the two deletion mutants generally reached lower maximal densities than SCHU S4. The Delta FTT0918 mutant, but not the Delta fslA mutant, upregulated the genes of the F. tularensis siderophore locus (fsl) operon even at high iron concentrations. A chrome azurol sulfonate plate assay confirmed siderophore production by all strains except the Delta fslA strain. In a cross-feeding experiment using medium devoid of free iron, SCHU S4 promoted growth of the Delta fslA strain but not of the Delta FTT0918 strain. The sensitivity of SCHU S4 and the Delta FTT0918 and Delta fslA strains to streptonigrin demonstrated that the Delta FTT0918 strain contained a smaller free intracellular iron pool and that the Delta fslA strain contained a larger one than SCHU S4. In contrast to the marked attenuation of the Delta FTT0918 strain, the Delta fslA strain was as virulent as SCHU S4 in a mouse model. Altogether, the data demonstrate that the FTT0918 protein is required for F. tularensis to utilize iron bound to siderophores and that it likely has a role also in siderophore-independent iron acquisition. We suggest that the FTT0918 protein be designated Fe utilization protein A, FupA.

  • 171. Lindgren, Lena
    et al.
    Lindkvist, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Överby, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Bucht, Göran
    Holmström, Anna
    Swedish Defence Research Agency, Division of CBRN Defence and Security, SE-901 82 Umeå, Sweden.
    Regions of importance for interaction of puumala virus nucleocapsid subunits2006In: Virus genes, ISSN 0920-8569, E-ISSN 1572-994X, Vol. 33, no 2, p. 169-174Article in journal (Refereed)
    Abstract [en]

    Puumala virus (PUUV) is a hantavirus that causes a mild form of hemorrhagic fever with renal syndrome in northern and central Europe, and in large parts of Russia. The nucleocapsid (N) protein encoded by hantaviruses plays an important role in the life-cycle of these viruses, and one important function for the N-protein is to oligomerize, surround and protect the viral RNAs. We have identified amino- and carboxy-terminal regions involved in PUUV N-N interactions, which comprise amino acids 100-120 and 330-405. Our findings strengthen the hypothesis that the amino-terminus of the N-protein of hantaviruses holds a more regulatory function regarding N-N interactions, while conserved residues in the carboxy-terminal region, F335 together with F336 and W392, in concert with Y388 and/or F400 seems to play a more critical role in the PUUV N-N formation. This study provides evidence that the amino-terminal regions involved in the N-N interaction of Puumala virus are similar to those reported for Seoul virus (SEOV) and to some extent Hantaan virus (HTNV), even though the identity between PUUV N and SEOV/HTNV N is markedly lower than between PUUV N and Tula virus (TULV) N or Sin Nombre virus (SNV) N.

  • 172.
    Lindkvist, Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Lahti, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Lilliehöök, Bo
    Holmström, Anna
    Swedish Defence Research Agency, Division of CBRN Defence and Security, SE-901 82 Umeå, Sweden.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Bucht, Göran
    Cross-reactive immune responses in mice after genetic vaccination with cDNA encoding hantavirus nucleocapsid proteins.2007In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 25, no 9, p. 1690-1699Article in journal (Refereed)
    Abstract [en]

    Hantaviruses cause hemorrhagic fever with renal syndrome (HFRS) in about 150,000 individuals in Eurasia, and several hundred cases of hantavirus pulmonary syndrome (HPS) on the American continent annually. There is consequently a need for rapid diagnostics and effective prevention of hantaviral infections. In this study we have performed DNA-vaccination of mice with full-length genes encoding the immunogenic nucleocapsid protein (NP) of Puumala (PUUV), Seoul (SEOV) and Sin Nombre virus (SNV). The antibody reactivity towards the NPs, and deleted or truncated variants thereof, were studied to localise and investigate the major polyclonal B-cell epitopes. Our findings clearly show that the antibody reactivity in each immunised mouse is unique, not only in a quantitative respect (titers) but also in cross-reactivity and most likely also in the epitope specificity. Our experimental data in combination with B-cell prediction software indicate that strong homologous virus species specific and cross-reactive epitopes are located around amino acid residue 40 in the nucleocapsid proteins.

  • 173. Lippman, Sheri A.
    et al.
    Pettifor, Audrey Pettifor
    Neilands, Torsten B.
    MacPhail, Catherine
    Peacock, Dean
    Maman, Suzanne
    Twine, Rhian
    Selin, Amanda
    Kahn, Kathleen
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Communities can mobilize to test: findings from a community randomized trial of a theory-based community mobilization intervention in South Africa2015In: Journal of the International AIDS Society, ISSN 1758-2652, E-ISSN 1758-2652, Vol. 18Article in journal (Other academic)
  • 174. Louis, Valérie R
    et al.
    Montenegro Quiñonez, Carlos Alberto
    Kusumawathie, Pad
    Palihawadana, Paba
    Janaki, Sakoo
    Tozan, Yesim
    Wijemuni, Ruwan
    Wilder-Smith, Annelies
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. nstitute of Public Health, Heidelberg University, Heidelberg, Germany; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
    Tissera, Hasitha A
    Characteristics of and factors associated with dengue vector breeding sites in the City of Colombo, Sri Lanka.2016In: Pathogens and Global Health, ISSN 2047-7724, E-ISSN 2047-7732, Vol. 110, no 2, p. 79-86Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Dengue has emerged as a major public health problem in Sri Lanka. Vector control at community level is a frequent and widespread strategy for dengue control. The aim of the study was to assess Aedes mosquito breeding sites and the prevention practices of community members in a heavily urbanized part of Colombo.

    METHODS: A cross-sectional entomological survey was conducted from April to June 2013 in 1469 premises located in a subdistrict of the City of Colombo. Types of breeding sites and, where found, their infestation with larvae or pupae were recorded. Furthermore, a questionnaire was administered to the occupants of these premises to record current practices of dengue vector control.

    RESULTS: The surveyed premises consisted of 1341 residential premises and 110 non-residential premises (11 schools, 99 work or public sites), 5 open lands, and 13 non-specified. In these 1469 premises, 15447 potential breeding sites suitable to host larvae of pupae were found; of these sites18.0% contained water. Among the 2775 potential breeding sites that contained water, 452 (16.3%) were positive for larvae and/or pupae. Schools were associated with the proportionally highest number of breeding sites; 85 out of 133 (63.9%) breeding sites were positive for larvae and/or pupae in schools compared with 338 out of 2288 (14.8%) in residential premises. The odds ratio (OR) for schools and work or public sites for being infested with larvae and/or pupae was 2.77 (95% CI 1.58, 4.86), when compared to residential premises. Occupants of 80.8% of the residential premises, 54.5% of the schools and 67.7% of the work or public sites reported using preventive measures. The main prevention practices were coverage of containers and elimination of mosquito breeding places. Occupants of residential premises were much more likely to practice preventive measures than were those of non-residential premises (OR 2.23; 1.49, 3.36).

