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

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

  • 2. Boman, J
    et al.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Forsberg, J
    Birgander, L S
    Allard, A
    Persson, K
    Jidell, E
    Kumlin, U
    Juto, P
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Wadell, G
    High prevalence of Chlamydia pneumoniae DNA in peripheral blood mononuclear cells in patients with cardiovascular disease and in middle-aged blood donors.1998In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 178, no 1Article in journal (Refereed)
    Abstract [en]

    Nested polymerase chain reaction (nPCR) demonstrated the presence of Chlamydia pneumoniae-specific DNA in peripheral blood mononuclear cells (PBMC). PBMC samples were obtained from 103 consecutive patients (62 male, 41 female) aged 22-85 years (mean, 64) admitted for coronary angiography because of suspected coronary heart disease and from 52 blood donors (43 male, 9 female) aged 40-64 years (mean, 49). Of the 101 evaluable patients, 60 (59%) were identified by nPCR assay as C. pneumoniae DNA carriers; C. pneumoniae-specific microimmunofluorescence (MIF) serology confirmed exposure to the bacterium in 57 (95%) of the 60 nPCR-positive patients. Among the 52 blood donors, the nPCR assay identified 24 (46%) C. pneumoniae DNA carriers, all of whom were positive by C. pneumoniae-specific serology. Thirty-two patients (32%) and 23 blood donors (44%) were MIF antibody-positive but repeatedly nPCR-negative; Bartonella henselae- or Bartonella quintana-specific antibodies were not detected among any of these subjects. In this study, C. pneumoniae DNA was common in PBMC of patients with coronary heart disease and in middle-aged blood donors.

  • 3. Browall, Sarah
    et al.
    Norman, Martin
    Tångrot, Jeanette
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Bioinformatics Infrastructure for Life Sciences, Computational Life Science Cluster.
    Galanis, Ilias
    Sjöstrom, Karin
    Dagerhamn, Jessica
    Hellberg, Christel
    Pathak, Anuj
    Spadafina, Tiziana
    Sandgren, Andreas
    Bättig, Patrick
    Franzén, Oscar
    Andersson, Björn
    Örtqvist, Åke
    Normark, Staffan
    Henriques-Normark, Birgitta
    Intraclonal Variations Among Streptococcus pneumoniae Isolates Influence the Likelihood of Invasive Disease in Children2014In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 209, no 3, p. 377-388Article in journal (Refereed)
    Abstract [en]

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

  • 4.
    Bröms, Jeanette
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Department of Medical Countermeasures, Swedish Defence Research Agency.
    Forslund, Anna-Lena
    Department of Medical Countermeasures, Swedish Defence Research Agency.
    Forsberg, Åke
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Medical Countermeasures, Swedish Defence Research Agency.
    Francis, Matthew
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    PcrH of Pseudomonas aeruginosa is essential for secretion and assembly of the type III translocon2003In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 188, no 12, p. 1909-1921Article in journal (Refereed)
    Abstract [en]

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

  • 5.
    Bröms, Jeanette
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Sundin, Charlotta
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Francis, Matthew
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Forsberg, Åke
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Comparative analysis of type III effector translocation by Yersinia pseudotuberculosis expressing native LcrV or PcrV from Pseudomonas aeruginosa2003In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 188, no 2, p. 239-249Article in journal (Refereed)
    Abstract [en]

    The homologues LcrV of Yersinia species and PcrV of Pseudomonas aeruginosa are pore-forming components. When expressed in a Yersinia lcrV background, PcrV formed smaller pores in infected erythrocyte membranes, correlating to a lowered translocation of Yersinia effectors. To understand this phenomenon, cytotoxins exoenzyme S of P. aeruginosa and YopE of Yersinia were introduced into a Yersinia background without Yop effectors but expressing LcrV or PcrV. Comparable translocation of each substrate indicated that substrate recognition by LcrV/PcrV is not a regulator of translocation. Yersinia harboring pcrV coexpressed with its native operon efficiently translocated effectors into HeLa cell monolayers and formed large LcrV-like pores in erythrocyte membranes. Thus, a PcrV complex with native P. aeruginosa translocon components is required to form fully functional pores for complete complementation of effector translocation in Yersinia.

