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  • 101.
    Elgh, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Tegnell, Anders
    [The Spanish influenza virus aroused from the dead]2006In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 103, no 24-25, p. 1937-1940Article in journal (Other academic)
  • 102.
    Elgh, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Wadell, G
    Juto, P
    Comparison of the kinetics of Puumala virus specific IgM and IgG antibody responses in nephropathia epidemica as measured by a recombinant antigen-based enzyme-linked immunosorbent assay and an immunofluorescence test.1995In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 45, no 2, p. 146-50Article in journal (Refereed)
    Abstract [en]

    Immunoglobulin M and G (IgM and IgG) responses were followed up to 6 months in patients with nephropathia epidemica (NE) by an enzyme-linked immunosorbent assay (ELISA) using a recombinant Puumala virus (PUU) nucleocapsid protein as antigen and an immunofluorescence test (IF) using PUU infected, acetone-treated cells as antigen. The recombinant protein was produced by cloning and expressing the nucleocapsid encoding gene of PUU as a polyhistidine fusion protein in Escherichia coli. The product was purified over a metal chelating ion affinity column. On admission, all 17 patients had an IgM response by both methods. The IgM titers decreased significantly by both methods 3 months after onset (ELISA P < 0.05 and IF P < 0.05). Four of six still had detectable IgM, however at low levels, after 6 months. Presence of specific IgG differed significantly on admission between the two methods: by ELISA 8 of 17 had detectable specific IgG, whereas by IF 15 of 17 had specific IgG (P < 0.02). There were 10 significant titer rises between acute and convalescent serum samples in the same patients by both methods. It is concluded that the IgG antibody response differs in the early phase of NE as measured by a method using a recombinant PUU nucleocapsid protein and a method using PUU infected acetone-treated cells as antigens. Furthermore, the results suggest that it is of importance to rely on specific IgM for serodiagnosis of NE during the acute phase.

  • 103.
    Engdahl, Cecilia
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Larsson, Pär
    Swedish Defense Research Agency, CBRN Defense and Security, Umeå, Sweden.
    Näslund, Jonas
    Swedish Defense Research Agency, CBRN Defense and Security, Umeå, Sweden.
    Bravo, Mayra
    Swedish Defense Research Agency, CBRN Defense and Security, Umeå, Sweden.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Lundström, Jan O.
    Department of Ecology and Genetics, Evolutionary Biology Centre, Uppsala University, Uppsala, Sweden.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Bucht, Göran
    Swedish Defense Research Agency, CBRN Defense and Security, Umeå, Sweden.
    Identification of Swedish mosquitoes based on molecular barcoding of the COI gene and SNP analysis2014In: Molecular Ecology Resources, ISSN 1755-098X, E-ISSN 1755-0998, Vol. 14, no 3, p. 478-488Article in journal (Refereed)
    Abstract [en]

    Mosquito-borne infectious diseases are emerging in many regions of the world. Consequently, surveillance of mosquitoes and concomitant infectious agents is of great importance for prediction and prevention of mosquito-borne infectious diseases. Currently, morphological identification of mosquitoes is the traditional procedure. However, sequencing of specified genes or standard genomic regions, DNA barcoding, has recently been suggested as a global standard for identification and classification of many different species. Our aim was to develop a genetic method to identify mosquitoes and to study their relationship. Mosquitoes were captured at collection sites in northern Sweden and identified morphologically before the cytochrome c oxidase subunit I (COI) gene sequences of 14 of the most common mosquito species were determined. The sequences obtained were then used for phylogenetic placement, for validation and benchmarking of phenetic classifications and finally to develop a hierarchical PCR-based typing scheme based on single nucleotide polymorphism sites (SNPs) to enable rapid genetic identification, circumventing the need for morphological characterization. The results showed that exact phylogenetic relationships between mosquito taxa were preserved at shorter evolutionary distances, but at deeper levels, they could not be inferred with confidence using COI gene sequence data alone. Fourteen of the most common mosquito species in Sweden were identified by the SNP/PCR-based typing scheme, demonstrating that genetic typing using SNPs of the COI gene is a useful method for identification of mosquitoes with potential for worldwide application.

  • 104.
    Eriksson, Catharina
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Kokkonen, Heidi
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Johansson, Martin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Autoantibodies predate the onset of Systemic Lupus Erythematosus in northern Sweden2011In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 13, no 1, p. R30-Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Autoantibodies have a central role in systemic lupus erythematosus (SLE). The presence of autoantibodies preceding disease onset by years has been reported both in patients with SLE and those with rheumatoid arthritis, suggesting a gradual development of these diseases. To identify autoantibodies in a Northern European population predating the onset of symptoms of SLE and their relationship to presenting symptoms.

    METHODS: The register of patients fulfilling the American College of Rheumatology (ACR) criteria for SLE and with a given date for the onset of symptoms was co-analysed with the register of the Medical Biobank, Umea, Sweden. Thirty-eight patients were identified as having donated blood samples prior to symptom onset. A nested case-control study (1:4) was performed with 152 age- and sex-matched controls identified from within the Biobank register. Antibodies against anti- Sjogren's syndrome antigen A (Ro/SSA) (60 and 52 kDa), anti- Sjogren's syndrome antigen B (La/SSB), anti-Smith antibody (Sm), ribonucleoprotein (RNP), scleroderma-70 (Scl-70), anti- histidyl-tRNA synthetase antibody (Jo-1), double-stranded DNA (dsDNA); Centromere protein B and histones were analysed using the anti-nuclear antibody test II (ANA-II) Plus Test System (Athena Multi-Lyte(R)) on a Bio-Plex Array Reader (Luminex200). ANA were analysed using indirect immunofluorescence on Human Epidermal cells-2 (HEp2-cells) at a sample dilution of 1:100.

    RESULTS: Autoantibodies against nuclear antigens were detected 5.6 (+/- 4.7; mean +/- SD) years before the onset of symptoms and 8.7 (+/- 5.6) years before diagnosis in 63% of the individuals who subsequently developed SLE. The sensitivity (45.7%) was highest for ANA with a specificity of 95%, followed by anti-dsDNA and anti-Ro/SSA antibodies both with sensitivities of 20.0% at specificities of 98.7% and 97.4%, respectively. The odds ratio (OR) for anti-dsDNA predicting disease was 18.13 (CI 95%; 3.58-91.84), and for ANA 11.5 (CI 95%; 4.54-28.87). Anti-Ro/SSA antibodies appeared first, 6.6 (+/- 2.5) years prior to symptom onset. The mean number of autoantibodies in pre-diseased individuals was 1.4 and after disease onset 3.1 (P< 0.0005). The time predating disease was shorter, and the number of autoantibodies greater, in those individuals with serositis as a presenting symptom in comparison to those with arthritis and skin manifestations.

    CONCLUSIONS: Autoantibodies against nuclear antigens were detected in individuals developing SLE several years before the onset of symptoms and diagnosis. The most sensitive autoantibodies were ANA, Ro/SSA and dsDNA, with the highest predictive OR for anti-dsDNA antibodies. The first autoantibodies detected were anti-Ro/SSA.

  • 105.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Detection of human papillomavirus: a study of normal cells, cervical intraepithelial neoplasia and cancer of the uterine cervix1991Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Human papillomavirus (HPV) infections of the genital tract are now recognized to be among the most prevalent sexually transmitted diseases and also a contributing factor to some cancers of the lower genital tract of women and men. Presence of HPV in a clinical specimen is confined to detection of the HPV genome by DNA hybridization techniques.

    In this thesis, the commonly used DNA hybridization techniques Southern blot and filter in situ hybridization (FISH), were first used for detection of genital HPV infection. In order to increase and simplify the detection of HPV in clinical specimens a more sensitive technique, the polymerase chain reaction (PCR) was subsequently utilized.

    For type-specific amplificaiton of HPV 6, 16, 18 and 33 by PCR, oligonucleotide primers located in the E6 and E7 regions of the HPV genome were selected. They were found to specifically amplify the four types. To be able to amplify a broad spectrum of genital HPV types, general primers located in the E7 and El region of the HPV genome, were designed and evaluated. They were found to amplify a wide range of genital HPV types. To further increase the sensitivity and specificity, a two-step PCR using general primers, was assembled and evaluated against a one-step PCR on cervical scrapes from young women in a population-based study. The two-step PCR increased the sensitivity about three-fold compared to the one-step PCR.

    By Southern blot and FISH, 46% of women with abnormal Papanicolaou (Pap) smears were shown to carry HPV DNA. Of the women analysed by Southern blot, 39 % harboured HPV DNA and 25 % proved HPV 16 positive. Of the samples analysed with FISH, 27 % contained HPV DNA, compared to 11 % of samples from a group of reference women with normal cytology. With the Southern blot technique, HPV DNA was detected in 66% of women with cervical intraepithelial neoplasia grade III (CIN III) lesions. Fifty-four percent of the women with CIN III lesions were positive for HPV 16 DNA.

    By type-specific PCR, 12 out of 13 women with cervical squamous carcinoma were shown to carry HPV 16 and/or 18. Among women with adenosquamous carcinoma of the cervix, HPV 18 was the most prevalent type (26%) but HPV 16 was also found in a proportion of the women(15 %). Nine of 13 premenopausal cases with cervical adenocarcinoma were HPV positive compared to only 2 of 13 postmenopausal cases (p< 0.015). HPV 16 DNA was detected in 48%of women with cervical intraepithelial neoplasia (CIN), by the use of type-specific PCR.

    Three different groups of women with normal cytology were studied. Among women attending a family planning clinic in Kenya, 19% were shown to carry HPV virus, by the use of general primers. HPV 16 was found in 5.2% of these women and HPV 18 in 3.9%. In anothergroup of women, attending the gynecological department in Umeå, HPV 16 DNA was detected in 21 % by type-specific PCR. However, if consideration was taken to the medical status of the women, only 10% of women without any medical history were HPV 16 DNA positive, versus 54% of women with diseases and women with a relative progesterone dominance. Finally, by use of a two-step PCR using general primers, 20% of young women from Umeå taking part in a population-based study were demonstrated to carry HPV DNA. The most prevalent types were HPV 6 (2.0%) and HPV 16(2.7%). Among the women in this study with normal cytology, 19%were HPV positive.