    CONCLUSION: Schools and working sites were associated with the highest numbers of breeding sites and lacked preventive measures for vector control. In addition to pursuing vector control measures at residential level, public health strategies should be expanded in schools and work places.

  • 175.
    Lundqvist, Jenny
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Larsson, Christer
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Nelson, Maria
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Andersson, Marie
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Persson, Cathrine
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Concomitant Infection Decreases the Malaria Burden but Escalates Relapsing Fever Borreliosis2010In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 78, no 5, p. 1924-1930Article in journal (Refereed)
    Abstract [en]

    About 500 million cases of malaria occur annually. However, a substantial number of patients who actually have relapsing fever (RF) Borrelia can be misdiagnosed with malaria due to similar manifestations and geographic distribution of the two diseases. More alarmingly, high prevalence of concomitant infections with malaria and RF Borrelia has been reported. Therefore, we used a mouse model to study the effects of such mixed infection. We observed a 21-fold increase in spirochete titers, whereas the numbers of parasitized erythrocytes were reduced 15-fold. This may be explained by polarization of the host immune response towards the intracellular malaria parasite, resulting in unaffected extracellular spirochetes and hosts that succumb to sepsis. Mixed infection also resulted in severe malaria anemia with low hemoglobin levels, even though the parasite counts were low. Overall, co-infected animals had higher fatality rate and shorter time to death than both malaria and RF single infection. Furthermore, secondary malaria infection reactivated a quiescent RF brain infection, which is the first evidence of a clinically and biologically relevant cue for reactivation of RF Borrelia infection. Our study highlights the importance of investigating concomitant infections in vivo to elucidate the immune responses that are involved in the clinical outcome.

  • 176. Lundström, Jan O
    et al.
    Schäfer, Martina L
    Hesson, Jenny C
    Blomgren, Eric
    Lindström, Anders
    Wahlqvist, Pernilla
    Halling, Arne
    Hagelin, Anna
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Broman, Tina
    CBNR Defense and Security, Swedish Defense Research Agency, SE-90185 Umeå, Sweden.
    Forsman, Mats
    CBNR Defense and Security, Swedish Defense Research Agency, SE-90185 Umeå, Sweden.
    Persson Vinnersten, Thomas Z
    The geographic distribution of mosquito species in Sweden2013In: Journal of the European Mosquito Control Association, Vol. 31, p. 21-35Article in journal (Refereed)
    Abstract [en]

    Surveillance of the actual distribution of mosquito species in Northern Europe is fundamental for evaluating risk for emerging pathogens, and for research on potential vectors. The Swedish mosquito fauna composition and geographic distribution, originally described by Professor Christine Dahl in the 1970´s, included 43 species. We have compiled the information published from 1978 to 2012, and our own surveillance data from 2001 to 2013, and compared this with the species list and geographic distribution provided in "Taxonomy and geographic distribution of Swedish Culicidae" by Dahl (1977). New species detected during these 36 years were Culiseta (Culicella) ochroptera (Peus, 1935) published 1984, Aedes (Aedes) rossicus Dolbeskin, Goritzkaja & Mitrofanova, 1930 published 1986, Anopheles (Anopheles) beklemishevi published 1986, Aedes (Ochlerotatus) euedes (Howard, Dyar & Knab, 1912) published 2001, Aedes (Ochlerotatus) nigrinus (Eckstein, 1918) first recorded in 2012, and Anopheles (Anopheles) algeriensis Theobald, 1903, first recorded in 2013. We provide maps with the distribution by province for each species, including historic information up until 1977, and new records from 1978 to 2013, showing the similarities and differences between the old and the new records. Important findings in recent years include the wide distribution of the Sindbis virus enzootic vector Culex (Culex) torrentium Martinii, 1925, and the more limited distribution of the potential West Nile virus vector Culex (Culex) pipiens Linnaeus, 1758. The updated list of mosquito species in Sweden now includes 49 species.

  • 177.
    Lwande, Olivia Wesula
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Obanda, Vincent
    Bucht, Göran
    Mosomtai, Gladys
    Otieno, Viola
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Global emergence of Alphaviruses that cause arthritis in humans2015In: Infection Ecology & Epidemiology, ISSN 2000-8686, E-ISSN 2000-8686, Vol. 5, article id 29853Article in journal (Refereed)
    Abstract [en]

    Arthropod-borne viruses (arboviruses) may cause severe emerging and re-emerging infectious diseases, which pose a significant threat to human and animal health in the world today. These infectious diseases range from mild febrile illnesses, arthritis, and encephalitis to haemorrhagic fevers. It is postulated that certain environmental factors, vector competence, and host susceptibility have a major impact on the ecology of arboviral diseases. Presently, there is a great interest in the emergence of Alphaviruses because these viruses, including Chikungunya virus, O'nyong'nyong virus, Sindbis virus, Ross River virus, and Mayaro virus, have caused outbreaks in Africa, Asia, Australia, Europe, and America. Some of these viruses are more common in the tropics, whereas others are also found in temperate regions, but the actual factors driving Alphavirus emergence and re-emergence remain unresolved. Furthermore, little is known about the transmission dynamics, pathophysiology, genetic diversity, and evolution of circulating viral strains. In addition, the clinical presentation of Alphaviruses may be similar to other diseases such as dengue, malaria, and typhoid, hence leading to misdiagnosis. However, the typical presence of arthritis may distinguish between Alphaviruses and other differential diagnoses. The absence of validated diagnostic kits for Alphaviruses makes even routine surveillance less feasible. For that purpose, this review describes the occurrence, genetic diversity, clinical characteristics, and the mechanisms involving Alphaviruses causing arthritis in humans. This information may serve as a basis for better awareness and detection of Alphavirus-caused diseases during outbreaks and in establishing appropriate prevention and control measures.

  • 178.
    Lwande, Olivia Wesula
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Consortium for Epidemiology and Ecology (CEER-Africa), Minnesota, USA.
    Paul, George Omondi
    Chiyo, Patrick I.
    Ng'ang'a, Eliud
    Otieno, Viola
    Obanda, Vincent
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Spatio-temporal variation in prevalence of Rift Valley fever: a post-epidemic serum survey in cattle and wildlife in Kenya2015In: Infection Ecology & Epidemiology, ISSN 2000-8686, E-ISSN 2000-8686, Vol. 5, article id 30106Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Rift Valley fever (RVF) is a fatal arthropod-borne zoonotic disease of livestock and humans. Since the identification of RVF in Kenya in the 1930s, repeated epizootics and epidemics coinciding with El Niño events have occurred in several locations in Africa and Saudi Arabia, causing mass deaths of livestock and humans. RVF is of great interest worldwide because of its negative effect on international livestock trade and its potential to spread globally. The latter is due to the increasing incidence of extreme climatic phenomena caused by global warming, as well as to the increase in global trade and international travel. How RVF is maintained and sustained between epidemics and epizootics is not clearly understood, but it has been speculated that wildlife reservoirs and trans-ovarian transmission in the vector may be important. Several studies have examined the role of wildlife and livestock in isolation or in a limited geographical location within the one country over a short time (usually less than a year). In this study, we examined the seroprevalence of anti-RVF antibodies in cattle and several wildlife species from several locations in Kenya over an inter-epidemic period spanning up to 7 years.