  • 6. Charpentier, E
    et al.
    Gerbaud, G
    Jacquet, C
    Rocourt, J
    Courvalin, P
    Incidence of antibiotic resistance in Listeria species.1995In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 172, no 1, p. 277-281Article in journal (Refereed)
    Abstract [en]

    To define the prevalence of antibiotic resistance in Listeria species pathogenic for humans and animals, 1100 isolates (60 from cases of listeriosis and 1040 from food and environment) collected worldwide were screened. Of the 61 tetracycline- and minocycline-resistant strains (37 Listeria monocytogenes), 57 harbored tet(M); 4 non-L. monocytogenes isolates contained tet(S). One Listeria innocua isolate was also resistant to streptomycin and contained the tet(M) and aad6 genes. An L. monocytogenes isolate was trimethoprim-resistant, a characteristic not reported previously in Listeria species, because of the presence of a yet-uncharacterized gene. Three clinical isolates of L. monocytogenes were resistant to low levels of streptomycin. Since the tet(M), tet(S), and aad6 genes are common in enterococci and streptococci, these data suggest transfer from the latter to Listeria species. Uniform susceptibility to tetracycline, minocycline, trimethoprim, and streptomycin cannot be assumed any longer for Listeria species.

  • 7. Chu, Y K
    et al.
    Jennings, G
    Schmaljohn, A
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Hjelle, B
    Lee, H W
    Jenison, S
    Ksiazek, T
    Peters, C J
    Rollin, P
    Cross-neutralization of hantaviruses with immune sera from experimentally infected animals and from hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome patients.1995In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 172, no 6, p. 1581-4Article in journal (Refereed)
    Abstract [en]

    Plaque-reduction neutralization tests were done with eight of nine known representative hantaviruses and immune sera from experimentally infected animals and from patients with hemorrhagic fever with renal syndrome (HFRS) or hantavirus pulmonary syndrome (HPS). Results obtained with animal sera demonstrated each virus to be antigenically unique. Neutralization with the HPS patient sera was highest with Sin Nombre (SN) virus and to a lesser extent with Black Creek Canal (BCC) virus. Sera from Korean HFRS patients reacted best with Hantaan virus, but cross-reactivity with all other viruses except Thottapalayam (TPM) virus was also observed. Sera from Swedish HFRS patients reacted best with Puumala virus but cross-reacted with Prospect Hill, SN, and BCC viruses and to a lesser extent with all of the other viruses except TPM virus.

  • 8.
    Connolly-Andersen, Anne-Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Sundberg, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Baudin, Maria
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Larsson, Johanna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Dunne, Eimear
    Clinical Research Centre, Royal College of Surgeons in Ireland, Dublin .
    Kenny, Dermot
    Clinical Research Centre, Royal College of Surgeons in Ireland, Dublin .
    Lindahl, Tomas L.
    Department of Clinical and Experimental Medicine, Linköping University, Sweden.
    Ramström, Sofia
    Department of Clinical and Experimental Medicine, Linköping University, Sweden.
    Nilsson, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Increased Thrombopoiesis and Platelet Activation in Hantavirus-Infected Patients2015In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 212, no 7, p. 1061-1069Article in journal (Refereed)
    Abstract [en]

    Background. Thrombocytopenia is a common finding during viral hemorrhagic fever, which includes hemorrhagic fever with renal syndrome (HFRS). The 2 main causes for thrombocytopenia are impaired thrombopoiesis and/or increased peripheral destruction of platelets. In addition, there is an increased intravascular coagulation risk during HFRS, which could be due to platelet activation. Methods. Thrombopoiesis was determined by quantification of platelet counts, thrombopoietin, immature platelet fraction, and mean platelet volume during HFRS. The in vivo platelet activation was determined by quantification of soluble P-selectin (sP-selectin) and glycoprotein VI (sGPVI). The function of circulating platelets was determined by ex vivo stimulation followed by flow cytometry analysis of platelet surface-bound fibrinogen and P-selectin exposure. Intravascular coagulation during disease was determined by scoring for disseminated intravascular coagulation (DIC) and recording thromboembolic complications. Results. The levels of thrombopoietin, immature platelet fraction, and mean platelet volume all indicate increased thrombopoiesis during HFRS. Circulating platelets had reduced ex vivo function during disease compared to follow-up. Most interestingly, we observed significantly increased in vivo platelet activation in HFRS patients with intravascular coagulation (DIC and thromboembolic complications) as shown by sP-selectin and sGPVI levels. Conclusions. HFRS patients have increased thrombopoiesis and platelet activation, which contributes to intravascular coagulation.

  • 9.
    Gekara, Nelson O
    et al.
    Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Dietrich, Nicole
    Lyszkiewicz, Marcin
    Lienenklaus, Stefan
    Weiss, Siegfried
    Signals triggered by a bacterial pore-forming toxin contribute to toll-like receptor redundancy in gram-positive bacterial recognition.2009In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 199, no 1, p. 124-33Article in journal (Refereed)
    Abstract [en]

    The results illustrate that signals triggered by LLO contribute to TLR2 redundancy in recognition of L. monocytogenes. Under normal conditions, multiple and, sometimes, redundant pathways cooperate to induce a rapid antimicrobial defense. When one signaling pathway-in this case, TLR2-is removed from the system, the other pathways are still capable of mounting a sufficient response to ensure survival of the host.