  • 106.
    Evander, Magnus
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Milder winters in northern Scandinavia may contribute to larger outbreaks of haemorrhagic fever virus2009In: Global Health Action, ISSN 1654-9716, E-ISSN 1654-9880, Vol. 2Article in journal (Refereed)
    Abstract [en]

    The spread of zoonotic infectious diseases may increase due to climate factors such as temperature, humidity and precipitation. This is also true for hantaviruses, which are globally spread haemorrhagic fever viruses carried by rodents. Hantaviruses are frequently transmitted to humans all over the world and regarded as emerging viral diseases. Climate variations affect the rodent reservoir populations and rodent population peaks coincide with increased number of human cases of hantavirus infections. In northern Sweden, a form of haemorrhagic fever called nephropathia epidemica (NE), caused by the Puumala hantavirus (PUUV) is endemic and during 2006-2007 an unexpected, sudden and large outbreak of NE occurred in this region. The incidence was 313 cases/100,000 inhabitants in the most endemic areas, and from January through March 2007 the outbreak had a dramatic and sudden start with 474 cases in the endemic region alone. The PUUV rodent reservoir is bank voles and immediately before and during the peak of disease outbreak the affected regions experienced extreme climate conditions with a record-breaking warm winter, registering temperatures 6-9 degrees C above normal. No protective snow cover was present before the outbreak and more bank voles than normal came in contact with humans inside or in close to human dwellings. These extreme climate conditions most probably affected the rodent reservoir and are important factors for the severity of the outbreak.

  • 107.
    Evander, Magnus
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Eriksson, Irene
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Pettersson, Lisa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Juto, Per
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Olsson, Gert E
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Bucht, Göran
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Allard, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Puumala hantavirus viremia diagnosed by real-time reverse transcriptase PCR using samples from patients with hemorrhagic fever and renal syndrome.2007In: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 45, no 8, p. 2491-7Article in journal (Refereed)
    Abstract [en]

    Puumala virus (PUUV) is the endemic hantavirus in northern Sweden and causes nephropathia epidemica (NE), a milder form of hemorrhagic fever with renal syndrome. There is a need for fast and reliable diagnostics to differentiate the disease from other infections. By aligning virus RNA sequences isolated from 11 different bank voles and one human patient, we designed a real-time reverse transcriptase (RT) PCR method for detection of PUUV RNA. The real-time RT-PCR assay showed linearity from 20 to 2 x 10(6) virus copies with a correlation coefficient above 0.98 to 0.99 for all experiments. The detection threshold for PUUV cDNA was two copies per reaction. A two-step qualitative RT-PCR to detect PUUV RNA showed 100% concordance with the real-time RT-PCR assay. PUUV RNA viremia was detected in 33 of 34 PUUV immunoglobulin M (IgM)-positive patients with typical clinical NE disease from the region of endemicity. One PUUV IgM-negative sample had PUUV RNA, and 4 days later, the patient was IgM positive. Of samples with indeterminate IgM, 43% were PUUV RNA positive. The kinetics of antibody titers and PUUV viremia were studied, and five of six NE patients displayed a decrease in PUUV viremia a few days after disease outbreak coupled with an increase in PUUV IgM and IgG. In one patient with continuously high PUUV RNA levels but low IgM and no IgG response, the infection was lethal. These findings demonstrated that real-time RT-PCR is a useful method for diagnosis of PUUV viremia and for detecting PUUV RNA at early time points, before the appearance of IgM antibodies.

  • 108.
    Evander, Magnus
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Putkuri, Niina
    Eliasson, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Lwande, Olivia Wesula
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Vapalahti, Olli
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Seroprevalence and Risk Factors of Inkoo Virus in Northern Sweden2016In: American Journal of Tropical Medicine and Hygiene, ISSN 0002-9637, E-ISSN 1476-1645, Vol. 94, no 5, p. 1103-1106Article in journal (Refereed)
    Abstract [en]

    The mosquito-borne Inkoo virus (INKV) is a member of the California serogroup in the family Bunyaviridae, genus Orthobunyavirus These viruses are associated with fever and encephalitis, although INKV infections are not usually reported and the incidence is largely unknown. The aim of the study was to determine the prevalence of anti-INKV antibodies and associated risk factors in humans living in northern Sweden. Seroprevalence was investigated using the World Health Organization Monitoring of Trends and Determinants in Cardiovascular Disease study, where a randomly selected population aged between 25 and 74 years (N = 1,607) was invited to participate. The presence of anti-INKV IgG antibodies was determined by immunofluorescence assay. Seropositivity for anti-INKV was significantly higher in men (46.9%) than in women (34.8%; P < 0.001). In women, but not in men, the prevalence increased somewhat with age (P = 0.06). The peak in seropositivity was 45-54 years for men and 55-64 years for women. Living in rural areas was associated with a higher seroprevalence. In conclusion, the prevalence of anti-INKV antibodies was high in northern Sweden and was associated with male sex, older age, and rural living. The age distribution indicates exposure to INKV at a relatively early age. These findings will be important for future epidemiological and clinical investigations of this relatively unknown mosquito-borne virus.

  • 109. Filén, Finn
    et al.
    Strand, Anders
    Allard, Annika
    Umeå University, Faculty of Medicine, Clinical Microbiology, Virology.
    Blomberg, Jonas
    Herrmann, Björn
    Duplex real-time polymerase chain reaction assay for detection and quantification of herpes simplex virus type 1 and herpes simplex virus type 2 in genital and cutaneous lesions.2004In: Sexually Transmitted Diseases, ISSN 0148-5717, E-ISSN 1537-4521, Vol. 31, no 6, p. 331-6Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A sensitive and specific method for detecting herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) is important for diagnosing genital and cutaneous infections. GOAL: The goal of this study was to compare quantitative real-time polymerase chain reaction (qPCR) with virus culture for diagnosis of genital and cutaneous HSV-1 and HSV-2. STUDY DESIGN: A duplex qPCR system for quantification of DNA from HSV-1 and HSV-2 was developed. Duplicate swabs for PCR and virus culture were collected from 89 patients attending our sexually transmitted infection and dermatology clinic. RESULTS: The duplex qPCR had a linear measure interval of 10-10 copies/mL. The detection limit was between 1 and 5 copies per reaction. qPCR detected HSV in 57 (64%) specimens and virus was isolated in 45 (50%) cases. First-episode infections showed higher viral quantities with a median value of 4.2 x 10 copies per reaction compared with recurrent infections with 1.0 x 10 (P = 0.0002). HSV-1 was more likely to be the cause of first-episode genital infections (72%), and HSV-2 of recurrent and atypical genital manifestations (73%). CONCLUSION: Real-time PCR is a sensitive method for diagnosing genital herpes, and the duplex format is convenient for typing. The method increased the detection rate by 27% compared with virus culture.

  • 110. Flick, Ramon
    et al.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Pettersson, Ralf F
    Mutational analysis of the Uukuniemi virus (Bunyaviridae family) promoter reveals two elements of functional importance2002In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 76, no 21, p. 10849-10860Article in journal (Refereed)
    Abstract [en]

    We have performed an extensive mutational analysis of the proposed promoter region of the phlebovirus Uukuniemi (UUK), a member of the Bunyaviridae family. This was achieved by using a recently developed RNA polymerase I (Pol I)-driven reverse genetics system (R. Flick and R. F. Pettersson, J. Virol. 75:1643-1655, 2001). Chimeric cDNAs containing the coding region for the reporter chloramphenicol acetyltransferase (CAT) in an antisense orientation were flanked by the 5'- and 3'-terminal nontranslated regions of the UUK virus-sense RNA (vRNA) derived from the medium-sized (M) RNA segment. The chimeric cDNAs (Pol I expression cassettes) were cloned between the murine Pol I promoter and terminator, and the plasmids were transfected into BHK-21 cells. CAT activity was determined after cotransfection with viral expression plasmids encoding the RNA-dependent RNA polymerase (L) and the nucleoprotein (N) or, alternatively, after superinfection with UUK virus helper virus. Using oligonucleotide-directed mutagenesis, single point mutations (substitutions, deletions, and insertions) were introduced into the viral promoter region. Differences in CAT activities were interpreted to reflect the efficiency of mRNA transcription from the mutated promoter and the influence on RNA replication. Analysis of 109 mutants allowed us to define two important regulatory regions within the proximal promoter region (site A, positions 3 to 5 and 2 to 4; site B, positions 8 and 8, where underlined nucleotides refer to positions in the vRNA 3' end). Complementary double nucleotide exchanges in the proximal promoter region, which maintained the possibility for base pairing between the 5' and 3' ends, demonstrated that nucleotides in the two described regions are essential for viral polymerase recognition in a base-specific manner. Thus, mere preservation of panhandle base pairing between the 5' and 3' ends is not sufficient for promoter activity. In conclusion, we have been able to demonstrate that both ends of the M RNA segment build up the promoter region and are involved in the specific recognition by the viral polymerase.