    METHODS: A serological survey of immunoglobulin G (IgG) antibodies to RVF using competitive ELISA was undertaken on 297 serum samples from different wildlife species at various locations in Kenya. The samples were collected between 2008 and 2015. Serum was also collected in 2014 from 177 cattle from Ol Pejeta Conservancy; 113 of the cattle were in close contact with wildlife and the other 64 were kept separate from buffalo and large game by an electric fence.

    RESULTS: The seroprevalence of RVF virus (RVFV) antibody was 11.6% in wildlife species during the study period. Cattle that could come in contact with wildlife and large game were all negative for RVFV. The seroprevalence was relatively high in elephants, rhinoceros, and buffalo, but there were no antibodies in zebras, baboons, vervet monkeys, or wildebeest.

    CONCLUSIONS: Diverse species in conservation areas are exposed to RVFV. RVFV exposure in buffalo may indicate distribution of the virus over wide geographical areas beyond known RVFV foci in Kenya. This finding calls for thorough studies on the epizootology of RVFV in specific wildlife species and locations.

  • 179. Massad, Eduardo
    et al.
    Bezerra Coutinhol, Francisco Antonio
    Wilder-Smith, Annelies
    Umeå University, Faculty of Medicine, Department of Epidemiology and Global Health. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Modelling an optimum vaccination strategy against ZIKA virus for outbreak use2019In: Epidemiology and Infection, ISSN 0950-2688, E-ISSN 1469-4409, Vol. 147, article id UNSP e196Article in journal (Refereed)
    Abstract [en]

    We present a model to optimise a vaccination campaign aiming to prevent or to curb a Zika virus outbreak. We show that the optimum vaccination strategy to reduce the number of cases by a mass vaccination campaign should start when the Aedes mosquitoes' density reaches the threshold of 1.5 mosquitoes per humans, the moment the reproduction number crosses one. The maximum time it is advisable to wait for the introduction of a vaccination campaign is when the first ZIKV case is identified, although this would not be as effective to minimise the number of infections as when the mosquitoes' density crosses the critical threshold. This suboptimum strategy, however, would still curb the outbreak. In both cases, the catch up strategy should aim to vaccinate at least 25% of the target population during a concentrated effort of 1 month immediately after identifying the threshold. This is the time taken to accumulate the herd immunity threshold of 56.5%. These calculations were done based on theoretical assumptions that vaccine implementation would be feasible within a very short time frame.

  • 180. Massad, Eduardo
    et al.
    Tan, Ser-Han
    Khan, Kamran
    Wilder-Smith, Annelies
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Institute of Public Health, University of Heidelberg, Germany ; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
    Estimated Zika virus importations to Europe by travellers from Brazil2016In: Global Health Action, ISSN 1654-9716, E-ISSN 1654-9880, Vol. 9, p. 1-7, article id 31669Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Given the interconnectivity of Brazil with the rest of the world, Zika virus (ZIKV) infections have the potential to spread rapidly around the world via viremic travellers. The extent of spread depends on the travel volume and the endemicity in the exporting country. In the absence of reliable surveillance data, we did mathematical modelling to estimate the number of importations of ZIKV from Brazil into Europe.

    DESIGN: We applied a previously developed mathematical model on importations of dengue to estimate the number of ZIKV importations into Europe, based on the travel volume, the probability of being infected at the time of travel, the population size of Brazil, and the estimated incidence of ZIKV infections.

    RESULTS: Our model estimated between 508 and 1,778 imported infections into Europe in 2016, of which we would expect between 116 and 355 symptomatic Zika infections; with the highest number of importations being into France, Portugal and Italy.

    CONCLUSIONS: Our model identified high-risk countries in Europe. Such data can assist policymakers and public health professionals in estimating the extent of importations in order to prepare for the scale up of laboratory diagnostic assays and estimate the occurrence of Guillain-Barré Syndrome, potential sexual transmission, and infants with congenital ZIKV syndrome.

  • 181.
    Massai, Francesco
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Saleeb, Michael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Doruk, Tugrul
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Forsberg, Åke
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Development, Optimization, and Validation of a High Throughput Screening Assay for Identification of Tat and Type II Secretion Inhibitors of Pseudomonas aeruginosa2019In: Frontiers in Cellular and Infection Microbiology, E-ISSN 2235-2988, Vol. 9, article id 250Article in journal (Refereed)
    Abstract [en]

    Antibiotics are becoming less effective in treatment of infections caused by multidrug-resistant Pseudomonas aeruginosa. Antimicrobial therapies based on the inhibition of specific virulence-related traits, as opposed to growth inhibitors, constitute an innovative and appealing approach to tackle the threat of P. aeruginosa infections. The twin-arginine translocation (Tat) pathway plays an important role in the pathogenesis of P. aeruginosa, and constitutes a promising target for the development of anti-pseudomonal drugs. In this study we developed and optimized a whole-cell, one-well assay, based on native phospholipase C activity, to identify compounds active against the Tat system. Statistical robustness, sensitivity and consequently suitability for high-throughput screening (HTS) were confirmed by a dry run/pre-screening test scoring a Z' of 0.82 and a signal-to-noise ratio of 49. Using this assay, we evaluated ca. 40,000 molecules and identified 59 initial hits as possible Tat inhibitors. Since phospholipase C is exported into the periplasm by Tat, and subsequently translocated across the outer membrane by the type II secretion system (T2SS), our assay could also identify T2SS inhibitors. To validate our hits and discriminate between compounds that inhibited either Tat or T2SS, two separate counter assays were developed and optimized. Finally, three Tat inhibitors and one T2SS inhibitor were confirmed by means of dose-response analysis and additional counter and confirming assays. Although none of the identified inhibitors was suitable as a lead compound for drug development, this study validates our assay as a simple, efficient, and HTS compatible method for the identification of Tat and T2SS inhibitors.