  • 10.
    Gekara, Nelson O
    et al.
    Molecular Immunology, Helmholtz Center for Infection Research, Braunschweig, Germany.
    Zietara, Natalia
    Molecular Immunology and 2Department of Cell Biology, Helmholtz Center for Infection Research, Braunschweig, Germany.
    Geffers, Robert
    Molecular Immunology and 2Department of Cell Biology, Helmholtz Center for Infection Research, Braunschweig, Germany.
    Weiss, Siegfried
    Molecular Immunology and 2Department of Cell Biology, Helmholtz Center for Infection Research, Braunschweig, Germany.
    Listeria monocytogenes induces T cell receptor unresponsiveness through pore-forming toxin listeriolysin O2010In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 202, no 11, p. 1698-1707Article in journal (Refereed)
    Abstract [en]

    Background.  The success of many pathogens relies on their ability to circumvent the innate and adaptive immune defenses. How bacterial pathogens subvert adaptive immune defenses is not clear. Cholesterol-dependent cytolysins (CDCs) represent an expansive family of homologous pore-forming toxins that are produced by more than 20 gram-positive bacterial species. Listeriolysin O (LLO), a prototype CDC, is the main virulence factor of Listeria monocytogenes. Methods.  We employed flow cytometric and microarray techniques to analyze the effect of LLO on T cell activation in vitro and in vivo. Results.  In vivo and in vitro proliferation of CD4(+) T cells upon T cell receptor (TCR) activation was highly diminished in the presence of LLO or wild-type L. monocytogenes but not in the presence of LLO-deficient L. monocytogenes. This block in T cell proliferation was specific to T cell activation via the TCR and not by phorbol 12-myristate 13-acetate-ionomycin, which bypasses the proximal TCR signaling event. The results of microarray analysis suggest that LLO-induced T cell unresponsiveness is due to the induction of a calcium-nuclear factor of activated T cells-dependent transcriptional program that drives the expression of negative regulators of TCR signaling. Conclusion. These findings provide important insights into how bacterial toxins silence adaptive immune responses and thus enable prolonged survival of the pathogen in the host.

  • 11. Goncalves, Adriana
    et al.
    Peeling, Rosanna W.
    Chu, May C.
    Gubler, Duane J.
    de Silva, Aravinda M.
    Harris, Eva
    Murtagh, Maurine
    Chua, Arlene
    Rodriguez, William
    Kelly, Cassandra
    Wilder-Smith, Annelies
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Lee Kong Chian School of Medicine, Singapore; Institute of Public Health, University of Heidelberg, Germany.
    Innovative and New Approaches to Laboratory Diagnosis of Zika and Dengue: A Meeting Report2018In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 217, no 7, p. 1060-1068Article in journal (Refereed)
    Abstract [en]

    Epidemics of dengue, Zika, and other arboviral diseases are increasing in frequency and severity. Current efforts to rapidly identify and manage these epidemics are limited by the short diagnostic window in acute infection, the extensive serologic cross-reactivity among flaviviruses, and the lack of point-of-care diagnostic tools to detect these viral species in primary care settings. The Partnership for Dengue Control organized a workshop to review the current landscape of Flavivirus diagnostic tools, identified current gaps, and developed strategies to accelerate the adoption of promising novel technologies into national programs. The rate-limiting step to bringing new diagnostic tools to the market is access to reference materials and well-characterized clinical samples to facilitate performance evaluation. We suggest the creation of an international laboratory-response consortium for flaviviruses with a decentralized biobank of well-characterized samples to facilitate assay validation. Access to proficiency panels are needed to ensure quality control, in additional to in-country capacity building.

  • 12.
    Gothefors, Leif
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Ahrén, C
    Stoll, B
    Barua, D K
    Orskov, F
    Salek, M A
    Svennerholm, A M
    Presence of colonization factor antigens on fresh isolates of fecal Escherichia coli: a prospective study.1985In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 152, no 6, p. 1128-33Article in journal (Refereed)
    Abstract [en]

    In Dhaka, Bangladesh, fresh isolates of Escherichia coli from 197 patients with diarrhea were investigated for production of enterotoxin and possession of colonization factor antigen (CFA) I or II. Enterotoxigenic E. coli (ETEC) was isolated from 34% of the patients, and of the 67 enterotoxin-positive strains, 75% carried CFAs. Among 68 healthy control persons no strains positive for both enterotoxin and CFA were found. The CFAs in general were restricted to certain serotypes of E. coli. In a subgroup of patients, part of an ongoing surveillance study, mixed infection was seen in 23% of those from whom recognized pathogens were identified. There was a tendency to more severe dehydration when the two virulence factors, enterotoxin and CFA, were simultaneously present.