  • 111. Flick, Ramon
    et al.
    Flick, Kirsten
    Feldmann, Heinz
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Reverse genetics for crimean-congo hemorrhagic fever virus.2003In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 77, no 10, p. 5997-6006Article in journal (Refereed)
    Abstract [en]

    The widespread geographical distribution of Crimean-Congo hemorrhagic fever (CCHF) virus (more than 30 countries) and its ability to produce severe human disease with high mortality rates (up to 60%) make CCHF a major public health concern worldwide. We describe here the successful establishment of a reverse genetics technology for CCHF virus, a member of the genus Nairovirus, family BUNYAVIRIDAE: The RNA polymerase I (pol I) system was used to generate artificial viral RNA genome segments (minigenomes), which contained different reporter genes in antisense (virus RNA) or sense (virus-complementary RNA) orientation flanked by the noncoding regions of the CCHF virus S segment. Reporter gene expression was observed in different eukaryotic cell lines following transfection and subsequent superinfection with CCHF virus, confirming encapsidation, transcription, and replication of the pol I-derived minigenomes. The successful transfer of reporter gene activity to fresh cells demonstrated the generation of recombinant CCHF viruses, thereby confirming the packaging of the pol I-derived minigenomes into progeny viruses. The system offers a unique opportunity to study the biology of nairoviruses and to develop therapeutic and prophylactic measures against CCHF infections. In addition, we demonstrated for the first time that the human pol I system can be used to develop reverse genetics approaches for viruses in the family BUNYAVIRIDAE: This is important since it might facilitate the manipulation of bunyaviruses with cell and host tropisms restricted to primates.

  • 112. Formiga-Cruz, M
    et al.
    Allard, Annika K
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Conden-Hansson, A-C
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Henshilwood, K
    Hernroth, B E
    Jofre, J
    Lees, D N
    Lucena, F
    Papapetropoulou, M
    Rangdale, R E
    Tsibouxi, A
    Vantarakis, A
    Girones, R
    Evaluation of potential indicators of viral contamination in shellfish and their applicability to diverse geographical areas2003In: Applied and Environmental Microbiology, ISSN 0099-2240, E-ISSN 1098-5336, Vol. 69, no 3, p. 1556-1563Article in journal (Refereed)
    Abstract [en]

    The distribution of the concentration of potential indicators of fecal viral pollution in shellfish was analyzed under diverse conditions over 18 months in diverse geographical areas. These microorganisms have been evaluated in relation to contamination by human viral pathogens detected in parallel in the analyzed shellfish samples. Thus, significant shellfish-growing areas from diverse countries in the north and south of Europe (Greece, Spain, Sweden, and the United Kingdom) were defined and studied by analyzing different physicochemical parameters in the water and the levels of Escherichia coli, F-specific RNA bacteriophages, and phages infecting Bacteroides fragilis strain RYC2056 in the shellfish produced, before and after depuration treatments. A total of 475 shellfish samples were studied, and the results were statistically analyzed. According to statistical analysis, the presence of human viruses seems to be related to the presence of all potential indicators in the heavily contaminated areas, where E. coli would probably be suitable as a fecal indicator. The F-RNA phages, which are present in higher numbers in Northern Europe, seem to be significantly related to the presence of viral contamination in shellfish, with a very weak predictive value for hepatitis A virus, human adenovirus, and enterovirus and a stronger one for Norwalk-like virus. However, it is important to note that shellfish produced in A or clean B areas can sporadically contain human viruses even in the absence of E. coli or F-RNA phages. The data presented here will be useful in defining microbiological parameters for improving the sanitary control of shellfish consumed raw or barely cooked.

  • 113. Formiga-Cruz, M
    et al.
    Tofiño-Quesada, G
    Bofill-Mas, S
    Lees, D N
    Henshilwood, K
    Allard, A K
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Conden-Hansson, A-C
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Hernroth, B E
    Vantarakis, A
    Tsibouxi, A
    Papapetropoulou, M
    Furones, M D
    Girones, R
    Distribution of human virus contamination in shellfish from different growing areas in Greece, Spain, Sweden, and the United Kingdom.2002In: Applied and Environmental Microbiology, ISSN 0099-2240, E-ISSN 1098-5336, Vol. 68, no 12, p. 5990-8Article in journal (Refereed)
    Abstract [en]

    Viral pollution in shellfish has been analyzed simultaneously across a wide range of geographical regions, with emphasis on the concomitant variations in physicochemical characteristics and social features. The methods for sample treatment and for the detection of human enteric viruses were optimized by the participating laboratories. The second part of this study involves the selection of a protocol for virus detection, which was validated by analyzing the distribution and concentration of human viral pathogens under diverse conditions during an 18-month period in four European countries. Shellfish-growing areas from diverse countries in the north and south of Europe were defined and studied, and the microbiological quality of the shellfish was analyzed. Human adenovirus, Norwalk-like virus, and enterovirus were identified as contaminants of shellfish in all the participating countries. Hepatitis A virus was also isolated in all areas except Sweden. The seasonal distribution of viral contamination was also described. Norwalk-like virus appeared to be the only group of viruses that demonstrated seasonal variation, with lower concentrations occurring during warm months. The depuration treatments currently applied were shown to be adequate for reducing Escherichia coli levels but ineffective for the elimination of viral particles. The human adenoviruses detected by PCR correlate with the presence of other human viruses and could be useful as a molecular index of viral contamination in shellfish.

  • 114. Formiga-Cruz, Meritxell
    et al.
    Hundesa, Ayalkibet
    Clemente-Casares, Pilar
    Albiñana-Gimenez, Nestor
    Allard, Annika
    Umeå University, Faculty of Medicine, Clinical Microbiology, Virology.
    Girones, Rosina
    Nested multiplex PCR assay for detection of human enteric viruses in shellfish and sewage.2005In: Journal of Virological Methods, ISSN 0166-0934, E-ISSN 1879-0984, Vol. 125, no 2, p. 111-8Article in journal (Refereed)
    Abstract [en]

    Environmental samples and contaminated shellfish present frequently low concentrations of more than one viral species. For this reason, a nested multiplex RT-PCR was developed for the detection of adenoviruses, enteroviruses and hepatitis A viruses in different environmental samples such as urban sewage and shellfish. This assay will save time and cost for detection of these enteric viruses with a smaller sample volume, which otherwise can be a limiting factor in routine analysis. The limit of detection was approximately 1 copy for adenovirus and 10 copies for enterovirus and hepatitis A virus per PCR reaction using titrated cell-cultured viruses as template material. In shellfish and environmental samples, this multiplex PCR was optimized to detect all three viruses simultaneously when the concentration of each virus was equal or lower than 1000 copies per PCR reaction. This is the level found predominantly in the environment and in shellfish when the numbers of fecal bacterial and phage indicators are low. The detection of human adenoviruses by PCR has been suggested as a molecular index of fecal contamination of human origin in the environment and food and the multiplex assay developed may be a tool for evaluating the presence of viral contamination in shellfish and water and to expand microbiological control to include viral markers.

  • 115. Forslund, Ola
    et al.
    Antonsson, Annika
    Edlund, Karin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    van den Brule, Adrian J C
    Hansson, Bengt-Göran
    Meijer, Chris J L M
    Ryd, Walter
    Rylander, Eva
    Strand, Anders
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Dillner, Joakim
    Johansson, Bo
    Population-based type-specific prevalence of high-risk human papillomavirus infection in middle-aged Swedish women.2002In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 66, no 4, p. 535-41Article in journal (Refereed)
    Abstract [en]

    Human papillomavirus (HPV) DNA testing can be used to identify women at risk of the development of cervical cancer. The cost-effectiveness of HPV screening is dependent on the type-specific HPV prevalence in the general population. The present study describes the prevalence and spectrum of high-risk HPV types found in a large real-life population-based HPV screening trial undertaken entirely within the cervical screening program offered to middle-aged Swedish women. Cervical brush samples from 6,123 women aged 32-38 years were analyzed using a general HPV primer (GP5+/6+) polymerase chain reaction-enzyme immunoassay (PCR-EIA) combined with reverse dot-blot hybridization for confirmation and HPV typing by a single assay. In this study, 6.8% (95% CI 6.2-7.5) (417/6,123) were confirmed as high-risk HPV positive. Infections with 13 different high-risk HPV types were detected, of which HPV 16 was the most prevalent type (2.1%; 128/6,123), followed by HPV 31 (1.1%; 67/6,123). Any one of the HPV types 18, 33, 35, 39, 45, 51, 52, 56, 58, 59, or 66 was detected in 3.6% (223/6,123) of the women. Infection with two, three, and five types simultaneously was identified in 32, 5, and 1 women, respectively. The combination of PCR-EIA as a screening test and reverse dot-blot hybridization as a confirmatory test, was found to be readily applicable to a real-life population-based cervical screening. The type-specific HPV prevalence found support in previous modeling studies suggesting that HPV screening may be a favorable cervical screening strategy.

  • 116.
    Frängsmyr, Lars
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Israelsson, Anne
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Teglund, S
    Matsunaga, T
    Hammarström, Sten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Evolution of the carcinoembryonic antigen family: Structures of CGM9, CGM11 and pregnancy-specific glycoprotein promoters.2000In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 21, no 2, p. 63-81Article in journal (Refereed)
  • 117.
    Gerold, Gisa
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Abu Ajaj, Khalid
    Bienert, Michael
    Laws, Hans-Jürgen
    Zychlinsky, Arturo
    de Diego, Juana L
    A Toll-like receptor 2-integrin beta3 complex senses bacterial lipopeptides via vitronectin.2008In: Nature Immunology, ISSN 1529-2908, E-ISSN 1529-2916, Vol. 9, no 7, p. 761-8Article in journal (Refereed)
    Abstract [en]

    Toll-like receptor 2 (TLR2) initiates inflammation in response to bacterial lipopeptide (BLP). However, the molecular mechanisms enabling the detection of BLP by TLR2 are unknown. Here we investigated the interaction of BLP with human serum proteins and identified vitronectin as a BLP-recognition molecule. Vitronectin and its receptor, integrin beta(3), were required for BLP-induced TLR2-mediated activation of human monocytes. Furthermore, monocytes from patients with Glanzmann thrombasthenia, which lack integrin beta(3), were completely unresponsive to BLP. In addition, integrin beta(3) formed a complex with TLR2 and this complex dissociated after BLP stimulation. Notably, vitronectin and integrin beta(3) coordinated responses to other TLR2 agonists such as lipoteichoic acid and zymosan. Our findings show that vitronectin and integrin beta(3) contribute to the initiation of TLR2 responses.