  • 182. Matiko, Mirende Kichuki
    et al.
    Salekwa, Linda Peniel
    Kasanga, Christopher Jacob
    Kimera, Sharadhuli Idd
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Nyangi, Wambura Philemon
    Serological evidence of inter-epizootic/interepidemic circulation of Rift Valley fever virus in domestic cattle in Kyela and Morogoro, Tanzania2018In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 12, no 11, article id e0006931Article in journal (Refereed)
    Abstract [en]

    Background: Tanzania is among the Rift Valley fever (RVF) epizootic/endemic countries in sub Saharan Africa, where RVF disease outbreaks occur within a range of 3 to 17-year intervals. Detection of Rift Valley fever virus (RVFV) antibodies in animals in regions with no previous history of outbreaks raises the question of whether the disease is overlooked due to lack-of effective surveillance systems, or if there are strains of RVFV with low pathogenicity. Furthermore, which vertebrate hosts are involved in the inter-epidemic and inter-epizootic maintenance of RVFV? In our study region, the Kyela and Morogoro districts in Tanzania, no previous RVF outbreaks have been reported.

    Methodology: The study was conducted from June 2014 to October 2015 in the Kyela and Morogoro districts, Tanzania. Samples (n = 356) were retrieved from both the local breed of zebu cattle (Bos indicus) and Bos indicus/Bos Taurus cross breed. RVFV antibodies were analyzed by two enzyme-linked immunosorbent assay (ELISA) approaches. Initially, samples were analyzed by a RVFV multi-species competition ELISA (cELISA), which detected both RVFV IgG and IgM antibodies. All serum samples that were positive with the cELISA method were specifically analysed for the presence of RVFV IgM antibodies to trace recent infection. A plaque reduction neutralization assay (PRNT80) was performed to determine presence of RVFV neutralizing antibodies in all cELISA positive samples.

    Findings: Overall RVFV seroprevalence rate in cattle by cELISA in both districts was 29.2% (104 of 356) with seroprevalence rates of 33% (47/147) in the Kyela district and 27% (57/209) in the Morogoro district. In total, 8.4% (30/356) of all cattle sampled had RVFV IgM antibodies, indicating current disease transmission. When segregated by districts, the IgM antibody seroprevalence was 2.0% (3/147) and 12.9% (27/209) in Kyela and Morogoro districts respectively. When the 104 cELISA positive samples were analyzed by PRNT80 to confirm that RVFV-specific antibodies were present, the majority (89%, 93/104) had RVFV neutralising antibodies.

    Conclusion: The results provided evidence of widespread prevalence of RVFV antibody among cattle during an inter-epizootic/inter-epidemic period in Tanzania in regions with no previous history of outbreaks. There is a need for further investigations of RVFV maintenance and transmission in vertebrates and vectors during the long inter-epizootic/inter-epidemic periods.

  • 183. McCormack, Ryan
    et al.
    Bahnan, Wael
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Univ Miami, Miller Sch Med, Dept Microbiol & Immunol, Miami, FL, USA.
    Shrestha, Niraj
    Boucher, Justin
    Barreto, Marcella
    Barrera, Carlos M.
    Dauer, Edward A.
    Freitag, Nancy E.
    Khan, Wasif N.
    Podack, Eckhard R.
    Schesser, Kurt
    Perforin-2 Protects Host Cells and Mice by Restricting the Vacuole to Cytosol Transitioning of a Bacterial Pathogen2016In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 84, no 4, p. 1083-1091Article in journal (Refereed)
    Abstract [en]

    The host-encoded Perforin-2 (encoded by the macrophage-expressed gene 1, Mpeg1), which possesses a pore-forming MACPF domain, reduces the viability of bacterial pathogens that reside within membrane-bound compartments. Here, it is shown that Perforin-2 also restricts the proliferation of the intracytosolic pathogen Listeria monocytogenes. Within a few hours of systemic infection, the massive proliferation of L. monocytogenes in Perforin-2(-/-) mice leads to a rapid appearance of acute disease symptoms. We go on to show in cultured Perforin-2(-/-) cells that the vacuole-to-cytosol transitioning of L. monocytogenes is greatly accelerated. Unexpectedly, we found that in Perforin-2(-/-) macrophages, Listeria-containing vacuoles quickly (<= 15 min) acidify, and that this was coincident with greater virulence gene expression, likely accounting for the more rapid translocation of L. monocytogenes to its replicative niche in the cytosol. This hypothesis was supported by our finding that a L. monocytogenes strain expressing virulence factors at a constitutively high level replicated equally well in Perforin-2(+/+) and Perforin-2(-/-) macrophages. Our findings suggest that the protective role of Perforin-2 against listeriosis is based on it limiting the intracellular replication of the pathogen. This cellular activity of Perforin-2 may derive from it regulating the acidification of Listeria-containing vacuoles, thereby depriving the pathogen of favorable intracellular conditions that promote its virulence gene activity.

  • 184.
    Mei, Ya-Fang
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Segerman, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Lindman, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Hörnsten, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Wahlin, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Human hematopoietic (CD34+) stem cells possess high-affinity receptors for adenovirus type 11p2004In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 328, no 2, p. 198-207Article in journal (Refereed)
    Abstract [en]

    Gene transfer into human hematopoietic stem cells using Ad5 is inefficient due to lack of the primary receptor CAR and the secondary receptors alphavbeta3 integrin and alphavbeta5 integrin, and due to the high seroprevalence of Ad5 antibodies in most adults, resulting in diminished gene transduction. In the present study, we screened six species (species A-F) of adenovirus, displaying different tropisms for interaction with CD34+ cells, at the level of virus attachment and expression. Virus particles were biotinylated and their binding capacity was determined by FACS analysis using streptavidin-FITC. Ad11p, Ad35, and Ad3 (species B) showed high binding affinity, while Ad7, Ad11a (species B), and Ad37 (species D) displayed intermediate affinity. Virions of Ad4 (species E), Ad5 (species C), Ad31 (species A), and Ad41 (species F) hardly bound to hematopoietic progenitor cells. Using a double-labeling system, we demonstrated that adenoviruses bind to quiescent CD34+ cells. Ad11p virions showed the highest affinity among the adenoviruses detected. We further confirmed that virus fiber-specific receptors were present on the hematopoietic progenitor cell surface, because both recombinant fiber of Ad11p and specific antiserum against rfiber could block virus attachment. The ability of the adenoviruses to infect hematopoietic cells was studied by immunofluorescence staining. The adenoviruses from species B and Ad37 showed higher infectivity than Ad31, Ad5, Ad4, and Ad41. Among the studied species B adenoviruses, Ad11p manifested a superior infectivity. Thus, we have confirmed that these cells have high-affinity receptors for species B:2 human adenovirus, Ad11p, and this virus may be used as candidate vector to target therapeutic genes to hematopoietic stem cells.

