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  • 1. Abbara, Aula
    et al.
    Rawson, Timothy M.
    Karah, Nabil
    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).
    El-Amin, Wael
    Hatcher, James
    Tajaldin, Bachir
    Dar, Osman
    Dewachi, Omar
    Abu Sitta, Ghassan
    Uhlin, Bernt Eric
    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, Department of Molecular Biology (Faculty of Medicine).
    Sparrow, Annie
    Antimicrobial resistance in the context of the Syrian conflict: Drivers before and after the onset of conflict and key recommendations2018In: International Journal of Infectious Diseases, ISSN 1201-9712, E-ISSN 1878-3511, Vol. 73, p. 1-6Article, review/survey (Refereed)
    Abstract [en]

    Current evidence describing antimicrobial resistance (AMR) in the context of the Syrian conflict is of poor quality and sparse in nature. This paper explores and reports the major drivers of AMR that were present in Syria pre-conflict and those that have emerged since its onset in March 2011. Drivers that existed before the conflict included a lack of enforcement of existing legislation to regulate over-the-counter antibiotics and notification of communicable diseases. This contributed to a number of drivers of AMR after the onset of conflict, and these were also compounded by the exodus of trained staff, the increase in overcrowding and unsanitary conditions, the increase in injuries, and economic sanctions limiting the availability of required laboratory medical materials and equipment. Addressing AMR in this context requires pragmatic, multifaceted action at the local, regional, and international levels to detect and manage potentially high rates of multidrug-resistant infections. Priorities are (1) the development of a competent surveillance system for hospital-acquired infections, (2) antimicrobial stewardship, and (3) the creation of cost-effective and implementable infection control policies. However, it is only by addressing the conflict and immediate cessation of the targeting of health facilities that the rehabilitation of the health system, which is key to addressing AMR in this context, can progress. 

  • 2. Adler, Sara
    et al.
    Widerström, Micael
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Lindh, Johan
    Lilja, Mikael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Symptoms and risk factors of Cryptosporidium hominis infection in children: data from a large waterborne outbreak in Sweden2017In: Parasitology Research, ISSN 0932-0113, E-ISSN 1432-1955, Vol. 116, no 10, p. 2613-2618Article in journal (Refereed)
    Abstract [en]

    Cryptosporidium is a major cause of diarrheal disease worldwide. In developing countries, this infection is endemic and in children, associated with growth faltering and cognitive function deficits, with the most severe impact on those aged <2 years. Little has been reported about symptoms and risk factors for children in industrialized countries, although the disease incidence is increasing in such regions. In November 2010, a large waterborne outbreak of C. hominis occurred in the city of Östersund in Sweden. Approximately 27,000 of the 60,000 inhabitants were symptomatic. We aimed to describe duration of symptoms and the risk factors for infection with C. hominis in children aged <15 years in a Western setting. Within 2 months after a boil water advisory, a questionnaire was sent to randomly selected inhabitants of all ages, including 753 children aged <15 years. Those with ≥3 loose stools/day were defined as cases of diarrhoea. The response rate was 70.3%, and 211 children (39.9%) fulfilled the case definition. Mean duration of diarrhoea was 7.5 days (median 6, range 1-80 days). Recurrence, defined as a new episode of diarrhoea after ≥2 days of normal stools, occurred in 52.5% of the cases. Significant risk factors for infection, besides living within the distribution area of the contaminated water plant, included a high level of water consumption, male sex, and a previous history of loose stools. The outbreak was characterized by high attack and recurrence rates, emphasizing the necessity of water surveillance to prevent future outbreaks.

  • 3. Affognon, H.
    et al.
    Mburu, P.
    Hassan, Osama Ahmed
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Kingori, S.
    Ahlm, C.
    Sang, R.
    Evander, M.
    Sociocultural differences affect Rift Valley fever exposureManuscript (preprint) (Other academic)
  • 4. Affognon, Hippolyte
    et al.
    Mburu, Peter
    Hassan, Osama Ahmed
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Kingori, Sarah
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Sang, Rosemary
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Ethnic groups' knowledge, attitude and practices and Rift Valley fever exposure in Isiolo County of Kenya2017In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 11, no 3, article id e0005405Article in journal (Refereed)
    Abstract [en]

    Rift Valley fever (RVF) is an emerging mosquito-borne viral hemorrhagic fever in Africa and the Arabian Peninsula, affecting humans and livestock. For spread of infectious diseases, including RVF, knowledge, attitude and practices play an important role, and the understanding of the influence of behavior is crucial to improve prevention and control efforts. The objective of the study was to assess RVF exposure, in a multiethnic region in Kenya known to experience RVF outbreaks, from the behavior perspective. We investigated how communities in Isiolo County, Kenya were affected, in relation to their knowledge, attitude and practices, by the RVF outbreak of 2006/2007. A cross-sectional study was conducted involving 698 households selected randomly from three different ethnic communities. Data were collected using a structured questionnaire regarding knowledge, attitudes and practices that could affect the spread of RVF. In addition, information was collected from the communities regarding the number of humans and livestock affected during the RVF outbreak. This study found that better knowledge about a specific disease does not always translate to better practices to avoid exposure to the disease. However, the high knowledge, attitude and practice score measured as a single index of the Maasai community may explain why they were less affected, compared to other investigated communities (Borana and Turkana), by RVF during the 2006/2007 outbreak. We conclude that RVF exposure in Isiolo County, Kenya during the outbreak was likely determined by the behavioral differences of different resident community groups. We then recommend that strategies to combat RVF should take into consideration behavioral differences among communities.

  • 5. Afset, J. E.
    et al.
    Larssen, K. W.
    Bergh, K.
    Larkeryd, A.
    Sjodin, A.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Forsman, M.
    Phylogeographical pattern of Francisella tularensis in a nationwide outbreak of tularaemia in Norway, 20112015In: Eurosurveillance, ISSN 1025-496X, E-ISSN 1560-7917, Vol. 20, no 19, p. 9-14, article id 21125Article in journal (Refereed)
    Abstract [en]

    In 2011, a nationwide outbreak of tularaemia occurred in Norway with 180 recorded cases. It was associated with the largest peak in lemming density seen in 40 years. Francisella tularensis was isolated from 18 patients. To study the geographical distribution of F. tularensis genotypes in Norway and correlate genotype with epidemiology and clinical presentation, we performed whole genome sequencing of patient isolates. All 18 genomes from the outbreak carried genetic signatures of F. tularensis subsp. holarctica and were assigned to genetic clades using canonical single nucleotide polymorphisms. Ten isolates were assigned to major genetic clade B.6 (subclade B.7), seven to clade B.12, and one to clade B.4. The B.6 subclade B.7 was most common in southern and central Norway, while clade B.12 was evenly distributed between the southern, central and northern parts of the country. There was no association between genotype and clinical presentation of tularaemia, time of year or specimen type. We found extensive sequence similarity with F. tularensis subsp. holarctica genomes from high-endemic tularaemia areas in Sweden. Finding nearly identical genomes across large geographical distances in Norway and Sweden imply a life cycle of the bacterium without replication between the outbreaks and raise new questions about long-range migration mechanisms.

  • 6.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Distribution of puumala virus in Sweden1997Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Puumala virus, belonging to the genus hantavirus, is the causative agent of nephropathia epidemica (NE), a relatively mild form of hemorrhagic fever with renal syndrome. Puumala virus occurs endemically in Central and Northern Europe and Western Russia. In Sweden, NE is reported from the northern and central parts but virtually not at all from the southern part of the country. The bank vole (Clethrionomys glareolus) is the main reservoir of Puumala virus and humans are infected by inhalation of aerosolized animal secreta. In northern Sweden, the density of the bank vole population varies cyclically in intervals of 3-4 years and the incidence of NE shows a covariation.

    The prevalence of serum antibodies to hantaviruses in northern Sweden was studied in a stratified and randomly selected adult population sample comprising 1538 subjects. As expected, the prevalence increased with age. There was no difference between men and women, which was unexpected based on a male:female ratio of > 2:1 in clinical reports. By use of an immunofiuorescent assay, a seroprevalence of 5.4% and by a newly developed enzyme-linked immunosorbent assay (ELISA) with recombinant Puumala virus nucleocapsid protein as antigen, a prevalence of 8.9% was recorded. This is about or more than ten times higher than what would be calculated from clinical reports.

    By use of the ELISA, an occupational risk of acquisition of Puumala virus infection was demonstrated. Serum samples from 910 farmers and 663 referent subjects living in various rural parts of Sweden were tested. Among farmers from the Puumala virus-endemic northern and central parts of the country, the seroprevalence (12.9%) was higher (p=0.01) than in referents (6.8%). In the southern part of Sweden, only 2/459 persons had antibodies. Only a limited number of children with NE had been previously reported. In a separate study, 32 children with Puumala virus infection were identified and the clinical picture of NE in children was found to be similar to that of adult cases.

    Variations in the prevalence of Puumala virus in the bank vole population within an endemic region are not well known. Here, a higher mean rodent density and a higher prevalence of Puumala virus-specific serum antibodies were recorded in the vicinity of households afflicted with NE than in rural control areas. The data indicated that the risk of exposure locally within an endemic region may vary widely and tentatively suggested that a threshold density of bank voles might be necessary to achieve before effective spread of Puumala virus within the rodent population may occur.

    There is no firm evidence of the occurrence of Puumala virus among wild living animals other than rodents. A study of Swedish moose, an animal which is ecologically well characterized, was performed. Convincing evidence of past Puumala virus infection was found in 5/260 moose originating from Puumala virus-endemic areas but in none of 167 animals from nonendemic areas. Based on the low seroprevalence recorded, moose seemed to serve as endstage hosts rather than being active parts of the enzootic circle of transmission.