  • 118.
    Gerold, Gisa
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Zychlinsky, Arturo
    de Diego, Juana L
    What is the role of Toll-like receptors in bacterial infections?2007In: Seminars in Immunology, ISSN 1044-5323, E-ISSN 1096-3618, Vol. 19, no 1, p. 41-7Article in journal (Refereed)
    Abstract [en]

    Innate immunity relies on signalling by Toll-like receptors (TLRs) to alert the immune system of the presence of invading bacteria. TLR activation leads to the release of cytokines that allow for effective innate and adaptive immune responses. However, the contribution of different TLRs depends on the site of the infection and the pathogen. This review will describe the involvement of TLRs in the development of three different bacterial infections as well as our current understanding of the role of TLRs during microbial pathogenesis.

  • 119.
    Gokumakulapalle, Madhuri
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Mei, Ya-Fang
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Replication-competent human adenovirus 11p vectors can propagate in Vero cells2016In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 495, p. 42-51Article in journal (Refereed)
    Abstract [en]

    The use of continuous cell lines derived from the African green monkey kidney (AGMK) has led to major advances in virus vaccine development. However, to date, these cells have not been used to facilitate the creation of human adenoviruses because most human adenoviruses undergo abortive infections in them. Here, we report the susceptibility of AGMK-derived cells to adenovirus lip (Ad11p) infection. First, we showed that CD46 molecules, which act as receptors for Ad11p, are expressed in AGMK cells. We then monitored Ad11p replication by measuring GFP expression as an indicator of viral transcription. We found that AGMK-derived cells were as capable as carcinoma cells at propagating full-length replication competent Ad11p (RCAd11p) DNA. Of the AGMK cell lines tested, Vero cells had the greatest capacity for adenovirus production. Thus, AGMK cells can be used to evaluate RCAd11p-mediated gene delivery, and Vero cells can be used for the production of RCAd11pGFP vectors at relatively high yields.

  • 120.
    Granström, Elin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Biomedical Laboratory Science. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    ELISA-metoders specificitet och sensitivitet för detektion av anti-HSV-1 IgG i human plasma2018Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 121.
    Granvik, Christoffer
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Traces of herpesvirus in brain tissue from patients with Alzheimer´s disease2018Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 122. Greber, Urs F.
    et al.
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Benko, Maria
    Kremer, Eric J.
    Adenoviruses: from pathogens to therapeutics: a report on the 10th International Adenovirus Meeting2013In: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 15, no 1, p. 16-23Article in journal (Refereed)
  • 123.
    Gustafsson, Dan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Adenovirus species B interactions with CD462012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Adenoviruses (Ad) are double-stranded (ds) DNA, non-enveloped viruses. There are seven species (A-G) of human Ads with 52 knownserotypes to date. Human Ads cause a broad range of pathologies, ranging from upper respiratory tract infections to persistent urinary tract infections. The main determinant for Ads tropism in vitro is the protruding, antenna-like, fiber protein. The fiberknob is responsible for the main interaction with the attachment receptor of the host cell. Most Ad species use the coxsackie- adenovirus receptor (CAR) as their main attachment receptor. Most species B Ads, however use CD46. CD46 is a cell surface complement regulatory protein, which is expressed on all nucleated cells in humans. Species B Ads exhibit a low seroprevalenc in the human population, making these Ads promising vector candidates for gene therapy. We have studied human Ad species B members, serotypes 7 and 11 (Ad7 and Ad11), as well as their interaction with CD46. Our first experiments showed that all species B Ads use CD46 as their main attachment receptor, with the exception of Ad3 and Ad7. Second, we performed mutational studies of recombinant Ad11p fiberknobs. These studies showed that arginine 279 in the Ad 11 fiberknob is necessary for CD46 binding. Finally we studied the effect of Ad11 binding to CD46. The results indicate that CD46 is rapidly downregulated on the cell surface after Ad11 binding. These results may provide a further understanding of the basic biology and pathology of species B Ads and may also be useful in construction of gene therapy vectors based on species B Ads.

  • 124.
    Gustafsson, Dan J
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Andersson, Emma K
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Hu, Yan-Ling
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Marttila, Marko
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Lindman, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Strand, Mårten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Wang, Li
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Mei, Ya-Fang
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Adenovirus 11p downregulates CD46 early in infection2010In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 405, no 2, p. 474-482Article in journal (Refereed)
    Abstract [en]

    Adenovirus 11 prototype (Ad11p), belonging to species B, uses CD46 as an attachment receptor. CD46, a complement regulatory molecule, is expressed on all human nucleated cells. We show here that Ad11p virions downregulate CD46 on the surface of K562 cells as early as 5min p.i. Specific binding to CD46 by the Ad11p fiber knob was required to mediate downregulation. The complement regulatory factors CD55 and CD59 were also reduced to a significant extent as a consequence of Ad11p binding to K562 cells. In contrast, binding of Ad7p did not result in downregulation of CD46 early in infection. Thus, the presumed interaction between Ad7p and CD46 did not have the same consequences as the Ad11p-CD46 interaction, the latter virus (Ad11p) being a promising gene therapy vector candidate. These findings may lead to a better understanding of the pathogenesis of species B adenovirus infections.

  • 125.
    Gustafsson, Dan J
    et al.
    Umeå University, Faculty of Medicine, Clinical Microbiology, Virology.
    Segerman, Anna
    Umeå University, Faculty of Medicine, Clinical Microbiology, Virology.
    Lindman, Kristina
    Umeå University, Faculty of Medicine, Clinical Microbiology, Virology.
    Mei, Ya-Fang
    Umeå University, Faculty of Medicine, Clinical Microbiology, Virology.
    Wadell, Göran
    Umeå University, Faculty of Medicine, Clinical Microbiology, Virology.
    The Arg279Gln [corrected] substitution in the adenovirus type 11p (Ad11p) fiber knob abolishes EDTA-resistant binding to A549 and CHO-CD46 cells, converting the phenotype to that of Ad7p.2006In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 80, no 4, p. 1897-905Article in journal (Refereed)
    Abstract [en]

    The major determinant of adenovirus (Ad) attachment to host cells is the C-terminal knob domain of the trimeric fiber protein. Ad type 11p (Ad11p; species B2) in contrast to Ad7p (species B1) utilizes at least two different cellular attachment receptors, designated sBAR (species B adenovirus receptor) and sB2AR (species B2 adenovirus receptor). CD46 has recently been identified as one of the Ad11p attachment receptors. However, CD46 did not seem to constitute a functional receptor for Ad7p. Although Ad7p shares high knob amino acid identity with Ad11p, Ad7p is deficient in binding to both sB2AR and CD46. To determine what regions of the Ad11p fiber knob are necessary for sB2AR-CD46 interaction, we constructed recombinant fiber knobs (rFK) with Ad11p/Ad7p chimeras and Ad11p sequences having a single amino acid substitution from Ad7p. Binding of the constructs to A549 and CHO-CD46 BC1 isoform-expressing cells was analyzed by flow cytometry. Our results indicate that an Arg279Gln [corrected] substitution is sufficient to convert the Ad11p receptor-interaction phenotype to that of Ad7p and abolish sB2AR and CD46 interaction. Also a Glu279Arg substitution in Ad7p rFKs increases CD46 binding. Thus, the lateral HI loop of the Ad11p fiber knob seems to be the key determinant for Ad11p sB2AR-CD46 interaction. This result is comparable to another non-coxsackie-adenovirus receptor binding Ad (Ad37p), where substitution of one amino acid abolishes virus-cell interaction. In conjunction with previous results, our findings also strongly suggest that sB2AR is equivalent to CD46.

  • 126.
    Gustafsson, Åke
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Functional and molecular aspects of interferon action in human natural killer cells and other leucocytes1985Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Interferons comprise a class of structurally related proteins which exert several regulatory effects in responsive cells. These effects include the establishment of an antiviral state, the inhibition of cellular proliferation and the alteration of different immune reactions. In particular, the IFN:s rapidly augment the lytic activity of the natural killer (NK) cells. In the present thesis, some of the functional and molecular mechanisms by which IFN:s act on NK cells and other leucocytes are studied. A good correlation is found between the ability of different tumor cell lines to induce IFN production among peripheral blood lymphocytes and their sensitivity to NK cell cytotoxicity, indicating that IFN might regulate the activity of NK cells through a positive feed-back mechanism. When studying the interaction between the NK cells and two target cell lines it is demonstrated that the two cell lines are not recognized by the same receptors. The augmentation of NK cell cytotoxicity by IFN is shown to involve both alteration of receptor structures on the NK cell and enhancement of steps in their lytic machinery. The effects of IFN on the synthesis of individual proteins is then studied by two-dimensional electrophoresis. It is demonstrated that IFN-a and IFN-ß within 1.5 hours induce the synthesis of nine proteins (Mf80, 75, 62, 58, 53, 38, 36, 33 and 30 kD) in human lymphocytes. Tne induction is dependent on a rapid de novo RNA synthesis, which is initiated less than 30 minutes after the addition of IFN. The expression of the nine proteins is well correlated to the development of augmented NK cell cytotoxicity. Four of the proteins (Mr 80, 62, 38 and 33 kD) are found to be expressed in a panel of ten hematopoetic and two anchorage-dependent cell lines, whereas the remaining proteins seem to be expressed in leucocytes only. IFN induce the synthesis of the same proteins in both purified large granular lymphocytes (responsible for the main NK cell activity in man), T cells and monocytes, demonstrating that the augmentation of NK cell activity does not involve the formation of unique 1NK-cel11 specific proteins. Rather, the augmentation of the lytic activity of both NK cells, cytotoxic T cells and monocytes seem to involve common stages in their lytic mechanisms. In contrast to IFN-a and IFN-ß, IFN-y, does not induce any detectable proteins in either NK cells or T cells. This lack of effect of IFN-y on the protein synthesis is not a general phenomenon, since the effects of IFN-a and IFN-y are similar 1n a glioma cell line. These results demonstrate that there exists at least one pathway to augment the NK cell cytotoxicity which does not involve the increased synthesis of the nine IFN-a/IFN-ß inducible proteins and indicates that either these proteins are mainly involved in other effects of IFN, or that the augmentation by IFN-a/IFN-ß and IFN-y involve different pathways. When the effects of IFN-a on the synthesis of membrane-associated proteins is studied, it is demonstrated that only the 80 kD IFN-a inducible protein is associated with the cell membrane. In addition, IFN-a seems to induce three additional, me mb rane-as so ci a ted proteins (Mr 94, 76 and 66 kD) which are not detected in whole cell lysates.