  • 185. Milhano, Natacha
    et al.
    Korslund, Lars
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Vainio, Kirsti
    Dudman, Susanne G.
    Andreassen, Ashild
    Circulation and diagnostics of Puumala virus in Norway: nephropatia epidemica incidence and rodent population dynamics2017In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 125, no 8, p. 732-742Article in journal (Refereed)
    Abstract [en]

    Hantaviruses pose a public health concern worldwide causing haemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Puumala virus (PUUV) is the most prevalent hantavirus in Central and Northern Europe, and causes a mild form of HFRS, also known as nephropathia epidemica (NE). In nature, the main host of PUUV is the bank vole (Myodes glareolus), and transmission to humans occurs through inhalation of aerosols from rodent excreta. Nephropathia epidemica is particularly prevalent in Nordic countries, however, few studies of PUUV have been performed in Norway. The aim of this study was to analyse the dynamics of PUUV in Norway and compare with bank vole population dynamics, and also to complement the current diagnostic methodology of NE in Norway. Our results showed a significant seasonal and geographical variation of NE, and a general parallel peak trend between bank vole population densities and human NE incidence. A real-time and a nested PCR were successfully established as an invaluable diagnostic tool, with detection and sequencing of PUUV in a human serum sample for the first time in Norway. Phylogenetic analysis showed clustering of the obtained human sample with previous Norwegian bank vole isolates.

  • 186.
    Monsen, Tor
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå university hospital.
    Ryden, Patrik
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    A new concept and a comprehensive evaluation of SYSMEX UF-1000i flow cytometer to identify culture-negative urine specimens in patients with UTI2017In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 36, no 9, p. 1691-1703Article in journal (Refereed)
    Abstract [en]

    Urinary tract infections (UTIs) are among the most common bacterial infections in men and urine culture is gold standard for diagnosis. Considering the high prevalence of culture-negative specimens, any method that identifies such specimens is of interest. The aim was to evaluate a new screening concept for flow cytometry analysis (FCA). The outcomes were evaluated against urine culture, uropathogen species and three conventional screening methods. A prospective, consecutive study examined 1,312 urine specimens, collected during January and February 2012. The specimens were analyzed using the Sysmex UF1000i FCA. Based on the FCA data culture negative specimens were identified in a new model by use of linear discriminant analysis (FCA-LDA). In total 1,312 patients were included. In- and outpatients represented 19.6% and 79.4%, respectively; 68.3% of the specimens originated from women. Of the 610 culture-positive specimens, Escherichia coli represented 64%, enterococci 8% and Klebsiella spp. 7%. Screening with FCA-LDA at 95% sensitivity identified 42% (552/1312) as culture negative specimens when UTI was defined according to European guidelines. The proposed screening method was either superior or similar in comparison to the three conventional screening methods. In conclusion, the proposed/suggested and new FCA-LDA screening method was superior or similar to three conventional screening methods. We recommend the proposed screening method to be used in clinic to exclude culture negative specimens, to reduce workload, costs and the turnaround time. In addition, the FCA data may add information that enhance handling and support diagnosis of patients with suspected UTI pending urine culture.

  • 187. Mosomtai, Gladys
    et al.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Mundia, Charles
    Sandström, Per
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Hassan, Osama Ahmed
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Lwande, Olivia Wesula
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Gachari, Moses K.
    Landmann, Tobias
    Sang, Rosemary
    Datasets for mapping pastoralist movement patterns and risk zones of Rift Valley fever occurrence2018In: Data in Brief, E-ISSN 2352-3409, Vol. 16, p. 762-770Article in journal (Refereed)
    Abstract [en]

    Rift Valley fever (RVF) is a zoonotic disease affecting humans and animals. It is caused by RVF virus transmitted primarily by Aedes mosquitoes. The data presented in this article propose environmental layers suitable for mapping RVF vector habitat zones and livestock migratory routes. Using species distribution modelling, we used RVF vector occurrence data sampled along livestock migratory routes to identify suitable vector habitats within the study region which is located in the central and the north-eastern part of Kenya. Eleven herds monitored with GPS collars were used to estimate cattle utilization distribution patterns. We used kernel density estimator to produce utilization contours where the 0.5 percentile represents core grazing areas and the 0.99 percentile represents the entire home range. The home ranges were overlaid on the vector suitability map to identify risks zones for possible RVF exposure. Assimilating high spatial and temporal livestock movement and vector distribution datasets generates new knowledge in understanding RVF epidemiology and generates spatially explicit risk maps. The results can be used to guide vector control and vaccination strategies for better disease control.

  • 188. Mosomtai, Gladys
    et al.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Sandström, Per
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Sang, Rosemary
    Hassan, Osama Ahmed
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Affognon, Hippolyte
    Landmann, Tobias
    Association of ecological factors with Rift Valley fever occurrence and mapping of risk zones in Kenya2016In: International Journal of Infectious Diseases, ISSN 1201-9712, E-ISSN 1878-3511, Vol. 46, p. 49-55Article in journal (Refereed)
    Abstract [en]

    Objective: Rift Valley fever (RVF) is a mosquito-borne infection with great impact on animal and human health. The objectives of this study were to identify ecological factors that explain the risk of RVF outbreaks in eastern and central Kenya and to produce a spatially explicit risk map. Methods: The sensitivity of seven selected ecological variables to RVF occurrence was assessed by generalized linear modelling (GLM). Vegetation seasonality variables (from normalized difference vegetation index (NDVI) data) and 'evapotranspiration' (ET) (metrics) were obtained from 0.25-1 km MODIS satellite data observations; 'livestock density' (N/km(2)), 'elevation' (m), and 'soil ratio' (fraction of all significant soil types within a certain county as a function of the total area of that county) were used as covariates. Results: 'Livestock density', 'small vegetation integral', and the second principal component of ET were the most significant determinants of RVF occurrence in Kenya (all p < 0.01), with high RVF risk areas identified in the counties of Tana River, Garissa, Isiolo, and Lamu. Conclusions: Wet soil fluxes measured with ET and vegetation seasonality variables could be used to map RVF risk zones on a sub-regional scale. Future outbreaks could be better managed if relevant RVF variables are integrated into early warning systems. 

  • 189. Mostafavi, Ehsan
    et al.
    Ghasemi, Ahmad
    Rohani, Mahdi
    Molaeipoor, Leila
    Esmaeili, Saber
    Mohammadi, Zeinolabedin
    Mahmoudi, Ahmad
    Aliabadian, Mansour
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Molecular Survey of Tularemia and Plague in Small Mammals From Iran2018In: Frontiers in Cellular and Infection Microbiology, E-ISSN 2235-2988, Vol. 8, article id 215Article in journal (Refereed)
    Abstract [en]

    Introduction: Plague and tularemia are zoonoses and their causative bacteria are circulating in certain regions of Iran. This study was conducted to investigate potential disease reservoirs amongst small wildlife species in different regions of Iran.

    Methods: Rodents, insectivores and hares from 17 different provinces of the country were collected in 2014 and 2015. Samples were taken from the spleens of the animals and Real-time PCR was applied to detect nucleic acid sequences that are specific to Francisella tularensis and Yersinia pestis, respectively.