    In conclusion, the present investigations confirmed that the exposure to Puumala virus is geographically well restricted in Sweden. Seroprevalence studies indicated that only a minor proportion of individuals infected with Puumala virus are clinically reported, with a bias in favour of men. NE was confirmed to occur in children, with a clinical picture similar to that of adults. An occupational risk was defined for acquisition of Puumala virus infection. Studies in rodents suggested that there may be wide local variations within a limited area in the risk of exposure to Puumala virus. The studies validated the usefulness of a newly developed ELISA based on recombinant nucleocapsid peptides of hantaviruses and finally, methodological progress was reached when Puumala virus was, for the first time, successfully isolated from a Scandinavian patient.

  • 7.
    Ahlm, Clas
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Eliasson, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Vapalahti, O.
    University of Helsinki and Helsinki University Central Hospital Laboratory, Finland.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Seroprevalence of Sindbis virus and associated risk factors in northern Sweden2014In: Epidemiology and Infection, ISSN 0950-2688, E-ISSN 1469-4409, Vol. 142, no 7, p. 1559-1565Article in journal (Refereed)
    Abstract [en]

    Mosquito-borne Sindbis virus (SINV) cause disease characterized by rash, fever and arthritis which often leads to long-lasting arthralgia. To determine the seroprevalence of SINV and associated risk factors in northern Sweden, a randomly selected population aged between 25 and 74 years were invited to join the MONICA study. Serum from 1611 samples were analysed for specific IgG antibodies. Overall, 2·9% had IgG against SINV. More men (3·7%) than women (2·0%) were SINV seropositive (P = 0·047) and it was more common in subjects with a lower educational level (P = 0·013) and living in small, rural communities (P < 0·001). Seropositivity was associated with higher waist circumference (P = 0·1), elevated diastolic blood pressure (P = 0·037), and history of a previous stroke (P = 0·011). In a multiple logistic regression analysis, adjusting for known risk factors for stroke, seropositivity for SINV was an independent predictor of having had a stroke (odds ratio 4·3, 95% confidence interval 1·4–13·0,P = 0·011).

  • 8. Albrecht, Letusa
    et al.
    Moll, Kirsten
    Blomqvist, Karin
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Chen, Qijun
    Wahlgren, Mats
    var gene transcription and PfEMP1 expression in the rosetting and cytoadhesive Plasmodium falciparum clone FCR3S1.22011In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 10, article id 17Article in journal (Refereed)
    Abstract [en]

    Background: The pathogenicity of Plasmodium falciparum is in part due to the ability of the parasitized red blood cell (pRBC) to adhere to intra- vascular host cell receptors and serum-proteins. Binding of the pRBC is mediated by Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), a large multi-variant molecule encoded by a family of approximate to 60 var genes. Methods: The study of var gene transcription in the parasite clone FCR3S1.2 was performed by semi-quantitative PCR and quantitative PCR (qPCR). The expression of the major PfEMP1 in FCR3S1.2 pRBC was analysed with polyclonal sera in rosette disruption assays and immunofluorecence. Results: Transcripts from var1 (FCR3S1.2(var1); IT4var21) and other var genes were detected by semi-quantitative PCR but results from qPCR showed that one var gene transcript dominated over the others (FCR3S1.2var2; IT4var60). Antibodies raised in rats to the recombinant NTS-DBL1a of var2 produced in E. coli completely and dosedependently disrupted rosettes (approximate to 95% at a dilution of 1/5). The sera reacted with the Maurer's clefts in trophozoite stages (IFA) and to the infected erythrocyte surface (FACS) indicating that FCR3S1.2var2 encodes the dominant PfEMP1 expressed in this parasite. Conclusion: The major transcript in the rosetting model parasite FCR3S1.2 is FCR3S1.2var2 (IT4var60). The results suggest that this gene encodes the PfEMP1-species responsible for the rosetting phenotype of this parasite. The activity of previously raised antibodies to the NTS-DBL1a of FCR3S1.2var1 is likely due to cross-reactivity with NTS-DBL1 alpha of the var2 encoded PfEMP1.

  • 9. Alqahtani, F. Y.
    et al.
    Aleanizy, F. S.
    Mohamed, R. Ali El Hadi
    Alanazi, M. S.
    Mohamed, Nahla
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. College of Medicine, Princess Nourah bint Abdulrahman University, Riyadh 12484, Saudi Arabia.
    Alrasheed, M. M.
    Abanmy, N.
    Alhawassi, T.
    Prevalence of comorbidities in cases of Middle East respiratory syndrome coronavirus: a retrospective study2019In: Epidemiology and Infection, ISSN 0950-2688, E-ISSN 1469-4409, Vol. 147, article id UNSP e35Article in journal (Refereed)
    Abstract [en]

    The Middle East respiratory syndrome coronavirus (MERS-CoV) is a life-threatening respiratory disease with a high case fatality rate; however, its risk factors remain unclear. We aimed to explore the influence of demographic factors, clinical manifestations and underlying comorbidities on mortality in MERS-CoV patients. Retrospective chart reviews were performed to identify all laboratory-confirmed cases of MERS-COV infection in Saudi Arabia that were reported to the Ministry of Health of Saudi Arabia between 23 April 2014 and 7 June 2016. Statistical analyses were conducted to assess the effect of sex, age, clinical presentation and comorbidities on mortality from MERS-CoV. A total of 281 confirmed MERS-CoV cases were identified: 167 (59.4%) patients were male and 55 (20%) died. Mortality predominantly occurred among Saudi nationals and older patients and was significantly associated with respiratory failure and shortness of breath. Of the 281 confirmed cases, 160 (56.9%) involved comorbidities, wherein diabetes mellitus, hypertension, ischemic heart disease, congestive heart failure, end-stage renal disease and chronic kidney disease were significantly associated with mortality from MERS-CoV and two or three comorbidities significantly affected the fatality rates from MERS-CoV. The findings of this study show that old age and the existence of underlying comorbidities significantly increase mortality from MERS-CoV.

  • 10. Amada, Takako
    et al.
    Yoshimatsu, Kumiko
    Koma, Takaaki
    Shimizu, Kenta
    Gamage, Chandika D.
    Shiokawa, Kanae
    Nishio, Sanae
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Arikawa, Jiro
    Development of an immunochromatography strip test based on truncated nucleocapsid antigens of three representative hantaviruses2014In: Virology Journal, ISSN 1743-422X, E-ISSN 1743-422X, Vol. 11, p. 87-Article in journal (Refereed)
    Abstract [en]

    Background: Hantaviruses are causative agents of hemorrhagic fever with renal syndrome (HFRS) and nephropathia epidemica (NE) in the Old World and hantavirus pulmonary syndrome (HPS) in the New World. There is a need for time-saving diagnostic methods. In the present study, recombinant N antigens were used as antigens in an immunochromatography strip (ICG) test to detect specific IgG antibodies. Methods: The N-terminal 103 amino acids (aa) of Hantaan virus (HTNV), Puumala virus (PUUV) and Andes virus (ANDV) nucleocapsid (N) protein were expressed in E. coli as representative antigens of three groups (HFRS, NE and HPS-causing viruses) of hantavirus. Five different types of ICG test strips, one antigen line on one strip for each of the three selected hantaviruses (HTNV, PUUV and ANDV), three antigen lines on one strip and a mixed antigen line on one strip, were developed and sensitivities were compared. Results: A total of 87 convalescent-phase patient sera, including sera from 35 HFRS patients, 36 NE patients and 16 HPS patients, and 25 sera from healthy seronegative people as negative controls were used to evaluate the ICG test. Sensitivities of the three-line strip and mixed-line strip were similar to those of the single antigen strip (97.2 to 100%). On the other hand, all of the ICG test strips showed high specificities to healthy donors. Conclusion: These results indicated that the ICG test with the three representative antigens is an effective serodiagnostic tool for screening and typing of hantavirus infection in humans.

  • 11. Amorim, Gisele C
    et al.
    Cisneros, David A.
    Unité de Génétique Moléculaire, Département de MicrobiologieInstitut Pasteur, Paris Cedex 15 France; CNRS, ERL 3526, Paris, France.
    Delepierre, Muriel
    Francetic, Olivera
    Izadi-Pruneyre, Nadia
    ¹H, ¹⁵N and ¹³C resonance assignments of PpdD, a type IV pilin from enterohemorrhagic Escherichia coli2014In: Biomolecular NMR Assignments, ISSN 1874-2718, E-ISSN 1874-270X, Vol. 8, no 1, p. 43-46Article in journal (Refereed)
    Abstract [en]

    Bacterial type 4 pili (T4P) are long flexible fibers involved in adhesion, DNA uptake, phage transduction, aggregation and a flagella-independent movement called "twitching motility". T4P comprise thousands of copies of the major pilin subunit, which is initially inserted in the plasma membrane, processed and assembled into dynamic helical filaments. T4P are crucial for host colonization and virulence of many Gram-negative bacteria. In enterohemorrhagic Escherichia coli the T4P, called hemorrhagic coli pili (HCP) promote cell adhesion, motility, biofilm formation and signaling. To understand the mechanism of HCP assembly and function, we analyzed the structure of the major subunit prepilin peptidase-dependent protein D (PpdD) (also called HcpA), a 15 kDa pilin with two potential disulfide bonds. Here we present the (1)H, (15)N and (13)C backbone and side chain resonance assignments of the C-terminal globular domain of PpdD as a first step to its structural determination.