  • 127.
    Gylfe, Åsa
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Ribers, Åsa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Forsman, Oscar
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Bucht, Göran
    Alenius, Gerd-Marie
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Wållberg-Jonsson, Solveig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    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.
    Mosquitoborne Sindbis Virus Infection and Long-Term Illness2018In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 24, no 6, p. 1141-1142Article in journal (Refereed)
    Abstract [en]

    An unexpected human outbreak of the mosquitoborne Sindbis virus occurred in a previously nonendemic area of Sweden. At follow-up, 6-8 months after infection, 39% of patients had chronic arthralgia that affected their daily activities. Vectorborne infections may disseminate rapidly into new areas and cause acute and chronic disease.

  • 128. Hammerschlag, Margaret R
    et al.
    Apfalter, Petra
    Boman, Jens
    Umeå University, Faculty of Medicine, Clinical Microbiology, Virology.
    Tondella, M Lucia
    Gaydos, Charlotte
    The role of Chlamydia pneumoniae in multiple sclerosis: real or fictitious?2005In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 192, no 7, p. 1305-7; author reply 1307Article in journal (Refereed)
  • 129. Hardestam, Jonas
    et al.
    Petterson, Lisa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    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.
    Lundkvist, Ake
    Klingström, Jonas
    Antiviral effect of human saliva against hantavirus.2008In: Journal of medical virology, ISSN 1096-9071, Vol. 80, no 12, p. 2122-6Article in journal (Refereed)
    Abstract [en]

    Hemorrhagic fever with renal syndrome (HFRS) and Hantavirus pulmonary syndrome are zoonotic diseases caused by rodent borne hantaviruses. Transmission to humans occurs usually by inhalation of aerozolized virus-contaminated rodent excreta. Although human-to-human transmission of Andes hantavirus has been observed, the mode of transmission is currently not known. Saliva from Puumala hantavirus (PUUV)-infected patients was shown recently to contain viral RNA. To test if human saliva interferes with hantavirus replication, the effect of saliva and salivary proteins on hantavirus replication was studied. It was observed that saliva from healthy individuals reduced Hantaan hantavirus (HTNV) infectivity, although not completely. Furthermore, HTNV was resistant against the antiviral capacity of histatin 5, lysozyme, lactoferrin, and SLPI, but was inhibited by mucin. Inoculation of bank voles (Myodes glareolus) with HFRS-patient saliva, positive for PUUV-RNA, did not induce sero-conversion. In conclusion, no evidence of infectious virus in patient saliva was found. However, the in vitro experiments showed that HTNV, the prototype hantavirus, is insensitive to several antiviral salivary proteins, and is partly resistant to the antiviral effect of saliva. It therefore remains to be shown if human saliva might contain infectious virions early during infection, that is, before seroconversion.

  • 130.
    Hassan, Osama Ahmed
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Public Health Institute, Khartoum, Sudan.
    Affognon, Hippolyte
    Rocklöv, Joacim
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Mburu, Peter
    Sang, Rosemary
    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.
    The One Health approach to identify knowledge, attitudes and practices that affect community involvement in the control of Rift Valley fever outbreaks2017In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 11, no 2, article id e0005383Article in journal (Refereed)
    Abstract [en]

    Rift Valley fever (RVF) is a viral mosquito-borne disease with the potential for global expansion, causes hemorrhagic fever, and has a high case fatality rate in young animals and in humans. Using a cross-sectional community-based study design, we investigated the knowledge, attitudes and practices of people living in small village in Sudan with respect to RVF outbreaks. A special One Health questionnaire was developed to compile data from 235 heads of household concerning their knowledge, attitudes, and practices with regard to controlling RVF. Although the 2007 RVF outbreak in Sudan had negatively affected the participants' food availability and livestock income, the participants did not fully understand how to identify RVF symptoms and risk factors for both humans and livestock. For example, the participants mistakenly believed that avoiding livestock that had suffered spontaneous abortions was the least important risk factor for RVF. Although the majority noticed an increase in mosquito population during the 2007 RVF outbreak, few used impregnated bed nets as preventive measures. The community was reluctant to notify the authorities about RVF suspicion in livestock, a sentinel for human RVF infection. Almost all the respondents stressed that they would not receive any compensation for their dead livestock if they notified the authorities. In addition, the participants believed that controlling RVF outbreaks was mainly the responsibility of human health authorities rather than veterinary authorities. The majority of the participants were aware that RVF could spread from one region to another within the country. Participants received most their information about RVF from social networks and the mass media, rather than the health system or veterinarians. Because the perceived role of the community in controlling RVF was fragmented, the probability of RVF spread increased.

  • 131.
    Hassan, Osama Ahmed
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. Department of Epidemiology and Diseases Control, Public Health Institute, Federal Ministry of Health, Khartoum, Sudan.
    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.
    A need for One Health approach: lessons learned from outbreaks of Rift Valley fever in Saudi Arabia and Sudan2014In: Infection Ecology & Epidemiology, ISSN 2000-8686, E-ISSN 2000-8686, Vol. 4, article id 20710Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Rift Valley fever (RVF) is an emerging viral zoonosis that impacts human and animal health. It is transmitted from animals to humans directly through exposure to blood, body fluids, or tissues of infected animals or via mosquito bites. The disease is endemic to Africa but has recently spread to Saudi Arabia and Yemen. Our aim was to compare two major outbreaks of RVF in Saudi Arabia (2000) and Sudan (2007) from a One Health perspective.

    METHODS: Using the terms 'Saudi Arabia', 'Sudan', and 'RVF', articles were identified by searching PubMed, Google Scholar, and web pages of international organizations as well as local sources in Saudi Arabia and Sudan.

    RESULTS: The outbreak in Saudi Arabia caused 883 human cases, with a case fatality rate of 14% and more than 40,000 dead sheep and goats. In Sudan, 698 human cases of RVF were recognized (case fatality, 31.5%), but no records of affected animals were available. The ecology and environment of the affected areas were similar with irrigation canals and excessive rains providing an attractive habitat for mosquito vectors to multiply. The outbreaks resulted in livestock trade bans leading to a vast economic impact on the animal market in the two countries. The surveillance system in Sudan showed a lack of data management and communication between the regional and federal health authorities, while in Saudi Arabia which is the stronger economy, better capacity and contingency plans resulted in efficient countermeasures. Studies of the epidemiology and vectors were also performed in Saudi Arabia, while in Sudan these issues were only partly studied.

    CONCLUSION: We conclude that a One Health approach is the best option to mitigate outbreaks of RVF. Collaboration between veterinary, health, and environmental authorities both on national and regional levels is needed.

  • 132.
    Hassan, Osama Ahmed
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. Federal Ministry of Health, Khartoum, Sudan.
    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.
    The 2007 rift valley Fever outbreak in Sudan2011In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 5, no 9, article id e1229Article, review/survey (Refereed)
    Abstract [en]

    Rift Valley fever (RVF) is a neglected, emerging, mosquito-borne disease with severe negative impact on human and animal health and economy. RVF is caused by RVF virus (RVFV) affecting humans and a wide range of animals. The virus is transmitted through bites from mosquitoes and exposure to viremic blood, body fluids, or tissues of infected animals. During 2007 a large RVF outbreak occurred in Sudan with a total of 747 confirmed human cases including 230 deaths (case fatality 30.8%); although it has been estimated 75,000 were infected. It was most severe in White Nile, El Gezira, and Sennar states near to the White Nile and the Blue Nile Rivers. Notably, RVF was not demonstrated in livestock until after the human cases appeared and unfortunately, there are no records or reports of the number of affected animals or deaths. Ideally, animals should serve as sentinels to prevent loss of human life, but the situation here was reversed. Animal contact seemed to be the most dominant risk factor followed by animal products and mosquito bites. The Sudan outbreak followed an unusually heavy rainfall in the country with severe flooding and previous studies on RVF in Sudan suggest that RVFV is endemic in parts of Sudan. An RVF outbreak results in human disease, but also large economic loss with an impact beyond the immediate influence on the directly affected agricultural producers. The outbreak emphasizes the need for collaboration between veterinary and health authorities, entomologists, environmental specialists, and biologists, as the best strategy towards the prevention and control of RVF.

  • 133.
    Hedin, Göran
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Eriksson, Iréne
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Kumlin, Urban
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Boman, Jens
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    A lack of serologic evidence of transmission of Chlamydia pneumoniae by transfusion of buffy coat-depleted RBCs2003In: Transfusion, ISSN 0041-1132, E-ISSN 1537-2995, Vol. 43, no 5, p. 646-650Article in journal (Refereed)
    Abstract [en]

    In our study, which was limited to 53 seronegative recipients of RBC units from seropositive donors, we found no serologic evidence that C. pneumoniae could be transmitted by RBC transfusion.