    Results: Among 140 collected rodents, 25 distinct species were identified out of which five were the most common: Microtus paradoxus (21% out of 140 rodents), Apodemus witherbyi (12%), Microtus irani (11%), Mus musculus (11%) and Microtus socialis (10%). Seventeen insectivores were collected and identified as Crocidura suaveolens (82%) and C. leucodon (18%). Fifty-one hares were collected and identified as Lepus europaeus (57%), Lepus tolai (14%) and Lepus sp. (29%). Three out of 140 explored rodents (1.91%) were positive for F. tularensis, an A. witherbyi, a Mus musculus domesticus, and a Chionomys nivalis collected from Golestan, Khuzestan and Razavi Khorasan provinces, respectively. Two hares (3.92%) were F. tularensis-positive, a L. europaeus from Khuzestan and a Lepus sp. from the Sistan and Baluchistan province. None of the tested animals were positive for Y. pestis.

    Conclusion: This is the first report of direct detection of F. tularensis in mammals of Iran and the first-time observation of the agent in a snow vole, C. nivalis worldwide. The results indicate that tularemia is more widespread in Iran than previously reported including the Northeast and Southwestern parts of the country. Future studies should address genetic characterization of F. tularensis positive DNA samples from Iran to achieve molecular subtyping and rule out assay cross-reactivity with near neighbor Francisella species.

  • 190. Moyes, Jocelyn
    et al.
    Walaza, Sibongile
    Pretorius, Marthi
    Groome, Michelle
    von Gottberg, Anne
    Wolter, Nicole
    Haffejee, Sumayya
    Variava, Ebrahim
    Cohen, Adam L.
    Tempia, Stefano
    Kahn, Kathleen
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. MRC/Wits Rural Public Health and Health Transitions Research Unit (Agincourt), School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; INDEPTH Network Accra, Ghana.
    Dawood, Halima
    Venter, Marietjie
    Cohen, Cheryl
    Madhi, Shabir A.
    Respiratory syncytial virus in adults with severe acute respiratory illness in a high HIV prevalence setting2017In: Journal of Infection, ISSN 0163-4453, E-ISSN 1532-2742, Vol. 75, no 4, p. 346-355Article in journal (Refereed)
    Abstract [en]

    Background: There are limited data on the epidemiology of respiratory syncytial virus (RSV) illness in HIV-infected adults or the elderly in Africa. We studied the epidemiology of RSV-associated severe acute respiratory illness (SARI) hospitalizations in adults in South Africa from 2009 through 2013. Methods: Individuals admitted to sentinel surveillance hospitals were investigated by respiratory tract swabs for RSV, using a multiplex real-time polymerase chain reaction assay. The incidence of RSV-associated SARI was calculated for the one site with population denominators. Results: Of 7796 participants investigated, 329 (4%) tested positive for RSV. On multivariable analysis, HIV-infected individuals with RSV-associated SARI had greater odds of being in the age groups 18-44 and 45-64 years (odd ratios (OR) 26.3; 95% confidence interval (CI) 6.2-112.1 and OR 11.4; 95% CI 2.6-50.0) compared with those >= 65 years and being female (OR 2.7; 95% CI 1.4-5.4). The relative risk of hospitalization with RSV-associated SARI was 12-18 times higher in HIV infected individual compared to that of HIV-uninfected. Conclusion: The incidence of RSV-associated SARI was higher in HIV-infected individuals and those aged 65 years and older. Further studies are warranted to describe the disease association of RSV detected in adults with SARI.

  • 191. Msimang, Veerle M. Y.
    et al.
    Page, Nicola
    Groome, Michelle J.
    Moyes, Jocelyn
    Cortese, Margaret M.
    Seheri, Mapaseka
    Kahn, Kathleen
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Chagan, Meera
    Madhi, Shabir A.
    Cohen, Cheryl
    Impact of Rotavirus Vaccine on Childhood Diarrheal Hospitalization After Introduction Into the South African Public Immunization Program2013In: The Pediatric Infectious Disease Journal, ISSN 0891-3668, E-ISSN 1532-0987, Vol. 32, no 12, p. 1359-1364Article in journal (Refereed)
    Abstract [en]

    Background: Oral rotavirus vaccine was introduced into the South African routine immunization program in August 2009 administered at 6 and 14 weeks with no catch-up. We described the change in rotavirus-associated diarrheal hospitalizations among children <5 years at 3 sentinel sites from 2009 through 2011. Methods: During 2009 through 2011, we compared the proportion of enrolled children aged <5 years hospitalized with acute gastroenteritis and testing rotavirus positive. We used hospital data to determine the change in diarrhea hospitalizations and estimated total numbers of rotavirus hospitalizations by adjusting for nonenrolled patients. Stool samples were tested for rotavirus using enzyme immunoassay. Results: In 2009 (May-December), 46% (404/883) of samples among children <5 years tested rotavirus positive, decreasing to 33% (192/580) (P < 0.001) in 2010 and 29% (113/396) (P < 0.001) in 2011. Compared with May-December 2009, total diarrhea hospitalizations among children aged <5 years was one-third lower in May-December of 2010 and 2011. Among infants, adjusted rotavirus hospitalizations were 61% (n = 267) and 69% (n = 214) lower, respectively, in 2010 and 2011 when compared with 2009 (n = 689), and 45 and 50 percentage points greater than the reduction in rotavirus-negative cases. Among children <5 years, rotavirus hospitalizations were 54% and 58% lower in 2010 and 2011, compared with 2009 (40 and 44 percentage points greater than reduction in rotavirus-negative cases). Rotavirus reductions occurred in rural and urban settings. Conclusion: Using published estimates of rotavirus hospitalization burden, we estimate that at least 13,000 to 20,000 hospitalizations in children <2 years were prevented in the 2 years after rotavirus vaccine introduction.

  • 192. Munster, Vincent J
    et al.
    Wallensten, Anders
    Baas, Chantal
    Rimmelzwaan, Guus F
    Schutten, Martin
    Olsen, Björn
    Kalmar University, Kalmar, Sweden..
    Osterhaus, Albert D M E
    Fouchier, Ron A M
    Mallards and highly pathogenic avian influenza ancestral viruses, northern Europe2005In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 11, no 10, p. 1545-1551Article in journal (Refereed)
    Abstract [en]

    Outbreaks of highly pathogenic avian influenza (HPAI), which originate in poultry upon transmission of low pathogenic viruses from wild birds, have occurred relatively frequently in the last decade. During our ongoing surveillance studies in wild birds, we isolated several influenza A viruses of hemagglutinin subtype H5 and H7 that contain various neuraminidase subtypes. For each of the recorded H5 and H7 HPAI outbreaks in Europe since 1997, our collection contained closely related virus isolates recovered from wild birds, as determined by sequencing and phylogenetic analyses of the hemagglutinin gene and antigenic characterization of the hemagglutinin glycoprotein. The minor genetic and antigenic diversity between the viruses recovered from wild birds and those causing HPAI outbreaks indicates that influenza A virus surveillance studies in wild birds can help generate prototypic vaccine candidates and design and evaluate diagnostic tests, before outbreaks occur in animals and humans.