  • 12. Anantharajah, Ahalieyah
    et al.
    Faure, Emmanuel
    Buyck, Julien M.
    Sundin, Charlotta
    Creative Antibiotics, Umeå, Sweden .
    Lindmark, Tuulikki
    Mecsas, Joan
    Yahr, Timothy L.
    Tulkens, Paul M.
    Mingeot-Leclercq, Marie-Paule
    Guery, Benoît
    Van Bambeke, Françoise
    Inhibition of the Injectisome and Flagellar Type III Secretion Systems by INP1855 Impairs Pseudomonas aeruginosa Pathogenicity and Inflammasome Activation2016In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 214, no 7, p. 1105-1116Article in journal (Refereed)
    Abstract [en]

    With the rise of multidrug resistance, Pseudomonas aeruginosa infections require alternative therapeutics. The injectisome (iT3SS) and flagellar (fT3SS) type III secretion systems are 2 virulence factors associated with poor clinical outcomes. iT3SS translocates toxins, rod, needle, or regulator proteins, and flagellin into the host cell cytoplasm and causes cytotoxicity and NLRC4-dependent inflammasome activation, which induces interleukin 1 beta (IL-1 beta) release and reduces interleukin 17 (IL-17) production and bacterial clearance. fT3SS ensures bacterial motility, attachment to the host cells, and triggers inflammation. INP1855 is an iT3SS inhibitor identified by in vitro screening, using Yersinia pseudotuberculosis. Using a mouse model of P. aeruginosa pulmonary infection, we show that INP1855 improves survival after infection with an iT3SS-positive strain, reduces bacterial pathogenicity and dissemination and IL-1 beta secretion, and increases IL-17 secretion. INP1855 also modified the cytokine balance in mice infected with an iT3SS-negative, fT3SS-positive strain. In vitro, INP1855 impaired iT3SS and fT3SS functionality, as evidenced by a reduction in secretory activity and flagellar motility and an increase in adenosine triphosphate levels. As a result, INP1855 decreased cytotoxicity mediated by toxins and by inflammasome activation induced by both laboratory strains and clinical isolates. We conclude that INP1855 acts by dual inhibition of iT3SS and fT3SS and represents a promising therapeutic approach.

  • 13.
    Andersson, T
    et al.
    Department of Mathematics, Stockholm University, Sweden and Swedish Institute for National Food Agency (SLV), Sweden and Communicable Disease Control (SMI), Solna, Sweden.
    Bjelkmar, P
    Swedish Institute for Communicable Disease Control (SMI), Solna, Sweden, and Inera AB, Sweden.
    Hulth, A
    Swedish Institute for Communicable Disease Control (SMI), Solna, Sweden.
    Lindh, J
    Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, Sweden and Swedish Institute for Communicable Disease Control (SMI), Solna, Sweden.
    Stenmark, Stephan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. County Medical Officer, Västerbotten, Sweden.
    Widerström, Micael
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Syndromic surveillance for local outbreak detection and awareness: evaluating outbreak signals of acute gastroenteritis in telephone triage, web-based queries and over-the-counter pharmacy sales2014In: Epidemiology and Infection, ISSN 0950-2688, E-ISSN 1469-4409, Vol. 142, no 2, p. 303-313Article in journal (Refereed)
    Abstract [en]

    For the purpose of developing a national system for outbreak surveillance, local outbreak signals were compared in three sources of syndromic data - telephone triage of acute gastroenteritis, web queries about symptoms of gastrointestinal illness, and over-the-counter (OTC) pharmacy sales of antidiarrhoeal medication. The data sources were compared against nine known waterborne and foodborne outbreaks in Sweden in 2007-2011. Outbreak signals were identified for the four largest outbreaks in the telephone triage data and the two largest outbreaks in the data on OTC sales of antidiarrhoeal medication. No signals could be identified in the data on web queries. The signal magnitude for the fourth largest outbreak indicated a tenfold larger outbreak than officially reported, supporting the use of telephone triage data for situational awareness. For the two largest outbreaks, telephone triage data on adult diarrhoea provided outbreak signals at an early stage, weeks and months in advance, respectively, potentially serving the purpose of early event detection. In conclusion, telephone triage data provided the most promising source for surveillance of point-source outbreaks.

  • 14.
    Andresen, Liis
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Varik, Vallo
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). University of Tartu, Institute of Technology, Nooruse 1, 50411 Tartu, Estonia.
    Tozawa, Yuzuru
    Jimmy, Steffi
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Lindberg, Stina
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Tenson, Tanel
    Hauryliuk, Vasili
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). University of Tartu, Institute of Technology, Nooruse 1, 50411 Tartu, Estonia.
    Auxotrophy-based High Throughput Screening assay for the identification of Bacillus subtilis stringent response inhibitors2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 35824Article in journal (Refereed)
    Abstract [en]

    The stringent response is a central adaptation mechanism that allows bacteria to adjust their growth and metabolism according to environmental conditions. The functionality of the stringent response is crucial for bacterial virulence, survival during host invasion as well as antibiotic resistance and tolerance. Therefore, specific inhibitors of the stringent response hold great promise as molecular tools for disarming and pacifying bacterial pathogens. By taking advantage of the valine amino acid auxotrophy of the Bacillus subtilis stringent response-deficient strain, we have set up a High Throughput Screening assay for the identification of stringent response inhibitors. By screening 17,500 compounds, we have identified a novel class of antibacterials based on the 4-(6-(phenoxy) alkyl)-3,5-dimethyl-1H-pyrazole core. Detailed characterization of the hit compounds as well as two previously identified promising stringent response inhibitors-a ppGpp-mimic nucleotide Relacin and cationic peptide 1018 - showed that neither of the compounds is sufficiently specific, thus motivating future application of our screening assay to larger and more diverse molecular libraries.

  • 15. Andrii, Dudnyk
    et al.
    Matthew, Burman
    Ludmyla, Kulyk
    Olena, Rzhepishevska
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    M/XDR‐TB treatment perspective: how to avoid mountains of pills via digital technologies2018In: Respirology (Carlton South. Print), ISSN 1323-7799, E-ISSN 1440-1843, Vol. 23, no 6, p. 636-637Article in journal (Refereed)
  • 16.
    Angelin, Martin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Travel – a risk factor for disease and spread of antibiotic resistance2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    As international travel is rapidly increasing, more people are being exposed to potentially more antibiotic resistant bacteria, a changed infectious disease epidemiology, and an increased risk of accidents and crime. Research-based advice is needed to adequately inform travellers about these risks. We studied travellers who sought advice from the Travel Medicine Clinic at the Department of Infectious Diseases, Umeå University Hospital, as well as university students from Umeå, Stockholm, and Gothenburg travelling abroad for study, research, and clinical exchange programs.

    From retrospective data at the Travel Medicine Clinic, we found that pre-existing health problems were rare among travellers from Umeå seeking pre- travel health advice and vaccinations. In addition, we found that the travel destination and the sex of the traveller affected vaccination levels. Although hepatitis A is endemic to both Thailand and Turkey, compared to travellers to Thailand few travellers to Turkey visited the clinic for hepatitis A vaccination. The data also revealed that more women than men were vaccinated against Japanese encephalitis despite comparable trips.

    A prospective survey study showed that travellers felt that the pre-travel health advice they received was helpful. Two-thirds of the travellers followed the advice given although they still fell ill to the same extent as those who were not compliant with the advice. Factors outside the control of travellers likely affect the travel-related morbidity. Compared to older travellers, younger travellers were less compliant with advice, fell ill to a greater extent, and took greater risks during travel.

    In a prospective survey study, we found that healthcare students had higher illness rates and risk exposure when abroad compared to students from other disciplines. This difference was mainly due to the fact that healthcare students more often travelled to developing regions during their study period abroad. When abroad, half of all students increased their alcohol consumption and this was linked to an increased risk of theft and higher likelihood of meeting a new sex partner.

    The healthcare students participating in the survey study also submitted stool samples before and after travel. These samples were tested for the presence of antibiotic resistance, both by selective culturing for ESBL-PE (Extended-Spectrum Beta-Lactamase Producing Enterobacteriaceae) as well as by metagenomic sequencing. About one-third (35%) of the students became colonised by ESBL-PE following their study abroad. The strongest risk factor for colonisation was travel destination; for example, 70% of students who had travelled to India became colonised. Antibiotic treatment during travel was also a significant risk factor for colonisation.

    The stool samples from a subset of study subjects were analysed using metagenomic sequencing. From this we learned that although the majority of resistance genes in the gut microbiome remained unchanged following travel, several clinically important resistance genes increased, most prominently genes encoding resistance to sulphonamide, trimethoprim, and beta-lactams. Overall, taxonomic changes associated with travel were small but the proportion of Proteobacteria, which includes several clinically important bacteria (e.g., Enterobacteriaceae), increased in a majority of the study subjects.

    Clearly, there are risks associated with international travel and these risks include outside factors as well as the personal behaviour of travellers. We believe our results can be used to develop better pre-travel advice for tourists as well as university students studying abroad resulting in safer travel.

  • 17.
    Angelin, Martin
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Evengård, Birgitta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Palmgren, Helena
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Travel and vaccination patterns: a report from a travel medicine clinic in northern Sweden2011In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 43, no 9, p. 714-720Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The Travel Medicine Clinic in Umeå is one of Sweden's largest public providers of vaccination and counselling prior to international travel. During the study period it was the only travel medicine clinic in Umeå. This study describes the demography of the visitors to the clinic and travel destinations and durations, as well as vaccinations administered. METHODS: This was a retrospective study for the period January 2005 to April 2008 based on pre-travel consultation questionnaires and on vaccine expenditure data. A 10% sample of 16,735 first visits prior to international travel was consecutively selected according to the chronology of the visits. RESULTS: Data on 1698 travellers were included in the study. Thailand was the most common destination among visitors, accounting for one third of all destinations. Medical problems affecting pre-travel health planning were rare. Four out of 5 visitors (79%) received only 1 vaccination, mainly for hepatitis A. Travellers to Thailand more often sought travel health advice compared to travellers to Turkey, despite the fact that the 2 destinations were almost equally distributed among travellers from Umeå. We found differences between men and women in money spent on vaccines and in particular in vaccination against Japanese encephalitis. CONCLUSIONS: To assess the optimal vaccination level at a travel medicine clinic is difficult. Decisions are affected by general recommendations and the risk perception of the travel medicine practitioner, as well as the risk perception of the traveller. The sex difference found in this study might be due to gender differences in risk perception and should be further investigated.