  • 134. Henningsson, Anna J.
    et al.
    Lindqvist, Richard
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Norberg, Peter
    Lindblom, Pontus
    Roth, Anette
    Forsberg, Pia
    Bergström, Tomas
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Lindgren, Per-Eric
    Human Tick-Borne Encephalitis and Characterization of Virus from Biting Tick2016In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 22, no 8, p. 1485-1487Article in journal (Refereed)
    Abstract [en]

    We report a case of human tick-borne encephalitis (TBE) in which the TBE virus was isolated from the biting tick. Viral growth and sequence were characterized and compared with those of a reference strain. Virus isolation from ticks from patients with TBE may offer a new approach for studies of epidemiology and pathogenicity.

  • 135. Hernroth, Bodil
    et al.
    Allard, Annika
    Umeå University, Faculty of Medicine, Clinical Microbiology, Virology.
    The persistence of infectious adenovirus (type 35) in mussels (Mytilus edulis) and oysters (Ostrea edulis).2007In: International Journal of Food Microbiology, ISSN 0168-1605, E-ISSN 1879-3460, Vol. 113, no 3, p. 296-302Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to provide information for improving risk assessment of viral contaminants in bivalves. The persistence of viable adenovirus type 35 (Ad35) after controlled contaminations of blue mussels, Mytilus edulis, and oysters, Ostrea edulis, was studied. Bivalves, kept in running seawater at two different temperatures (4 and 18 degrees C) were sampled after 1, 3, 7, 14, 21, 35, 42, 49, 56, and 70 days. Virus particles were separated from the gills and the digestive gland through ultra high-speed centrifugation. Qualitative PCR analyses of DNA in the virus extracts showed that Ad35 was detectable for 6-10 weeks and quantitative real-time PCR verified a gradual but not linear decrease in copy numbers, within this time interval. The virus genome was detectable to the same degree on the gills as in the digestive gland. When viral extractions were inoculated on A549 cells to investigate the cytopathic effect (CPE) it was shown that Ad35 stayed infectious in oysters, kept at 4 degrees C, for about six weeks, which was double the time compared to that for mussels. The detection of the viral genome exceeded the persistence of their infectivity, in most cases with 4-6 weeks. The data were highly variable and the sporadic occurrence of high numbers of accumulated viruses and their remaining infectivity is seemingly a significant factor regarding food safety.

  • 136. Hernroth, Bodil E
    et al.
    Conden-Hansson, Ann-Christine
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Rehnstam-Holm, Ann-Sofi
    Girones, Rosina
    Allard, Annika K
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Environmental factors influencing human viral pathogens and their potential indicator organisms in the blue mussel, Mytilus edulis: the first Scandinavian report.2002In: Applied and Environmental Microbiology, ISSN 0099-2240, E-ISSN 1098-5336, Vol. 68, no 9, p. 4523-33Article in journal (Refereed)
    Abstract [en]

    This study was carried out in order to investigate human enteric virus contaminants in mussels from three sites on the west coast of Sweden, representing a gradient of anthropogenic influence. Mussels were sampled monthly during the period from February 2000 to July 2001 and analyzed for adeno-, entero-, Norwalk-like, and hepatitis A viruses as well as the potential viral indicator organisms somatic coliphages, F-specific RNA bacteriophages, bacteriophages infecting Bacteroides fragilis, and Escherichia coli. The influence of environmental factors such as water temperature, salinity, and land runoff on the occurrence of these microbes was also included in this study. Enteric viruses were found in 50 to 60% of the mussel samples, and there were no pronounced differences between the samples from the three sites. E. coli counts exceeded the limit for category A for shellfish sanitary safety in 40% of the samples from the sites situated in fjords. However, at the site in the outer archipelago, this limit was exceeded only once, in March 2001, when extremely high levels of atypical indole-negative strains of E. coli were registered at all three sites. The environmental factors influenced the occurrence of viruses and phages differently, and therefore, it was hard to find a coexistence between them. This study shows that, for risk assessment, separate modeling should be done for every specific area, with special emphasis on environmental factors such as temperature and land runoff. The present standard for human fecal contamination, E. coli, seems to be an acceptable indicator of only local sanitary contamination; it is not a reliable indicator of viral contaminants in mussels. To protect consumers and get verification of "clean" mussels, it seems necessary to analyze for viruses as well. The use of a molecular index of the human contamination of Swedish shellfish underscores the need for reference laboratories with high-technology facilities.

  • 137. Hjelle, B
    et al.
    Jenison, S
    Torrez-Martinez, N
    Herring, B
    Quan, S
    Polito, A
    Pichuantes, S
    Yamada, T
    Morris, C
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Lee, H W
    Artsob, H
    Dinello, R
    Rapid and specific detection of Sin Nombre virus antibodies in patients with hantavirus pulmonary syndrome by a strip immunoblot assay suitable for field diagnosis.1997In: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 35, no 3, p. 600-8Article in journal (Refereed)
    Abstract [en]

    To develop a rapid antibody test for Sin Nombre hantavirus (SNV) infection for diagnosis of hantavirus pulmonary syndrome (HPS) in field settings where advanced instrumentation is not available, a strip immunoblot assay bearing four immobilized antigens for SNV and a recombinant nucleocapsid protein antigen of Seoul hantavirus (SEOV) was prepared. The SNV antigens included a full-length recombinant-expressed nucleocapsid (N) protein (rN), a recombinant-expressed G1 protein (residues 35 to 117), and synthetic peptides derived from N (residues 17 to 59) and G1 (residues 55 to 88). On the basis of the observed reactivities of hantavirus-infected patient and control sera, we determined that a positive assay requires reactivity with SNV or SEOV rN antigen and at least one other antigen. Isolated reactivity to either viral rN antigen is indeterminate, and any pattern of reactivity that does not include reactivity to an rN antigen is considered indeterminate but is unlikely to represent hantavirus infection. Fifty-eight of 59 samples from patients with acute SNV-associated HPS were positive according to these criteria, and one was initially indeterminate. Four of four samples from patients with HPS due to other hantaviruses were positive, as were most samples from patients with SEOV and Puumala virus infections. Of 192 control serum samples, 2 (1%) were positive and 2 were indeterminate. Acute SNV infection was distinguishable from remote SNV infection or infection with hantaviruses other than SNV by the presence of G1 peptide antigen reactivities in the former. The strip immunoblot assay shows promise for the detection of SNV antibodies early in the course of HPS.

  • 138. Hoffman, Tove
    et al.
    Lindeborg, Mats
    Barboutis, Christos
    Erciyas-Yavuz, Kiraz
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Fransson, Thord
    Figuerola, Jordi
    Jaenson, Thomas G. T.
    Kiat, Yosef
    Lindgren, Per-Eric
    Lundkvist, Åke
    Mohamed, Nahla
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Moutailler, Sara
    Nyström, Fredrik
    Olsen, Björn
    Salaneck, Erik
    Alkhurma Hemorrhagic Fever Virus RNA in Hyalomma rufipes Ticks Infesting Migratory Birds, Europe and Asia Minor2018In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 24, no 5, p. 879-882Article in journal (Refereed)
    Abstract [en]

    Alkhurma hemorrhagic fever virus RNA was detected in immature Hyalomma rufipes ticks infesting northward migratory birds caught in the North Mediterranean Basin. This finding suggests a role for birds in the ecology of the Alkhurma hemorrhagic fever virus and a potential mechanism for dissemination to novel regions. Increased surveillance is warranted.

  • 139. Holl, Katsiaryna
    et al.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Surcel, Heljä-Marja
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Koskela, Pentti
    Dillner, Joakim
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Olafsdottir, Gudridur H
    Ogmundsdottir, Helga M
    Pukkala, Eero
    Lehtinen, Matti
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Lukanova, Annekatrin
    Endogenous steroid hormone levels in early pregnancy and risk of testicular cancer in the offspring: A nested case-referent study.2009In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 124, no 12, p. 2923-2928Article in journal (Refereed)
    Abstract [en]

    According to the leading hypothesis on testicular cancer (TC) etiology exposure to a specific pattern of steroid hormones in utero, in particular, to high levels of estrogens and low levels of androgens is the major determinant of TC risk in the offspring. We performed a case-referent study nested within Finnish, Swedish and Icelandic maternity cohorts exploiting early pregnancy serum samples to evaluate the role of maternal endogenous steroid hormones with regard to the risk of TC. TC cases and referents were aged between 0 and 25 years. For each case-index mother pair, three or four matched referent-referent mother pairs were identified using national population registries. First trimester or early second trimester sera were retrieved from the index mothers of 73 TC cases and 286 matched referent mothers, and were tested for dehydroepiandrosterone sulfate (DHEAS), androstenedione, testosterone, estradiol, estrone, and sex hormone binding globulin (SHBG). Offspring of mothers with high DHEAS levels had a significantly decreased risk of TC (OR for highest vs. lowest DHEAS quartile, 0.18 (95% CI 0.06-0.58). In contrast, offspring of mothers with high androstenedione levels had an increased risk of TC (OR 4.1; 95% CI 1.2-12.0). High maternal total estradiol level also tended to be associated with an increased risk of TC in the offspring (OR 32; 95% CI 0.98-1,090). We report the first direct evidence that interplay of maternal steroid hormones in the early pregnancy is important in the etiology of TC in the offspring. (c) 2009 UICC.