  • 193.
    Müller, Daniel C.
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Kauppi, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Edin, Alicia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Gylfe, Åsa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Sjöstedt, Anders B.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Phospholipid Levels in Blood during Community-Acquired Pneumonia2019In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 5, article id e0216379Article in journal (Refereed)
    Abstract [en]

    Phospholipids, major constituents of bilayer cell membranes, are present in large amounts in pulmonary surfactant and play key roles in cell signaling. Here, we aim at finding clinically useful disease markers in community-acquired pneumonia (CAP) using comprehensive phospholipid profiling in blood and modeling of changes between sampling time points. Serum samples from 33 patients hospitalized with CAP were collected at admission, three hours after the start of intravenous antibiotics, Day 1 (at 12–24 h), Day 2 (at 36–48 h), and several weeks after recovery. A profile of 75 phospholipid species including quantification of the bioactive lysophosphatidylcholines (LPCs) was determined using liquid chromatography coupled to time-of-flight mass spectrometry. To control for possible enzymatic degradation of LPCs, serum autotaxin levels were examined. Twenty-two of the 33 patients with a clinical diagnosis of CAP received a laboratory-verified CAP diagnosis by microbial culture or microbial DNA detection by qPCR. All major phospholipid species, especially the LPCs, were pronouncedly decreased in the acute stage of illness. Total and individual LPC concentrations increased shortly after the initiation of antibiotic treatment, concentrations were at their lowest 3h after the initiation, and increased after Day 1. The total LPC concentration increased by a change ratio of 1.6–1.7 between acute illness and Day 2, and by a ratio of 3.7 between acute illness and full disease resolution. Autotaxin levels were low in acute illness and showed little changes over time, contradicting a hypothesis of enzymatic degradation causing the low levels of LPCs. In this sample of patients with CAP, the results demonstrate that LPC concentration changes in serum of patients with CAP closely mirrored the early transition from acute illness to recovery after the initiation of antibiotics. LPCs should be further explored as potential disease stage biomarkers in CAP and for their potential physiological role during recovery.

  • 194. Na, Manli
    et al.
    Wang, Wanzhong
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Fei, Ying
    Josefsson, Elisabet
    Ali, Abukar
    Jin, Tao
    Both anti-TNF and CTLA4 Ig treatments attenuate the disease severity of staphylococcal dermatitis in mice2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 3, article id e0173492Article in journal (Refereed)
    Abstract [en]

    Background RA patients being treated with biologics are known to have an increased risk of infections. We recently demonstrated that both CTLA4 Ig and anti-TNF treatment aggravate systemic Staphylococcus aureus (S. aureus) infection in mice, but with distinct clinical manifestations. However, the effects of CTLA4 Ig and anti-TNF treatments on a local S. aureus infection (e.g., skin infection) might differ from their effects on a systemic infection. Aims The aim of this study was to examine the differential effects of anti-TNF versus CTLA4 Ig treatment on S. aureus skin infections in mice. Method Abatacept (CTLA4 Ig), etanercept (anti-TNF treatment) or PBS was given to NMRI mice subcutaneously inoculated with S. aureus strain SH1000. The clinical signs of dermatitis, along with histopathological changes due to skin infection, were compared between the groups. Results Both CTLA4 Ig and anti-TNF treatment resulted in less severe skin infections and smaller post-infectious hyperpigmentation compared with controls. Consistent with the clinical signs of dermatitis, smaller lesion size, more epithelial hyperplasia and more granulation were found in skin biopsies from mice receiving anti-TNF compared with PBS controls. However, both CTLA4 Ig and anti-TNF therapy tended to prolong the healing time, although this finding was not statistically significant. Serum MCP-1 levels were elevated in the anti-TNF group relative to the CTLA4 Ig and PBS groups, whereas IL-6 levels were higher in PBS controls than in the other two groups. Both anti-TNF and CTLA4 Ig treatments tended to down-regulate the necrosis/apoptosis ratio in the locally infected skin tissue. Importantly, no tangible difference was found in the bacterial burden among groups. Conclusion Both CTLA4 Ig and anti-TNF therapies attenuate disease severity but may prolong the healing time required for S. aureus skin infections. Neither treatment has an impact on bacterial clearance in skin tissues.

  • 195. Napier, Brooke A
    et al.
    Meyer, Lena
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Bina, James E
    Miller, Mark A
    Sjöstedt, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Weiss, David S
    Link between intraphagosomal biotin and rapid phagosomal escape in Francisella2012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 44, p. 18084-18089Article in journal (Refereed)
    Abstract [en]

    Cytosolic bacterial pathogens require extensive metabolic adaptations within the host to replicate intracellularly and cause disease. In phagocytic cells such as macrophages, these pathogens must respond rapidly to nutrient limitation within the harsh environment of the phagosome. Many cytosolic pathogens escape the phagosome quickly (15-60 min) and thereby subvert this host defense, reaching the cytosol where they can replicate. Although a great deal of research has focused on strategies used by bacteria to resist antimicrobial phagosomal defenses and transiently pass through this compartment, the metabolic requirements of bacteria in the phagosome are largely uncharacterized. We previously identified a Francisella protein, FTN_0818, as being essential for intracellular replication and involved in virulence in vivo. We now show that FTN_0818 is involved in biotin biosynthesis and required for rapid escape from the Francisella-containing phagosome (FCP). Addition of biotin complemented the phagosomal escape defect of the FTN_0818 mutant, demonstrating that biotin is critical for promoting rapid escape during the short time that the bacteria are in the phagosome. Biotin also rescued the attenuation of the FTN_0818 mutant during infection in vitro and in vivo, highlighting the importance of this process. The key role of biotin in phagosomal escape implies biotin may be a limiting factor during infection. We demonstrate that a bacterial metabolite is required for phagosomal escape of an intracellular pathogen, providing insight into the link between bacterial metabolism and virulence, likely serving as a paradigm for other cytosolic pathogens.