  • 18.
    Angelin, Martin
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Evengård, Birgitta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Palmgren, Helena
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Travel health advice: Benefits, compliance, and outcome2014In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 46, no 6, p. 447-453Article in journal (Refereed)
    Abstract [en]

    Background: Travel health advice is an important and difficult part of a pre-travel consultation. The aim of this study was to determine whether the travel health advice given is followed by the traveller and whether it affects disease and injury experienced during travel. Methods: A prospective survey study was carried out from October 2009 to April 2012 at the Travel Medicine Clinic of the Department of Infectious Diseases, Umea University Hospital, Umea, Sweden. The Travel Medicine Clinic in Umea is the largest travel clinic in northern Sweden. Results: We included 1277 individuals in the study; 1059 (83%) responded to the post-travel questionnaire. Most visitors (88%) remembered having received travel health advice; among these, 95% found some of the health advice useful. Two-thirds (67%) claimed to have followed the advice, but fell ill during travel to the same extent as those who did not. Younger travellers (< 31 y) found our travel health advice less beneficial, were less compliant with the advice, took more risks during travel, and fell ill during travel to a greater extent than older travellers. Conclusions: Helping travellers stay healthy during travel is the main goal of travel medicine. Younger travellers are a risk group for illness during travel and there is a need to find new methods to help them avoid illness. Travellers find travel health advice useful, but it does not protect them from travel-related illness. Factors not easily influenced by the traveller play a role, but a comprehensive analysis of the benefits of travel health advice is needed.

  • 19.
    Angelin, Martin
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Forsell, Joakim
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Granlund, Margareta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Evengård, Birgitta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Palmgren, Helena
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Risk factors for colonization with extended-spectrum beta-lactamase producing Enterobacteriaceae in healthcare students on clinical assignment abroad: A prospective study2015In: Travel Medicine and Infectious Disease, ISSN 1477-8939, E-ISSN 1873-0442, Vol. 13, no 3, p. 223-229Article in journal (Refereed)
    Abstract [en]

    Background: The increase of antibiotic resistance in clinically important bacteria is a worldwide threat, especially in healthcare environments. International travel is a risk factor for gut colonization with extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE). The risk for healthcare students of being colonized with ESBL-PE when participating in patient-related work abroad has not been previously investigated. Methods: Swedish healthcare students travelling for pre-clinical and clinical courses outside Scandinavia submitted faecal samples and survey data before and after travel. The faecal samples were screened for ESBL-PE and carbapenemase-producing Enterobacteriaceae (CPE). Screening results and survey data were analysed to identify risk factors for colonization. Results: In the 99 subjects who submitted a full set of samples, 35% were colonized with a new ESBL-PE strain during travel. No CPE was found. The most important risk factor for ESBL-PE colonization was travel destination, and the highest colonization rate was found in the South East Asia region. Antibiotic treatment during travel was an independent risk factor for ESBL-PE colonization but patient-related work was not significantly associated with an increased risk. Conclusions: Patient-related work abroad was not a risk factor for ESBL-PE suggesting that transmission from patients is uncommon. Pre-travel advice on avoiding unnecessary antibiotic treatment during travel is recommended.

  • 20.
    Antti, Henrik
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Fahlgren, Anna
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Näsström, Elin
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Kouremenos, Konstantinos
    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).
    Sundén-Cullberg, Jonas
    Guo, Yongzhi
    Moritz, Thomas
    Wolf-Watz, Hans
    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).
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Fällman, Maria
    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).
    Metabolic profiling for detection of staphylococcus aureus infection and antibiotic resistance2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 2, article id e56971Article in journal (Refereed)
    Abstract [en]

    Due to slow diagnostics, physicians must optimize antibiotic therapies based on clinical evaluation of patients without specific information on causative bacteria. We have investigated metabolomic analysis of blood for the detection of acute bacterial infection and early differentiation between ineffective and effective antibiotic treatment. A vital and timely therapeutic difficulty was thereby addressed: the ability to rapidly detect treatment failures because of antibiotic-resistant bacteria. Methicillin-resistant (MRSA) and methicillin-sensitive (MSSA) were used and for infecting mice, while natural MSSA infection was studied in humans. Samples of bacterial growth media, the blood of infected mice and of humans were analyzed with combined Gas Chromatography/Mass Spectrometry. Multivariate data analysis was used to reveal the metabolic profiles of infection and the responses to different antibiotic treatments. experiments resulted in the detection of 256 putative metabolites and mice infection experiments resulted in the detection of 474 putative metabolites. Importantly, ineffective and effective antibiotic treatments were differentiated already two hours after treatment start in both experimental systems. That is, the ineffective treatment of MRSA using cloxacillin and untreated controls produced one metabolic profile while all effective treatment combinations using cloxacillin or vancomycin for MSSA or MRSA produced another profile. For further evaluation of the concept, blood samples of humans admitted to intensive care with severe sepsis were analyzed. One hundred thirty-three putative metabolites differentiated severe MSSA sepsis (n = 6) from severe sepsis (n = 10) and identified treatment responses over time. Combined analysis of human, , and mice samples identified 25 metabolites indicative of effective treatment of sepsis. Taken together, this study provides a proof of concept of the utility of analyzing metabolite patterns in blood for early differentiation between ineffective and effective antibiotic treatment in acute infections.

  • 21. Aoki, Koki
    et al.
    Benkö, Mária
    Davison, Andrew J
    De Jong, Jan C
    Echavarria, Marcela
    Erdman, Dean D
    Harrach, Balázs
    Kajon, Adriana E
    Schnurr, David
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Towards an integrated human adenovirus designation system that utilizes molecular and serological data and serves both clinical and fundamental virology2011In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 85, no 11, p. 5703-5704Article in journal (Refereed)
  • 22.
    Arvidsson, Malin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Five-year follow-up after the outbreak of Cryptosporidium hominis in Östersund2018Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 23. Asghar, Naveed
    et al.
    Lee, Yi-Ping
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Nilsson, Emma
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Lindqvist, Richard
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Melik, Wessam
    Kröger, Andrea
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Johansson, Magnus
    The role of the poly(A) tract in the replication and virulence of tick-borne encephalitis virus2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 39265Article in journal (Refereed)
    Abstract [en]

    The tick-borne encephalitis virus (TBEV) is a flavivirus transmitted to humans, usually via tick bites. The virus causes tick-borne encephalitis (TBE) in humans, and symptoms range from mild flu-like symptoms to severe and long-lasting sequelae, including permanent brain damage. It has been suggested that within the population of viruses transmitted to the mammalian host, quasispecies with neurotropic properties might become dominant in the host resulting in neurological symptoms. We previously demonstrated the existence of TBEV variants with variable poly(A) tracts within a single blood-fed tick. To characterize the role of the poly(A) tract in TBEV replication and virulence, we generated infectious clones of Toro-2003 with the wild-type (A)(3)C(A)(6) sequence (Toro-6A) or with a modified (A)(3)C(A)(38) sequence (Toro-38A). Toro-38A replicated poorly compared to Toro-6A in cell culture, but Toro-38A was more virulent than Toro-6A in a mouse model of TBE. Next-generation sequencing of TBEV genomes after passaging in cell culture and/or mouse brain revealed mutations in specific genomic regions and the presence of quasispecies that might contribute to the observed differences in virulence. These data suggest a role for quasispecies development within the poly(A) tract as a virulence determinant for TBEV in mice.

  • 24. Asghar, Naveed
    et al.
    Lindblom, Pontus
    Melik, Wessam
    Lindqvist, Richard
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Haglund, Mats
    Forsberg, Pia
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Andreassen, Åshild
    Lindgren, Per-Eric
    Johansson, Magnus
    Tick-borne encephalitis virus sequenced directly from questing and blood-feeding ticks reveals quasispecies variance2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 7, p. e103264-Article in journal (Refereed)
    Abstract [en]

    The increased distribution of the tick-borne encephalitis virus (TBEV) in Scandinavia highlights the importance of characterizing novel sequences within the natural foci. In this study, two TBEV strains: the Norwegian Mandal 2009 (questing nymphs pool) and the Swedish Saringe 2009 (blood-fed nymph) were sequenced and phylogenetically characterized. Interestingly, the sequence of Mandal 2009 revealed the shorter form of the TBEV genome, similar to the highly virulent Hypr strain, within the 3' non-coding region (3'NCR). A different genomic structure was found in the 3'NCR of Saringe 2009, as in-depth analysis demonstrated TBEV variants with different lengths within the poly(A) tract. This shows that TBEV quasispecies exists in nature and indicates a putative shift in the quasispecies pool when the virus switches between invertebrate and vertebrate environments. This prompted us to further sequence and analyze the 3'NCRs of additional Scandinavian TBEV strains and control strains, Hypr and Neudoerfl. Toro 2003 and Habo 2011 contained mainly a short (A) 3C(A)6 poly(A) tract. A similar pattern was observed for the human TBEV isolates 1993/783 and 1991/4944; however, one clone of 1991/4944 contained an (A) 3C(A)11 poly(A) sequence, demonstrating that quasispecies with longer poly(A) could be present in human isolates. Neudoerfl has previously been reported to contain a poly(A) region, but to our surprise the resequenced genome contained two major quasispecies variants, both lacking the poly(A) tract. We speculate that the observed differences are important factors for the understanding of virulence, spread, and control of the TBEV.