  • 140. Holl, Katsiaryna
    et al.
    Surcel, Helja-Marja
    Koskela, Pentti
    Dillner, Joakim
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Kaasila, Marjo
    Olafsdottir, Gudridur H
    Ogmundsdottir, Helga M
    Pukkala, Eero
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Lehtinen, Matti
    Maternal Epstein-Barr virus and cytomegalovirus infections and risk of testicular cancer in the offspring: a nested case-control study2008In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 116, no 9, p. 816-822Article in journal (Refereed)
    Abstract [en]

    During recent decades the incidence of testicular cancer (TC) has increased rapidly around the world. Associated exogenous etiological factors might therefore be identifiable. We performed a case-control study nested within Finnish, Swedish and Icelandic maternity cohorts exploiting early pregnancy serum samples to evaluate the role of congenital or neonatal infections with Epstein-Barr virus (EBV) and cytomegalovirus (CMV) as risk factors of TC in the offspring. For each case-index mother pair, three or four matched control-control mother pairs were identified using national population registries. First trimester sera were retrieved from the index mothers of 66 TC cases and 258 matched control mothers, and were tested for antibodies to EBV and CMV. High level of maternal EBV IgG antibodies was associated with significantly increased risk of TC in the offspring (odds ratio (OR), 2.50; 95% confidence interval (CI), 1.15, 5.40), especially with risk of non-seminoma TC (OR, 2.73; 950% CI, 1.25, 5.99) and non-seminoma TC diagnosed under 8 years of age (OR, 2.72; 95% CI, 1.05, 7.04). In contrast, offspring of CMV IgG-seropositive mothers had a decreased risk of TC diagnosed under 8 years of age (OR, 0.35; 95% CI, 0.14, 0.89). Our results suggest that EBV and CMV infections may be associated with TC.

  • 141. Hooper, J W
    et al.
    Kamrud, K I
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Custer, D
    Schmaljohn, C S
    DNA vaccination with hantavirus M segment elicits neutralizing antibodies and protects against seoul virus infection.1999In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 255, no 2, p. 269-78Article in journal (Refereed)
    Abstract [en]

    Seoul virus (SEOV) is one of four known hantaviruses causing hemorrhagic fever with renal syndrome (HFRS). Candidate naked DNA vaccines for HFRS were constructed by subcloning cDNA representing the medium (M; encoding the G1 and G2 glycoproteins) or small (S; encoding the nucleocapsid protein) genome segment of SEOV into the DNA expression vector pWRG7077. We vaccinated BALB/c mice with three doses of the M or S DNA vaccine at 4-week intervals by either gene gun inoculation of the epidermis or needle inoculation into the gastrocnemius muscle. Both routes of vaccination resulted in antibody responses as measured by ELISA; however, gene gun inoculation elicited a higher frequency of seroconversion and higher levels of antibodies in individual mice. We vaccinated Syrian hamsters with the M or S construct using the gene gun and found hantavirus-specific antibodies in five of five and four of five hamsters, respectively. Animals vaccinated with the M construct developed a neutralizing antibody response that was greatly enhanced in the presence of guinea pig complement. Immunized hamsters were challenged with SEOV and, after 28 days, were monitored for evidence of infection. Hamsters vaccinated with M were protected from infection, but hamsters vaccinated with S were not protected.

  • 142. Ianevski, Aleksandr
    et al.
    Zusinaite, Eva
    Kuivanen, Suvi
    Strand, Mårten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Lysvand, Hilde
    Teppor, Mona
    Kakkola, Laura
    Paavilainen, Henrik
    Laajala, Mira
    Kallio-Kokko, Hannimari
    Valkonen, Miia
    Kantele, Anu
    Telling, Kaidi
    Lutsar, Irja
    Letjuka, Pille
    Metelitsa, Natalja
    Oksenych, Valentyn
    Bjoras, Magnar
    Nordbo, Svein Arne
    Dumpis, Uga
    Vitkauskiene, Astra
    Ohrmalm, Christina
    Bondeson, Kare
    Bergqvist, Anders
    Aittokallio, Tero
    Cox, Rebecca J.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Hukkanen, Veijo
    Marjomaki, Varpu
    Julkunen, Ilkka
    Vapalahti, Olli
    Tenson, Tanel
    Merits, Andres
    Kainov, Denis
    Novel activities of safe-in-human broad-spectrum antiviral agents2018In: Antiviral Research, ISSN 0166-3542, E-ISSN 1872-9096, Vol. 154, p. 174-182Article in journal (Refereed)
    Abstract [en]

    According to the WHO, there is an urgent need for better control of viral diseases. Re-positioning existing safe-inhuman antiviral agents from one viral disease to another could play a pivotal role in this process. Here, we reviewed all approved, investigational and experimental antiviral agents, which are safe in man, and identified 59 compounds that target at least three viral diseases. We tested 55 of these compounds against eight different RNA and DNA viruses. We found novel activities for dalbavancin against echovirus 1, ezetimibe against human immunodeficiency virus 1 and Zika virus, as well as azacitidine, cyclosporine, minocycline, oritavancin and ritonavir against Rift valley fever virus. Thus, the spectrum of antiviral activities of existing antiviral agents could be expanded towards other viral diseases.

  • 143.
    Idahl, Annika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Obstetrik och gynekologi.
    Abramsson, Leif
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Urologi och andrologi.
    Kumlin, U
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Liljeqvist, J A
    Olofsson, J I
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Obstetrik och gynekologi.
    Male serum Chlamydia trachomatis IgA and IgG, but not heat shock protein 60 IgG, correlates with negatively affected semen characteristics and lower pregnancy rates in the infertile couple2007In: International Journal of Andrology, ISSN 0105-6263, E-ISSN 1365-2605, Vol. 30, no 2, p. 99-107Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The objective of this study was to evaluate whether serum Chlamydia trachomatis immunoglobulin-A (IgA), IgM and C. trachomatis heat shock protein 60 (CHSP60) IgG are of additional value to C. trachomatis IgG regarding the impact on fecundity in infertile couples, and to relate C. trachomatis serum antibodies to semen characteristics, diagnoses and pregnancy outcome.

    METHODS: A total of 226 infertile couples, previously tested for C. trachomatis IgG, were tested for C. trachomatis IgA, IgM and CHSP60 IgG, and semen samples from all men were analysed.

    RESULTS: Chlamydia trachomatis serum IgA in men (but not in women) correlated with reduced chances of achieving pregnancy [p = 0.021, relative risk (RR) =0.65, 95% confidence interval (CI) 0.42-1.005] and in combination with C. trachomatis IgG the chance was further reduced (p =0.001, RR = 0.35, 95% CI 0.15-0.84). Chlamydia trachomatis serum IgA was also significantly correlated with reduced motility of the spermatozoa (-8.7%, p = 0.023), increased number of dead spermatozoa (+10.5%, p = 0.014) and higher prevalence of leucocytes in semen (+122%, p = 0.005), and in combination with C. trachomatis IgG positivity, there was also a decrease in sperm concentration (-35%, p = 0.033), the number of progressive spermatozoa (-14.8%, p = 0.029) and a rise in the teratozoospermia index (+4.4%, p = 0.010). CHSP60 IgG correlated with reduced motility (-5.6%, p = 0.033), and in the women to tubal factor infertility (p = 0.033), but no correlations of C. trachomatis serum IgM or CHSP60 IgG with pregnancy rates were found.

    CONCLUSIONS: Chlamydia trachomatis serum IgA in the male partner of the infertile couple has an additive value to IgG in predicting pregnancy chances, and serum IgA and IgG are associated with subtle negative changes in semen characteristics.

  • 144.
    Idahl, Annika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Boman, Jens
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Kumlin, Urban
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Olofsson, Jan I
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Demonstration of Chlamydia trachomatis IgG antibodies in the male partner of the infertile couple is correlated with a reduced likelihood of achieving pregnancy2004In: Human Reproduction, ISSN 0268-1161, E-ISSN 1460-2350, Vol. 19, no 5, p. 1121-1126Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The objective of this study was to determine the prevalence of Chlamydia trachomatis among both men and women seeking help at an infertility clinic, and to prospectively follow the effect of previous infection on pregnancy rates and pregnancy outcome after a long follow-up period (mean 37 months). 

    METHODS: A total of 244 infertile couples was tested for C. trachomatis IgG antibodies, and IgG(+) couples were also tested for C. trachomatis DNA by PCR in a first-void urine sample. Study parameters were serology, PCR results, clinical diagnoses, treatments, pregnancy rates and pregnancy outcome. As controls, age-matched and spontaneously pregnant women were also tested with serology. 

    RESULTS: The prevalence of IgG antibodies was 24.2, 20.1 and 15.6% among infertile women, infertile men and control women respectively. The prevalence of C. trachomatis DNA was 6.8 and 7.1% among tested women and men respectively. The presence of C. trachomatis IgG antibodies in women was related to tubal factor infertility (TFI) (P = 0.002). Decreased pregnancy rates were seen in couples where the man was IgG(+) (P = 0.005) with no relationship to TFI. Among women who achieved pregnancy, there was no difference in pregnancy outcome between IgG(+) or negative couples. 

    CONCLUSIONS: C. trachomatis IgG antibodies in the man of the infertile couple was related to decreased pregnancy rates and to the presence of IgG antibodies in the woman. There was a high prevalence of asymptomatic persistent infections among infertile couples.

  • 145.
    Idahl, Annika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Jurstrand, Margaretha
    Kliniskt forskingscentrum, Örebro universitetssjukhus.
    Møller, Jens K
    Klinisk mikrobiologi, Århus universitetssjukhus, Skejby, Danmark.
    Marklund, Ingrid
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Lindgren, Peter
    Inst för kvinnors och barns hälsa, obstetrik och gynekologi, Uppsala universitet.
    Ottander, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Chlamydia trachomatis, Mycoplasma genitalium, Neisseria gonorrhoeae, human papillomavirus, and polyomavirus are not detectable in human tissue with epithelial ovarian cancer, borderline tumor, or benign conditions2010In: American Journal of Obstetrics and Gynecology, ISSN 0002-9378, E-ISSN 1097-6868, Vol. 202, no 1, p. 71.e1-71.e6Article in journal (Other academic)
    Abstract [en]

    OBJECTIVE: We sought to analyze the presence of the microorganisms Chlamydia trachomatis, Mycoplasma genitalium, Neisseria gonorrhoeae, human papillomavirus (HPV), and the polyomaviruses BK virus (BKV) and JC virus (JCV) in ovarian tissues of women with ovarian carcinomas, borderline tumors, and benign conditions. STUDY DESIGN: Ovarian tissue, snap-frozen and stored at -80 degrees C, from 186 women with benign conditions, borderline tumors, and epithelial ovarian cancer, as well as tissue from the contralateral ovary of 126 of these women, were analyzed regarding presence of C trachomatis and N gonorrhoeae (transcription mediated amplification), M genitalium (real-time polymerase chain reaction [PCR]), HPV (PCR), and BKV and JCV (PCR). RESULTS: All the tissue samples studied were found negative for the microorganisms analyzed. CONCLUSION: C trachomatis, M genitalium, N gonorrhoeae, HPV, and the polyomaviruses BKV and JCV are not detectable in ovarian tissues either from women with benign conditions and borderline tumors or from women with ovarian cancer.