  • 196.
    Negash Atsbeha, Maasho
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Biomedicinprogrammet.
    The role of H-NS in the expression of virulence factors in Escherichia coli and Acinetobacter baumannii: Diverse virulence phenotypes among A. baumannii clinical isolates2014Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 197.
    Negi, Neema
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Ahmad, Aijaz
    Current updates on fungal endocarditis2018In: Fungal Biology Reviews, ISSN 1749-4613, E-ISSN 1878-0253, Vol. 32, no 1, p. 1-9Article, review/survey (Refereed)
    Abstract [en]

    Fungal endocarditis (FE) is a rare disease but in recent years its incidence as well as mortality is increasing particularly in developing nations. Candida and Aspergillus species occupy the prominent position as etiological agents of this invasive disease. Intravenous devices such as pacemakers, central line related thrombosis and prolonged use of antibiotics are major risk factors for FE. The epidemiology of endocarditis cases is also evolving over time with exceptionally rare species causing more invasive disease. Research over the last decade has also delineated the underlying pathogenic mechanism of FE. Improved understanding of these mechanisms will help to combat the increasing problem of antimicrobial drug resistance. The diagnosis of FE is dependent on the sensitivity and specificity of the method as fungi generally do not grow well in blood cultures. More advanced techniques including molecular and immunological assays now play a central role in accurate identification of causative fungal pathogens especially in culture negative scenario. In developing nations such as India, blood culture reports are generally negative due to prior antibiotic therapy. Echocardiography has emerged as the potential imaging technique for identifying invasive endocarditis including small masses of vegetation or abscess. Successful treatment often requires both the surgical interventions and prolonged antifungal therapy. In the present review, we briefly highlight the mechanisms of pathogenesis of this rare emerging disease along with the risk factors involved, the diagnostic criteria and the treatment strategy.

  • 198. Neumayr, Andreas
    et al.
    Muñoz, Jose
    Schunk, Mirjam
    Bottieau, Emmanuel
    Cramer, Jakob
    Calleri, Guido
    López-Vélez, Rogelio
    Angheben, Andrea
    Zoller, Thomas
    Visser, Leo
    Serre-Delcor, Núria
    Genton, Blaise
    Castelli, Francesco
    Van Esbroeck, Marjan
    Matteelli, Alberto
    Rochat, Laurence
    Sulleiro, Elena
    Kurth, Florian
    Gobbi, Federico
    Norman, Francesca
    Torta, Ilaria
    Clerinx, Jan
    Poluda, David
    Martinez, Miguel
    Calvo-Cano, Antonia
    Sanchez-Seco, Maria Paz
    Wilder-Smith, Annelies
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Institute of Public Health, University of Heidelberg, Germany.
    Hatz, Christoph
    Franco, Leticia
    Sentinel surveillance of imported dengue via travellers to Europe 2012 to 2014: TropNet data from the DengueTools Research Initiative2017In: Eurosurveillance, ISSN 1025-496X, E-ISSN 1560-7917, Vol. 22, no 1, p. 39-47Article in journal (Refereed)
    Abstract [en]

    We describe the epidemiological pattern and genetic characteristics of 242 acute dengue infections imported to Europe by returning travellers from 2012 to 2014. The overall geographical pattern of imported dengue (South-east Asia > Americas > western Pacific region > Africa) remained stable compared with 1999 to 2010. We isolated the majority of dengue virus genotypes and epidemic lineages causing outbreaks and epidemics in Asia, America and Africa during the study period. Travellers acted as sentinels for four unusual dengue outbreaks (Madeira, 2012-13; Luanda, 2013; Dar es Salaam, 2014; Tokyo, 2014). We were able to characterise dengue viruses imported from regions where currently no virological surveillance data are available. Up to 36% of travellers infected with dengue while travelling returned during the acute phase of the infection (up to 7 days after symptom onset) or became symptomatic after returning to Europe, and 58% of the patients with acute dengue infection were viraemic when seeking medical care. Epidemiological and virological data from dengue-infected international travellers can add an important layer to global surveillance efforts. A considerable number of dengue-infected travellers are viraemic after arrival back home, which poses a risk for dengue introduction and autochthonous transmission in European regions where suitable mosquito vectors are prevalent.

  • 199.
    Nkulu Kalengayi, Faustine Kyungu
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Hurtig, Anna-Karin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Krantz, Ingela
    Skaraborg Inst Res & Dev, Skövde, Sweden.
    Fear of deportation may limit legal immigrants' access to HIV/AIDS-related care: a survey of Swedish language school students in Northern Sweden2012In: Journal of Immigrant and Minority Health, ISSN 1557-1912, E-ISSN 1557-1920, Vol. 14, no 1, p. 39-47Article in journal (Refereed)
    Abstract [en]

    The increasing rates of HIV infection that are currently being reported in high-income countries can be partly explained by migration from countries with generalized epidemics. Yet, early diagnosis of HIV/AIDS in immigrants remains a challenge. This study investigated factors that might be limiting immigrants' access to HIV/AIDS care. Data from 268 legal immigrant students of two Swedish language schools in Northern Sweden were analyzed using logistic regression. Thirty-seven percent reported reluctance to seek medical attention if they had HIV/AIDS. Fear of deportation emerged as the most important determinant of reluctance to seek care after adjusting for socio-demographic factors, knowledge level, stigmatizing attitudes and fear of disclosure. Targeted interventions should consider the heterogeneity of migrant communities and the complex interplay of various factors which may impede access to HIV-related services. The myth about deportation because of HIV/AIDS should be countered.

  • 200. Nykvist, Marie
    et al.
    Gillman, Anna
    Söderström Lindström, Hanna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Tang, Chaojun
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Fedorova, Ganna
    Lundkvist, Åke
    Latorre-Margalef, Neus
    Wille, Michelle
    Järhult, Josef D.
    In vivo mallard experiments indicate that zanamivir has less potential for environmental influenza A virus resistance development than oseltamivir2017In: Journal of General Virology, ISSN 0022-1317, E-ISSN 1465-2099, Vol. 98, p. 2937-2949Article in journal (Refereed)
    Abstract [en]

    Neuraminidase inhibitors are a cornerstone of influenza pandemic preparedness before vaccines can be mass-produced and thus a neuraminidase inhibitor-resistant pandemic is a serious threat to public health. Earlier work has demonstrated the potential for development and persistence of oseltamivir resistance in influenza A viruses exposed to environmentally relevant water concentrations of the drug when infecting mallards, the natural influenza reservoir that serves as the genetic base for human pandemics. As zanamivir is the major second-line neuraminidase inhibitor treatment, this study aimed to assess the potential for development and persistence of zanamivir resistance in an in vivo mallard model; especially important as zanamivir will probably be increasingly used. Our results indicate less potential for development and persistence of resistance due to zanamivir than oseltamivir in an environmental setting. This conclusion is based on: (1) the lower increase in zanamivir IC50 conferred by the mutations caused by zanamivir exposure (2-17-fold); (2) the higher zanamivir water concentration needed to induce resistance (at least 10 µg l-1); (3) the lack of zanamivir resistance persistence without drug pressure; and (4) the multiple resistance-related substitutions seen during zanamivir exposure (V116A, A138V, R152K, T157I and D199G) suggesting lack of one straight-forward evolutionary path to resistance. Our study also adds further evidence regarding the stability of the oseltamivir-induced substitution H275Y without drug pressure, and demonstrates the ability of a H275Y-carrying virus to acquire secondary mutations, further boosting oseltamivir resistance when exposed to zanamivir. Similar studies using influenza A viruses of the N2-phylogenetic group of neuraminidases are recommended.

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