  • 25. Baharom, Faezzah
    et al.
    Rankin, Gregory
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Scholz, Saskia
    Pourazar, Jamshid
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Smed-Sörensen, Anna
    Human lung dendritic cells: spatial distribution and phenotypic identification in endobronchial biopsies using immunohistochemistry and flow cytometry2017In: Jove-journal pf visualized experiments, ISSN 1940-087X, no 119, article id e55222Article in journal (Refereed)
    Abstract [en]

    The lungs are constantly exposed to the external environment, which in addition to harmless particles, also contains pathogens, allergens, and toxins. In order to maintain tolerance or to induce an immune response, the immune system must appropriately handle inhaled antigens. Lung dendritic cells (DCs) are essential in maintaining a delicate balance to initiate immunity when required without causing collateral damage to the lungs due to an exaggerated inflammatory response. While there is a detailed understanding of the phenotype and function of immune cells such as DCs in human blood, the knowledge of these cells in less accessible tissues, such as the lungs, is much more limited, since studies of human lung tissue samples, especially from healthy individuals, are scarce. This work presents a strategy to generate detailed spatial and phenotypic characterization of lung tissue resident DCs in healthy humans that undergo a bronchoscopy for the sampling of endobronchial biopsies. Several small biopsies can be collected from each individual and can be subsequently embedded for ultrafine sectioning or enzymatically digested for advanced flow cytometric analysis. The outlined protocols have been optimized to yield maximum information from small tissue samples that, under steady-state conditions, contain only a low frequency of DCs. While the present work focuses on DCs, the methods described can directly be expanded to include other (immune) cells of interest found in mucosal lung tissue. Furthermore, the protocols are also directly applicable to samples obtained from patients suffering from pulmonary diseases where bronchoscopy is part of establishing the diagnosis, such as chronic obstructive pulmonary disease (COPD), sarcoidosis, or lung cancer.

  • 26.
    Bailey, Leslie
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Engström, Patrik
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Nordström, Anna
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Rehabilitation Medicine. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Nordström, Peter
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Chlamydia pneumoniae infection results in generalized bone loss in mice2008In: Microbes and infection, ISSN 1286-4579, E-ISSN 1769-714X, Vol. 10, no 10-11, p. 1175-1181Article in journal (Refereed)
  • 27. Balasingam, Shobana
    et al.
    Wilder-Smith, Annelies
    Lee Kong Chian School of Medicine, Nanyang Technology University, Singapore 308232, Singapore.
    Randomized controlled trials for influenza drugs and vaccines: a review of controlled human infection studies2016In: International Journal of Infectious Diseases, ISSN 1201-9712, E-ISSN 1878-3511, Vol. 49, p. 18-29Article, review/survey (Refereed)
    Abstract [en]

    OBJECTIVES: Controlled human infection, the intentional infection of healthy volunteers, allows disease pathogenesis to be studied and vaccines and therapeutic interventions to be evaluated in a controlled setting. A systematic review of randomized controlled trials of countermeasures for influenza that used the experimental human infection platform was performed. The primary objective was to document the scope of trials performed to date and the main efficacy outcome in the trials. The secondary objective was to assess safety and identify serious adverse events.

    METHODS: The PubMed database was searched for randomized controlled influenza human challenge studies with predetermined search terms. Review papers, papers without outcomes, community-acquired infections, duplicated data, pathogenesis studies, and observational studies were excluded.

    RESULTS: Twenty-six randomized controlled trials published between 1947 and 2014 fit the study inclusion criteria. Two-thirds of these trials investigated antivirals and one-third investigated influenza vaccines. Among 2462 subjects inoculated with influenza virus, the incidence of serious adverse events was low (0.04%). These challenge studies helped to down-select three antivirals and one vaccine that were subsequently approved by the US Food and Drug Administration (FDA).

    CONCLUSIONS: Controlled human infection studies are an important research tool in assessing promising influenza vaccines and antivirals. These studies are performed quickly and are cost-effective and safe, with a low incidence of serious adverse events.

  • 28. Banse, Pia
    et al.
    Moeller, Rebecca
    Bruening, Janina
    Lasswitz, Lisa
    Kahl, Sina
    Khan, Abdul G
    Marcotrigiano, Joseph
    Pietschmann, Thomas
    Gerold, Gisa
    Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, 30625 Hannover, Germany.
    CD81 receptor regions outside the large extracellular loop determine hepatitis C virus entry into hepatoma cells2018In: Viruses, ISSN 1999-4915, E-ISSN 1999-4915, Vol. 10, no 4, article id 207Article in journal (Refereed)
    Abstract [en]

    Hepatitis C virus (HCV) enters human hepatocytes using four essential entry factors, one of which is human CD81 (hCD81). The tetraspanin hCD81 contains a large extracellular loop (LEL), which interacts with the E2 glycoprotein of HCV. The role of the non-LEL regions of hCD81 (intracellular tails, four transmembrane domains, small extracellular loop and intracellular loop) is poorly understood. Here, we studied the contribution of these domains to HCV susceptibility of hepatoma cells by generating chimeras of related tetraspanins with the hCD81 LEL. Our results show that non-LEL regions in addition to the LEL determine susceptibility of cells to HCV. While closely related tetraspanins (X. tropicalis CD81 and D. rerio CD81) functionally complement hCD81 non-LEL regions, distantly related tetraspanins (C. elegans TSP9 amd D. melanogaster TSP96F) do not and tetraspanins with intermediate homology (hCD9) show an intermediate phenotype. Tetraspanin homology and susceptibility to HCV correlate positively. For some chimeras, infectivity correlates with surface expression. In contrast, the hCD9 chimera is fully surface expressed, binds HCV E2 glycoprotein but is impaired in HCV receptor function. We demonstrate that a cholesterol-coordinating glutamate residue in CD81, which hCD9 lacks, promotes HCV infection. This work highlights the hCD81 non-LEL regions as additional HCV susceptibility-determining factors.

  • 29.
    Baudin, Maria
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Rift Valley fever: consequences of virus-host interactions2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Rift Valley fever virus (RVFV) is a mosquito-borne virus which has the ability to infect a large variety of animals including humans in Africa and Arabian Peninsula. The abortion rate among these animals are close to 100%, and young animals develop severe disease which often are lethal.

    In humans, Rift Valley fever (RVF) presents in most cases as a mild illness with influenza-like symptoms. However, in about 8% of the cases it progresses into a more severe disease with a high case fatality rate. Since there is such a high abortion rate among infected animals, a link between human miscarriage and RVFV has been suggested, but never proven.

    We could in paper I for the first time show an association between acute RVFV infection and miscarriage in humans. We observed an increase in pregnant women arriving at the Port Sudan Hospital with fever of unknown origin, and several of the patients experienced miscarriage. When we analysed their blood samples for several viral diseases we found that many had an acute RVFV infection and of these, 54% experienced a miscarriage. The odds of having a miscarriage was 7 times higher for RVFV patients compared to the RVFV negative women of which only 12% miscarried. These results indicated that RVFV infection could be a contributing factor to miscarriage.

    RVFV is an enveloped virus containing the viral glycoproteins n and c (Gn and Gc respectively), where Gn most likely is responsible for the initial cellular contact. The protein DC-SIGN on dendritic cells and the glycosaminoglycan heparan sulfate has been suggested as cellular receptors for RVFV, however other mechanisms are probably also involved in binding and entry. Charge is a driving force for molecular interaction and has been shown to be important for cellular attachment of several viruses, and in paper II we could show that when the charge around the cells was altered, the infection was affected. We also showed that Gn most likely has a positive charge at a physiological pH.

    When we added negatively charged molecules to the viral particles before infection, we observed a decreased infection efficiency, which we also observed after removal of carbohydrate structures from the cell surface.

    Our results suggested that the cellular interaction partner for initial attachment is a negatively charged carbohydrate. Further investigations into the mechanisms of RVFV cellular interactions has to be undertaken in order to understand, and ultimately prevent, infection and disease.

    There is currently no vaccine approved for human use and no specific treatments for RVF, so there is a great need for developing safe effective drugs targeting this virus. We designed a whole-cell based high-throughput screen (HTS) assay which we used to screen libraries of small molecular compounds for anti-RVFV properties. After dose-response and toxicity analysis of the initial hits, we identified six safe and effective inhibitors of RVFV infection that with further testing could become drug candidates for treatment of RVF. This study demonstrated the application of HTS using a whole-cell virus replication reporter gene assay as an effective method to identify novel compounds with potential antiviral activity against RVFV.

  • 30.
    Baudin, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Jumaa, Ammar M.
    Jomma, Huda J. E.
    Karsany, Mubarak S.
    Bucht, Göran
    Näslund, Jonas
    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.
    Mohamed, Nahla
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Association of Rift Valley fever virus infection with miscarriage in Sudanese women: a cross-sectional study2016In: The Lancet Global Health, E-ISSN 2214-109X, Vol. 4, no 11, p. e864-e871Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Rift Valley fever virus is an emerging mosquito-borne virus that causes infections in animals and human beings in Africa and the Arabian Peninsula. Outbreaks of Rift Valley fever lead to mass abortions in livestock, but such abortions have not been identified in human bezings. Our aim was to investigate the cause of miscarriages in febrile pregnant women in an area endemic for Rift Valley fever.

    METHODS: Pregnant women with fever of unknown origin who attended the governmental hospital of Port Sudan, Sudan, between June 30, 2011, and Nov 17, 2012, were sampled at admission and included in this cross-sectional study. Medical records were retrieved and haematological tests were done on patient samples. Presence of viral RNA as well as antibodies against a variety of viruses were analysed. Any association of viral infections, symptoms, and laboratory parameters to pregnancy outcome was investigated using Pearson's χ(2) test.