  • 146.
    Idahl, Annika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Jurstrand, Margaretha
    Clinical Research Centre, Örebro University Hospital.
    Kumlin, Urban
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Ohlson, Nina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Ottander, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Chlamydia trachomatis and Mycoplasma genitalium plasma antibodies in relation to epithelial ovarian tumors2011In: Infectious diseases in obstetrics and gynecology, ISSN 1064-7449, E-ISSN 1098-0997, Vol. 2011, p. 824627-Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To assess associations of Chlamydia trachomatis and Mycoplasma genitalium antibodies with epithelial ovarian tumors.

    METHODS: Plasma samples from 291 women, undergoing surgery due to suspected ovarian pathology, were analyzed with respect to C. trachomatis IgG and IgA, chlamydial Heat Shock Protein 60-1 (cHSP60-1) IgG and M. genitalium IgG antibodies. Women with borderline tumors (n=12), ovarian carcinoma (n=45), or other pelvic malignancies (n=11) were matched to four healthy controls each.

    RESULTS: Overall, there were no associations of antibodies with EOC. However, chlamydial HSP60-1 IgG antibodies were associated with type II ovarian cancer (P=.002) in women with plasma samples obtained >1 year prior to diagnosis (n=7). M. genitalium IgG antibodies were associated with borderline ovarian tumors (P=.01).

    CONCLUSION: Chlamydial HSP60-1 IgG and M. genitalium IgG antibodies are in this study associated with epithelial ovarian tumors in some subsets, which support the hypothesis linking upper-genital tract infections and ovarian tumor development.

  • 147.
    Idahl, Annika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jurstrand, Margaretha
    Kliniskt forskningscentrum, Örebro universitetssjukhus.
    Kumlin, Urban
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Elgh, Fredrik
    Hälsoakademin, Örebro universitet.
    Ohlson, Nina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ottander, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Chlamydia trachomatis and Mycoplasma genitalium plasma antibodies in relation to epithelial ovarian tumorsArticle in journal (Other academic)
  • 148. Imagawa, A
    et al.
    Hanafusa, T
    Makino, H
    Miyagawa, J-I
    Juto, Per
    Umeå University, Faculty of Medicine, Clinical Microbiology, Virology.
    High titres of IgA antibodies to enterovirus in fulminant type-1 diabetes.2005In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 48, no 2, p. 290-3Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: We have recently proposed that fulminant type-1 diabetes is a novel subtype of type-1 diabetes with abrupt onset of insulin-deficient hyperglycaemia without islet-related autoantibodies. The pathogenesis is still unknown, but flu-like symptoms are frequently observed before the onset of disease of this subtype. Enterovirus infection is a candidate environmental factor causing type-1 diabetes. The aim of this study was to determine whether enterovirus infection contributes to the development of fulminant type-1 diabetes. METHODS: We investigated 19 patients with recent-onset fulminant type-1 diabetes, 18 patients with recent-onset typical type-1A diabetes, and 19 healthy controls. IgM, IgG, and IgA subclasses of antibodies to enterovirus were determined by ELISA. RESULTS: IgA antibody titres to enterovirus were significantly higher in fulminant type-1 diabetes than in typical type-1A diabetes (p=0.033) and controls (p=0.0003). IgM antibodies to enterovirus were not detected in any subject. IgG titres were lower in autoimmune diabetes than fulminant type and controls (p=0.014 and 0.019, respectively). CONCLUSIONS/INTERPRETATION: High titres of enterovirus IgA antibodies in serum suggest recurrent enterovirus infection in fulminant type-1 diabetic patients, indicating higher susceptibility to enteroviral infections among them. Such infections might have pathogenetic importance in the triggering of fulminant type-1 diabetes.

  • 149.
    Islam, Koushikul
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Identification and evaluation of antiviral compounds targeting Rift Valley fever virus2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Rift Valley fever virus (RVFV), a negative-stranded RNA virus, is the etiological agent of the vector-borne zoonotic disease Rift Valley fever (RVF). RVFV causes significant morbidity and mortality in humans and livestock throughout Africa and the Arabian Peninsula. RVFV is an emerging virus and is capable of infecting a broad range of mosquito species distributed around the world, so it poses a potential threat globally. A wide range of livestock animals (e.g. sheep, goats, cows, and camels) and some wild animals become highly affected by RVFV. In humans, RVFV infection presents as an acute self-limiting febrile illness that may lead to more severe hemorrhagic fever and encephalitis. The severity of the disease is mostly dependent on age and the species of mammal, but other factors are also important.

    There are no licensed RVFV vaccines for humans, and there is a lack of effective antiviral drugs. Moreover, due to the severe pathogenicity, higher-level facilities are needed―biosafety level 3 (BSL-3) or more―to work with RVFV, which makes antiviral drug development more challenging. Because RVFV causes severe disease in Africa and the Arabian Peninsula, and has the potential to spread globally, it is essential that safe, efficient antiviral drugs against this virus are developed.

    The previously reported antiviral compound benzavir-2 inhibits the replication of several DNA viruses, i.e. human adenoviruses, herpes simplex virus (HSV) type 1, and HSV type 2, indicating a broadranging activity. We wanted to evaluate whether benzavir-2 had an effect against the RNA virus RVFV. For these and subsequent studies, we used a recombinant, modified RVFV strain with a deleted NSs gene, which was replaced by a reporter gene (rRVFVΔNSs::Katushka), enabling the studies to be conducted under BSL-2 conditions. The NSs gene is the main virulence factor for RVFV and without it, RVFV become less pathogenic. The reporter gene made it possible for us to quantify infection with the help of the red fluorescent protein. We found that benzavir-2 effectively inhibited RVFV infection in cell culture at an effective concentration showing 50% inhibition (EC50) of 0.6 μM. Benzavir-2 also inhibited the production of progeny virus. When we studied the pharmacokinetic properties, we found that benzavir-2 had good in vitro solubility, permeability, and metabolic stability. When we investigated the oral bioavailability in mice by administering benzavir-2 in peanut butter pellets, high systemic distribution was observed without any adverse toxic effects. Benzavir-2 thus inhibited RVFV infection in cell culture and showed excellent pharmacokinetic properties, suggesting the possibility of evaluating its effectiveness in an animal model. Since benzavir-2 has a broad effect against both RNA and DNA viruses, we speculated that the antiviral mechanism affects cellular targets.

    We also wanted to explore a large number of small chemical compounds with unknown properties and identify any anti-RVFV activities. Thus, we developed a whole-cell-based high-throughput reporter-based assay, and screened 28,437 small chemical compounds. The assay was established after optimization of several parameters. After primary and secondary screening, we identified 63 compounds that inhibited RVFV infection by 60% at a concentration of 3.12 μM and showed ≥ 50% cell viability at 25 μM. After a dose-dependent screening of these 63 compounds, several compounds were identified with highly efficient anti-RVFV properties. Finally, N1-(2-(biphenyl-4-yloxy)ethyl)propane-1,3-diamine (compound 1) was selected as the lead compound. We performed a structure-activity relationship (SAR) analysis of compound 1 by replacing and changing component after component of the chemical compound to see how this affected the antiviral activity. After the SAR analysis, the antiviral activity did not change, but we could improve the cytotoxicity profile. Our studies suggested that the improved compound, 13a, might be targeting the early phase of the RVFV lifecycle.

    In conclusion, we developed an efficient and reliable screening method that creates possibilities for discovering and developing antivirals against RVFV under BSL-2 conditions. We also identified several chemical compounds with anti-RVFV activities, which might lead to development of therapies for RVFV infection.

  • 150.
    Islam, Md. Koushikul
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Baudin, Maria
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Eriksson, Jonas
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Öberg, Christopher
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Habjan, Matthias
    Weber, Friedemann
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    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.
    High-Throughput Screening Using a Whole-Cell Virus Replication Reporter Gene Assay to Identify Inhibitory Compounds against Rift Valley Fever Virus Infection2016In: Journal of Biomolecular Screening, ISSN 1087-0571, E-ISSN 1552-454X, Vol. 21, no 4, p. 354-362Article in journal (Refereed)
    Abstract [en]

    Rift Valley fever virus (RVFV) is an emerging virus that causes serious illness in humans and livestock. There are no approved vaccines or treatments for humans. The purpose of the study was to identify inhibitory compounds of RVFV infection without any preconceived idea of the mechanism of action. A whole-cell-based high-throughput drug screening assay was developed to screen 28,437 small chemical compounds targeting RVFV infection. To accomplish both speed and robustness, a replication-competent NSs-deleted RVFV expressing a fluorescent reporter gene was developed. Inhibition of fluorescence intensity was quantified by spectrophotometry and related to virus infection in human lung epithelial cells (A549). Cell toxicity was assessed by the Resazurin cell viability assay. After primary screening, 641 compounds were identified that inhibited RVFV infection by 80%, with 50% cell viability at 50 mu M concentration. These compounds were subjected to a second screening regarding dose-response profiles, and 63 compounds with 60% inhibition of RVFV infection at 3.12 mu M compound concentration and 50% cell viability at 25 mu M were considered hits. Of these, six compounds with high inhibitory activity were identified. In conclusion, the high-throughput assay could efficiently and safely identify several promising compounds that inhibited RVFV infection.

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