    FINDINGS: Of 130 pregnant women with febrile disease, 28 were infected with Rift Valley fever virus and 31 with chikungunya virus, with typical clinical and laboratory findings for the infection in question. 15 (54%) of 28 women with an acute Rift Valley fever virus infection had miscarriages compared with 12 (12%) of 102 women negative for Rift Valley fever virus (p<0·0001). In a multiple logistic regression analysis, adjusting for age, haemorrhagic disease, and chikungunya virus infection, an acute Rift Valley fever virus infection was an independent predictor of having a miscarriage (odds ratio 7·4, 95% CI 2·7-20·1; p<0·0001).

    INTERPRETATION: This study is the first to show an association between infection with Rift Valley fever virus and miscarriage in pregnant women. Further studies are warranted to investigate the possible mechanisms. Our findings have implications for implementation of preventive measures, and evidence-based information to the public in endemic countries should be strongly recommended during Rift Valley fever outbreaks.

    FUNDING: Schlumberger Faculty for the Future, CRDF Global (31141), the Swedish International Development Cooperation Agency, the County Council of Västerbotten, and the Faculty of Medicine, Umeå University.

  • 31.
    Bergstedt Oscarsson, Kristina
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Brorstad, Alette
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Baudin, Maria
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Lindberg, Anne
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Forssén, Annika
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Eriksson, Marie
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Human Puumala hantavirus infection in northern Sweden: increased seroprevalence and association to risk and health factors2016In: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 16, article id 566Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The rodent borne Puumala hantavirus (PUUV) causes haemorrhagic fever with renal syndrome in central and northern Europe. The number of cases has increased and northern Sweden has experienced large outbreaks in 1998 and 2006-2007 which raised questions regarding the level of immunity in the human population.

    METHODS: A randomly selected population aged between 25 and 74 years from northern Sweden were invited during 2009 to participate in a WHO project for monitoring of trends and determinants in cardiovascular disease. Health and risk factors were evaluated and sera from 1,600 participants were available for analysis for specific PUUV IgG antibodies using a recombinant PUUV nucleocapsid protein ELISA.

    RESULTS: The overall seroprevalence in the investigated population was 13.4 %, which is a 50 % increase compared to a similar study only two decades previously. The prevalence of PUUV IgG increased with age, and among 65-75 years it was 22 %. More men (15.3 %) than women (11.4 %) were seropositive (p < 0.05). The identified risk factors were smoking (OR = 1.67), living in rural areas (OR = 1.92), and owning farmland or forest (OR = 2.44). No associations were found between previous PUUV exposure and chronic lung disease, diabetes, hypertension, renal dysfunction, stroke or myocardial infarction.

    CONCLUSIONS: PUUV is a common infection in northern Sweden and there is a high life time risk to acquire PUUV infection in endemic areas. Certain risk factors as living in rural areas and smoking were identified. Groups with increased risk should be targeted for future vaccination when available, and should also be informed about appropriate protection from rodent secreta.

  • 32.
    Bergstedt-Oskarsson, Kristina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Brorstad, Alette
    Baudin, Maria
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Lindberg, Anne
    Forssén, Annika
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    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.
    Seroepidemiology, comorbidity and riskfactors for Puumula hantavirus in a highly endemic area of Sweden2011Conference paper (Other academic)
  • 33.
    Binesse, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Lindgren, Helena
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Lindgren, Lena
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Conlan, Wayne
    Sjöstedt, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Roles of Reactive Oxygen Species-Degrading Enzymes of Francisella tularensis SCHU S42015In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 83, no 6, p. 2255-2263Article in journal (Refereed)
    Abstract [en]

    Francisella tularensis is a facultative intracellular bacterium utilizing macrophages as its primary intracellular habitat and is therefore highly capable of resisting the effects of reactive oxygen species (ROS), potent mediators of the bactericidal activity of macrophages. We investigated the roles of enzymes presumed to be important for protection against ROS. Four mutants of the highly virulent SCHU S4 strain with deletions of the genes encoding catalase (katG), glutathione peroxidase (gpx), a DyP-type peroxidase (FTT0086), or double deletion of FTT0086 and katG showed much increased susceptibility to hydrogen peroxide (H2O2) and slightly increased susceptibility to paraquat but not to peroxynitrite (ONOO-) and displayed intact intramacrophage replication. Nevertheless, mice infected with the double deletion mutant showed significantly longer survival than SCHU S4-infected mice. Unlike the aforementioned mutants, deletion of the gene coding for alkyl-hydroperoxide reductase subunit C (ahpC) generated a mutant much more susceptible to paraquat and ONOO- but not to H2O2. It showed intact replication in J774 cells but impaired replication in bone marrow-derived macrophages and in internal organs of mice. The live vaccine strain, LVS, is more susceptible than virulent strains to ROS-mediated killing and possesses a truncated form of FTT0086. Expression of the SCHU S4 FTT0086 gene rendered LVS more resistant to H2O2, which demonstrates that the SCHU S4 strain possesses additional detoxifying mechanisms. Collectively, the results demonstrate that SCHU S4 ROS-detoxifying enzymes have overlapping functions, and therefore, deletion of one or the other does not critically impair the intracellular replication or virulence, although AhpC appears to have a unique function.

  • 34. Birdsell, D. N.
    et al.
    Özsürekci, Y.
    Rawat, A.
    Aycan, A. E.
    Mitchell, C. L.
    Sahl, J. W.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Colman, R. E.
    Schupp, J. M.
    Ceyhan, M.
    Keim, P. S.
    Wagner, D. M.
    Coinfections identified from metagenomic analysis of cervical lymph nodes from tularemia patients2018In: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 18, article id 319Article in journal (Refereed)
    Abstract [en]

    Background: Underlying coinfections may complicate infectious disease states but commonly go unnoticed because an a priori clinical suspicion is usually required so they can be detected via targeted diagnostic tools. Shotgun metagenomics is a broad diagnostic tool that can be useful for identifying multiple microbes simultaneously especially if coupled with lymph node aspirates, a clinical matrix known to house disparate pathogens. The objective of this study was to analyze the utility of this unconventional diagnostic approach (shotgun metagenomics) using clinical samples from human tularemia cases as a test model. Tularemia, caused by the bacterium Francisella tularensis, is an emerging infectious disease in Turkey. This disease commonly manifests as swelling of the lymph nodes nearest to the entry of infection. Because swollen cervical nodes are observed from many different types of human infections we used these clinical sample types to analyze the utility of shotgun metagenomics.

    Methods: We conducted an unbiased molecular survey using shotgun metagenomics sequencing of DNA extracts from fine-needle aspirates of neck lymph nodes from eight tularemia patients who displayed protracted symptoms. The resulting metagenomics data were searched for microbial sequences (bacterial and viral).

    Results: F. tularensis sequences were detected in all samples. In addition, we detected DNA of other known pathogens in three patients. Both Hepatitis B virus (HBV) and Human Parvovirus B-19 were detected in one individual and Human Parvovirus B-19 alone was detected in two other individuals. Subsequent PCR coupled with Sanger sequencing verified the metagenomics results. The HBV status was independently confirmed via serological diagnostics, despite evading notice during the initial assessment.

    Conclusion: Our data highlight that shotgun metagenomics of fine-needle lymph node aspirates is a promising clinical diagnostic strategy to identify coinfections. Given the feasibility of the diagnostic approach demonstrated here, further steps to promote integration of this type of diagnostic capability into mainstream clinical practice are warranted.

  • 35. Björkström, Niklas K
    et al.
    Lindgren, Therese
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Stoltz, Malin
    Fauriat, Cyril
    Braun, Monika
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Michaëlsson, Jakob
    Malmberg, Karl-Johan
    Klingström, Jonas
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Ljunggren, Hans-Gustaf
    Rapid expansion and long-term persistence of elevated NK cell numbers in humans infected with hantavirus2011In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 208, no 1, p. 13-21Article in journal (Refereed)
    Abstract [en]

    Natural killer (NK) cells are known to mount a rapid response to several virus infections. In experimental models of acute viral infection, this response has been characterized by prompt NK cell activation and expansion followed by rapid contraction. In contrast to experimental model systems, much less is known about NK cell responses to acute viral infections in humans. We demonstrate that NK cells can rapidly expand and persist at highly elevated levels for >60 d after human hantavirus infection. A large part of the expanding NK cells expressed the activating receptor NKG2C and were functional in terms of expressing a licensing inhibitory killer cell immunoglobulin-like receptor (KIR) and ability to respond to target cell stimulation. These results demonstrate that NK cells can expand and remain elevated in numbers for a prolonged period of time in humans after a virus infection. In time, this response extends far beyond what is considered normal for an innate immune response.

  • 36.
    Boman, Jens
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Lindqvist, Helena
    Forsberg, Lars
    Janlert, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Granåsen, Gabriel
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Nylander, Elisabet
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Brief manual-based single-session Motivational Interviewing for reducing high-risk sexual behaviour in women: an evaluation2018In: International Journal of STD and AIDS (London), ISSN 0956-4624, E-ISSN 1758-1052, Vol. 29, no 4, p. 396-403Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to develop and evaluate brief Motivational Interviewing (MI) to facilitate behaviour change in women at high risk of contracting sexually transmitted infections (STIs). One hundred and seventy-three women (mean age 24.7) at high risk of contracting STIs were randomized to a brief risk-reducing MI counselling intervention (n = 74) or assigned to the control group (n = 99). MI skill was assessed using the Motivational Interviewing Treatment Integrity (MITI) Coding System. Seventeen of 74 (23%) women tested for Chlamydia trachomatis (CT) in the MI intervention group and 22 of 99 (22%) in the control group had a genital CT infection 0-24 months before baseline. All additional CT testing was monitored up to 24 months for all 173 women in the study. None of the 49 CT-retested women in the MI group was CT infected, as compared to 3 of 72 (4%) women in the control group. A generalized estimating equations model with sexual high-risk behaviour measured at baseline and at six-month follow-up produced an adjusted estimated odds ratio of 0.38 (95% confidence interval = 0.158, 0.909), indicating efficacy. Brief manual-based single-session MI counselling seems to be effective in reducing high-risk sexual behaviour in women at high risk of acquiring STIs.

  • 37. Boman, Jens
    et al.
    Schneede, Jörn
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Nylander, Elisabet
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Genitala klamydiainfektioner: rekommenderad handläggning2011In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 108, no 13, p. 730-733Article in journal (Refereed)
    Abstract [sv]

    Klamydia är den vanligaste anmälningspliktiga infektionen i Sverige: 37 791 fall rapporterades till Smittskyddsinstitutet år 2009, och 87 procent av de smittade var i åldern 15–29 år.

    Klamydiainfektion är klassad som allmänfarlig sjukdom enligt smittskyddslagen, vilket bl a innebär att en läkare som misstänker att en patient bär på smitta är skyldig att se till att patienten lämnar prov, och vid positivt provresultat se till att förhållningsregler ges samt att smittskyddsanmälan och smittspårning görs.

    Provtagning görs vanligen med urinprov hos män och med självtaget vaginalprov hos kvinnor, eventuellt kombinerat med urinprov.

    Majoriteten av personer med klamydia har subkliniska infektioner men kan ändå få bestående reproduktiva skador och föra smittan vidare. Ungefär var tionde kvinna med obehandlad klamydiainfektion utvecklar klinisk salpingit inom en tolvmånadersperiod. Klamydiaorsakad salpingit ökar risken för utomkvedshavandeskap och nedsatt fertilitet.

    Okomplicerad genital klamydiainfektion behandlas i Sverige med doxycyklin, vanligen i lägre dosering än i många andra länder. Det är därför viktigt att se till att hela kuren tas enligt anvisningarna och att patienten informeras om att samtidigt intag av vissa läkemedel, spårämnen och födoämnen liksom alkohol kan resultera i suboptimal antibiotikaeffekt.

  • 38. Bonnedahl, J
    et al.
    Drobni, P
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Hernandez, J
    Melhus, A
    Stedt, J
    Olsen, B
    Drobni, M
    Characterization, and comparison, of human clinical and black-headed gull (Larus ridibundus) extended-spectrum beta-lactamase-producing bacterial isolates from Kalmar, on the southeast coast of Sweden2010In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 65, no 9, p. 1939-1944Article in journal (Refereed)
    Abstract [en]

    The finding of CTX-M-type ESBLs in E. coli isolated from black-headed gulls in Sweden, where 'background resistance' is low, is consistent with an ongoing environmental spread of these plasmid-borne resistance genes. The results indicate that a potential for transfer between the human population and environment exists even in countries with a low level of antibiotic resistance.

  • 39.
    Bonnedahl, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Palmgren, Helena
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Hernandez, Jorge
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Waldenström, Jonas
    Naturvetenskapliga institutionen, Högskolan i Kalmar.
    Olsen, Björn
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Salmonella in migrating birds - myth or reality?Manuscript (preprint) (Other academic)
  • 40. Booth, Malcolm G
    et al.
    Hood, John
    Brooks, Timothy J G
    Hart, Andrew
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Glasgow Royal Infirmary, Glasgow, UK; Centre for Cell Engineering, Faculty for Biological & Life Sciences, University of Glasgow, Hillhead, Glasgow, UK.
    Anthrax infection in drug users2010In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 375, no 9723, p. 1345-1346Article in journal (Refereed)
  • 41.
    Bowman, Leigh
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR), Geneva, Switzerland.
    Rocklöv, Joacim
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Kroeger, Axel
    Olliaro, Piero
    Skewes, Ronald
    A comparison of Zika and dengue outbreaks using national surveillance data in the Dominican Republic2018In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 12, no 11, article id e0006876Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Aedes-borne arboviruses continue to precipitate epidemics worldwide. In Dominican Republic, the appearance of Zika virus cases that closely followed a large dengue epidemic provided an opportunity to study the different transmission drivers behind these two flaviviruses. Retrospective datasets were used to collect information on the populations at risk and descriptive statistics were used to describe the outbreaks on a national scale.

    METHODOLOGY/ PRINCIPAL FINDINGS: Expectedly, box plots showed that 75% of dengue was reported in those aged <20 years while Zika infections were more widely dispersed among the population. Dengue attack rates were marginally higher among males at 25.9 per 10,000 population vs. 21.5 per 10,000 population for females. Zika infections appeared to be highly clustered among females (73.8% (95% CI 72.6%, 75.0%; p<0.05)); age-adjusted Zika attack rates among females were 7.64 per 10,000 population compared with 2.72 per 10,000 population among males. R0 calculations stratified by sex also showed a significantly higher metric among females: 1.84 (1.82, 1.87; p<0.05) when compared to males at 1.72 (1.69, 1.75; p<0.05). However, GBS attack rates stratified by sex revealed slightly higher risk in males vs. females, at 0.62 and 0.57 per 10,000 population respectively.

    CONCLUSIONS/ SIGNIFICANCE: Evidence suggests little impact of existing dengue immunity on reported attack rates of Zika at the population level. Confounding of R0 and incident risk calculations by sex-specific over-reporting can alter the reliability of epidemiological metrics, which could be addressed using associated proxy syndromes or conditions to explore seemingly sex-skewed incidence. The findings indicate that community awareness campaigns, through influencing short-term health seeking behaviour, remain the most plausible mechanism behind increased reporting among women of reproductive age, although biological susceptibility cannot yet be ruled out. Media campaigns and screening are therefore recommended for women of reproductive age during Zika outbreaks. Future research should focus on clinical Zika outcomes among dengue seropositive individuals.

  • 42. Braun, Monika
    et al.
    Bjorkström, Niklas K.
    Gupta, Shawon
    Sundström, Karin
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Klingström, Jonas
    Ljunggren, Hans-Gustaf
    NK Cell Activation in Human Hantavirus Infection Explained by Virus-Induced IL-15/IL15R alpha Expression2014In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 10, no 11, p. e1004521-Article in journal (Refereed)
    Abstract [en]

    Clinical infection with hantaviruses cause two severe acute diseases, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). These diseases are characterized by strong immune activation, increased vascular permeability, and up to 50% case-fatality rates. One prominent feature observed in clinical hantavirus infection is rapid expansion of natural killer (NK) cells in peripheral blood of affected individuals. We here describe an unusually high state of activation of such expanding NK cells in the acute phase of clinical Puumala hantavirus infection. Expanding NK cells expressed markedly increased levels of activating NK cell receptors and cytotoxic effector molecules. In search for possible mechanisms behind this NK cell activation, we observed virus-induced IL-15 and IL-15R alpha on infected endothelial and epithelial cells. Hantavirus-infected cells were shown to strongly activate NK cells in a cell-cell contact-dependent way, and this response was blocked with anti-IL-15 antibodies. Surprisingly, the strength of the IL-15-dependent NK cell response was such that it led to killing of uninfected endothelial cells despite expression of normal levels of HLA class I. In contrast, hantavirus-infected cells were resistant to NK cell lysis, due to a combination of virus-induced increase in HLA class I expression levels and hantavirus-mediated inhibition of apoptosis induction. In summary, we here describe a possible mechanism explaining the massive NK cell activation and proliferation observed in HFRS patients caused by Puumala hantavirus infection. The results add further insights into mechanisms behind the immunopathogenesis of hantavirus infections in humans and identify new possible targets for intervention.

  • 43. Bronner, Ulf
    et al.
    Karlsson, Lillemor
    Evengård, Birgitta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Evaluation of rapid diagnostic tests for malaria in Swedish travellers2011In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 119, no 2, p. 88-92Article in journal (Refereed)
    Abstract [en]

    Rapid diagnostic tests (RDTs) for malaria have become valuable tools for the diagnosis of malaria in both endemic and non-endemic areas. During a 7-year period, first the MalaQuick rapid test and then the NOW Malaria test, were evaluated by well-trained laboratory technicians in a university hospital laboratory of parasitology. A total of 635 blood samples were selected from 4731 blood specimens obtained from travellers at the emergency department, at wards and at out-patient clinics. The samples were analysed by microscopy and RDT. Malaria parasites were detected in the blood films of 134 (21%) samples. The sensitivity of the RDT for Plasmodium falciparum was 97.7% (84 of 86 samples) with a negative predictive value of 99.6%. The two false-negative results were associated with low levels of parasitaemia. For non-falciparum species the sensitivity was only 58.3% (28 of 48 samples). Based on the excellent ability of the RDTs to detect P. falciparum infections, we recommend the use of the NOW Malaria test as a complement to microscopy in the laboratory.

  • 44. Bronner, Ulf
    et al.
    Karlsson, Lillemor
    Evengård, Birgitta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    [Rapid malaria tests--good complement to microscopy. High sensitivity for Plasmodium falciparum in Swedish travellers]2011In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 108, no 42, p. 2087-2089Article in journal (Refereed)
  • 45. Browall, Sarah
    et al.
    Norman, Martin
    Tångrot, Jeanette
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Bioinformatics Infrastructure for Life Sciences, Computational Life Science Cluster.
    Galanis, Ilias
    Sjöstrom, Karin
    Dagerhamn, Jessica
    Hellberg, Christel
    Pathak, Anuj
    Spadafina, Tiziana
    Sandgren, Andreas
    Bättig, Patrick
    Franzén, Oscar
    Andersson, Björn
    Örtqvist, Åke
    Normark, Staffan
    Henriques-Normark, Birgitta
    Intraclonal Variations Among Streptococcus pneumoniae Isolates Influence the Likelihood of Invasive Disease in Children2014In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 209, no 3, p. 377-388Article in journal (Refereed)
    Abstract [en]

    Background. Pneumococcal serotypes are represented by a varying number of clonal lineages with different genetic contents, potentially affecting invasiveness. However, genetic variation within the same genetic lineage may be larger than anticipated. Methods. A total of 715 invasive and carriage isolates from children in the same region and during the same period were compared using pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing. Bacterial genome sequencing, functional assays, and in vivo virulence mice studies were performed. Results. Clonal types of the same serotype but also intraclonal variants within clonal complexes (CCs) showed differences in invasive-disease potential. CC138, a common CC, was divided into several PFGE patterns, partly explained by number, location, and type of temperate bacteriophages. Whole-genome sequencing of 4 CC138 isolates representing PFGE clones with different invasive-disease potentials revealed intraclonal sequence variations of the virulence-associated proteins pneumococcal surface protein A (PspA) and pneumococcal choline-binding protein C (PspC). A carrier isolate lacking PcpA exhibited decreased virulence in mice, and there was a differential binding of human factor H, depending on invasiveness. Conclusions. Pneumococcal clonal types but also intraclonal variants exhibited different invasive-disease potentials in children. Intraclonal variants, reflecting different prophage contents, showed differences in major surface antigens. This suggests ongoing immune selection, such as that due to PspC-mediated complement resistance through varied human factor H binding, that may affect invasiveness in children.

  • 46.
    Brundin, Peik
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Zhao, Chunyan
    Dahlman-Wright, Karin
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Evengård, Birgitta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Gene Expression of Estrogen Receptors in Pbmc From Patients With Puumala-Virus Infection2012In: Shock, ISSN 1073-2322, E-ISSN 1540-0514, Vol. 37, no 4, p. 355-359Article in journal (Refereed)
    Abstract [en]

    The influence of estrogen signaling on infectious diseases is not fully known. Males seem to be more susceptible to infections than females. This has also been noted for the Scandinavian form of hemorrhagic fever with renal syndrome caused by Puumala hantavirus (PUUV). To investigate the differences in estrogen receptors in relation to sex and clinical severity, 20 patients (10 males, 10 females) with confirmed PUUV infection were studied. Real-time polymerase chain reaction was performed for analyzing mRNA expression of estrogen receptor-alpha (ERV), ER beta, and ER beta 2 (ER beta cx) in peripheral blood mononuclear cells from patients and healthy age-and sex-matched blood donors. Blood chemistry and peripheral blood mononuclear cells sampling were performed during the acute and convalescent phases. None or very small amounts of ER beta were detected, and ER alpha and ER beta 2 mRNA were elevated in the patient group. The samples from the males were correlated with ER beta 2; the female samples, with ER alpha. Furthermore, the female and male samples are partly separated using multivariate statistic analysis (principal component analysis), supporting findings that clinical symptoms differ depending on sex.

  • 47.
    Bröms, Jeanette E
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Lavander, Moa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Meyer, Lena
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Sjöstedt, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    IglG and IglI of the Francisella pathogenicity island are important virulence determinants of Francisella tularensis LVS2011In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 79, no 9, p. 3683-3696Article in journal (Refereed)
    Abstract [en]

    The Gram-negative bacterium Francisella tularensis is the causative agent of tularemia, a disease intimately associated with the multiplication of the bacterium within host macrophages. This in turn requires the expression of Francisella pathogenicity island (FPI) genes, believed to encode a type VI secretion system. While the exact functions of many of the components have yet to be revealed, some have been found to contribute to the ability of Francisella to cause systemic infection in mice as well as to prevent phagolysosomal fusion and facilitate escape into the host cytosol. Upon reaching this compartment, the bacterium rapidly multiplies, inhibits activation of the inflammasome, and ultimately causes apoptosis of the host cell. In this study, we analyzed the contribution of the FPI-encoded proteins IglG, IglI, and PdpE to the aforementioned processes in F. tularensis LVS. The ΔpdpE mutant behaved similarly to the parental strain in all investigated assays. In contrast, ΔiglG and ΔiglI mutants, although they were efficiently replicating in J774A.1 cells, both exhibited delayed phagosomal escape, conferred a delayed activation of the inflammasome, and exhibited reduced cytopathogenicity as well as marked attenuation in the mouse model. Thus, IglG and IglI play key roles for modulation of the intracellular host response and also for the virulence of F. tularensis.

  • 48.
    Bröms, Jeanette E
    et al.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Lavander, Moa
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Sjöstedt, Anders
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Dissection of the Functions of the IglC Protein of Francisella tularensis2010In: The challenge of highly pathogenic microorganisms: mechanisms of virulence and novel medical countermeasures, Springer, 2010, p. 67-75Conference paper (Refereed)
    Abstract [en]

    Francisella tularensis harbors genes with similarity to genes encoding components of a type VI secretion system (T6SS). These include iglA and iglB, the homologues of which are conserved in T6SSs. They are part of the igl operon, also encompassing the iglC and iglD genes. We have used a yeast two-hybrid system to study the interaction of the Igl proteins of E tularensis LVS. Previously, we identified a region of IglA necessary for efficient binding to IglB as well as for IglAB protein stability and intra-macrophage growth with an essential role for a conserved alpha-helical region. Thus, IglA-IglB complex formation is clearly crucial for Francisella pathogenicity and the same interaction is conserved in other human pathogens. Herein, the interaction of IglC with other members of the operon was investigated. It showed no binding to the other members in the yeast two-hybrid assay and we found also that two cysteine residues, C191 and C192, predicted to be putative prenylation sites, played no role for the important contribution of IglC to the intracellular replication of E tularensis although C191 was important for the stability of the protein.

  • 49.
    Bröms, Jeanette
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Department of Medical Countermeasures, Swedish Defence Research Agency.
    Forslund, Anna-Lena
    Department of Medical Countermeasures, Swedish Defence Research Agency.
    Forsberg, Åke
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Medical Countermeasures, Swedish Defence Research Agency.
    Francis, Matthew
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    PcrH of Pseudomonas aeruginosa is essential for secretion and assembly of the type III translocon2003In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 188, no 12, p. 1909-1921Article in journal (Refereed)
    Abstract [en]

    Pseudomonas aeruginosa harbors a type III secretion system that translocates antihost effectors into an infected eukaryotic cell. PcrH is a key component of type III secretion in this essential virulence strategy. In the absence of PcrH, P. aeruginosa is translocation deficient because of a specific reduction in presecretory stability and subsequent secretion of PopB and PopD, 2 proteins essential for the translocation process. PcrH exerts this chaperone function by binding directly to PopB and PopD. Consistent with the genetic relatedness of PcrH with LcrH of pathogenic Yersinia species, these proteins are functionally interchangeable with respect to their ability to complement the translocation defect associated with either a lcrH or pcrH null mutant, respectively. Thus, the translocator class of chaperones performs a critical function in ensuring the assembly of a translocation competent type III secreton. Finally, unlike the regulatory roles of other translocator-class chaperones (e.g., LcrH, SicA of Salmonella enterica, and IpgC of Shigella species), in vitro regulation of P. aeruginosa type III secretion does not involve PcrH.

  • 50.
    Burman, Lars Å.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Streptococcus pneumoniae: epidemiological, clinical and serological studies1993Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    A retrospective study of invasive pneumococcal disease in patients from Greater Göteborg in 1964- 1980 identified 125 cases of meningitis, 305 of pneumonia, 61 of septicemia with unknown focus, and 17 with other manifestations, all verified by cultures from normally sterile body fluids. The incidence was several times higher in infants and in the elderly than in any other age-group. A wide variety of underlying conditions were present in 23% of the infants, 34% of the children, and 81% of the adults. In adults alcoholism was known in one third of the cases. The case fatality rate was 24% among patients with underlying conditions and 9% among previously healthy individuals. The case fatality rate was 50% in patients with hospital-acquired infection.

    Twohundred-fifteen pneumococcal strains, isolated from blood or CSF from 1971 to 1983 at the laboratories of clinical bacteriology of Göteborg, Malmö, and Umeå were serotyped by coagglutination (COA). Of all isolates, 89% belonged to serotypes represented in the 23-valent vaccine. In a separate study COA was compared with counterimmunoelectrophoresis (CIE). COA was found to have several advantages; rapidity, lower cost, and ability to disclose serotypes with neutral charge, which constituted 19% of all strains.

    In a prospective study the etiology was determined in 196 hospitalized patients with pneumonia, most of them community-acquired. Culture of specimens from blood, transtracheal aspirate (TTA), sputum, and nasopharynx, assays of antigen in sputum, urine, and TTA, and assays of pneumococcal antibodies to capsular polysaccharide, C-polysaccharide, and pneumolysin in paired sera were performed. The etiology was established in 64% of the patients. Streptococcus pneumoniae was the most common agent (32%).

    In a serological study of patients with pneumococcal infection, diagnosed by culture of CSF, TTA, or blood, IgG antibodies against C-polysaccharide and pneumolysin were determined by ELISA. The diagnostic sensitivity was only 51% and 60%, respectively.

    In conclusion, invasive pneumococcal disease is strongly overrepresented at tender and high age and in patients with concomitant conditions, notably alcoholism. S. pneumoniae remains a predominant causative agent of community-acquired pneumonia in adults needing hospitalization. Due to the low sensitivity and/or specificity of individual microbiological techniques, a combined use of several techniques is necessary when trying to assess the relative importance of pneumococci and other agents in pneumonia. Extended use of the currently available pneumococcal vaccine and development of improved pneumococcal vaccines seem highly warranted.

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