  • 13.
    Gothefors, Leif
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Wadell, G
    Juto, P
    Taniguchi, K
    Kapikian, A Z
    Glass, R I
    Prolonged efficacy of rhesus rotavirus vaccine in Swedish children.1989In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 159, no 4, p. 753-7Article in journal (Refereed)
  • 14. Grankvist, Olof
    et al.
    Juto, Per
    Settergren, Bo
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Bjermer, L
    Linderholm, M
    Tärnvik, A
    Wadell, G
    Detection of nephropathia epidemica virus RNA in patient samples using a nested primer-based polymerase chain reaction.1992In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 165, no 5, p. 934-7Article in journal (Refereed)
    Abstract [en]

    A nested primer-based polymerase chain reaction was constructed for the detection of Puumala virus RNA in patient samples. Puumala virus RNA was detected in cells from the urinary and the respiratory tracts and in peripheral blood mononuclear cells of patients with nephropathia epidemica. After inoculation with nephropathia epidemica patient material on Vero E6 cells and propagation for nine passages (4 months), Puumala virus RNA was detected at every passage. Hybridization under high-stringency conditions revealed that the overall nucleotide homology between the different patient isolates and the prototype strain (Puumala) is high. Using cDNA from Hällnäs B1 strain as a probe, hybridization occurred only under low-stringency conditions.

  • 15. 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)
  • 16. Henningsson, Louise
    et al.
    Jirholt, Pernilla
    Bogestal, Yalda Rahpeymai
    Eneljung, Tove
    Adiels, Martin
    Lindholm, Catharina
    McInnes, Iain
    Bulfone-Paus, Silvia
    Lerner, Ulf H
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Gjertsson, Inger
    Interleukin 15 mediates joint destruction in staphylococcus aureus arthritis2012In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 206, no 5, p. 687-696Article in journal (Refereed)
    Abstract [en]

    Background. Staphylococcus aureus arthritis causes severe and rapid joint damage despite antibiotics. Thus, there is a need to identify new treatment targets in addition to antibiotics. Lately, interleukin 15 (IL-15) has been implicated both in osteoclastogenesis and in bacterial clearance-2 important issues in S. aureus-induced joint destruction. This has prompted us to investigate the importance of IL-15 in S. aureus-induced arthritis.

    Methods.Toxic shock syndrome toxin-1 producing S. aureus was intravenously inoculated in IL-15 knockout and wildtype mice and in wildtype mice treated with anti-IL-15 antibodies (aIL-15ab) or isotype control antibody.

    Results. Absence of IL-15, either in knockout mice or after treatment with aIL-15ab, significantly reduced weight loss compared with controls during the infection. The severity of synovitis and joint destruction was significantly decreased in IL-15 knockout and aIL-15ab treated mice compared with controls. In IL-15 knockout mice there was a reduced number of osteoclasts in the joints. The host's ability to clear bacteria was not influenced in the IL-15 knockout mice, but significantly increased after treatment with aIL-15ab.

    Conclusions. IL-15 is a mediator of joint destruction in S. aureus-induced arthritis and contributes to general morbidity, which makes this cytokine an interesting treatment target in addition to conventional antibiotics.

  • 17. Kubler, Andre
    et al.
    Larsson, Christer
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Luna, Brian
    Andrade, Bruno B.
    Amaral, Eduardo P.
    Urbanowski, Michael
    Orandle, Marlene
    Bock, Kevin
    Ammerman, Nicole C.
    Cheung, Laurene S.
    Winglee, Kathryn
    Halushka, Marc
    Park, Jin Kyun
    Sher, Alan
    Friedland, Jon S.
    Elkington, Paul T.
    Bishai, William R.
    Cathepsin K Contributes to Cavitation and Collagen Turnover in Pulmonary Tuberculosis2016In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 213, no 4, p. 618-627Article in journal (Refereed)
    Abstract [en]

    Cavitation in tuberculosis enables highly efficient person-to-person aerosol transmission. We performed transcriptomics in the rabbit cavitary tuberculosis model. Among 17 318 transcripts, we identified 22 upregulated proteases. Five type I collagenases were overrepresented: cathepsin K (CTSK), mast cell chymase-1 (CMA1), matrix metalloproteinase 1 (MMP-1), MMP-13, and MMP-14. Studies of collagen turnover markers, specifically, collagen type I C-terminal propeptide (CICP), urinary deoxypyridinoline (DPD), and urinary helical peptide, revealed that cavitation in tuberculosis leads to both type I collagen destruction and synthesis and that proteases other than MMP-1, MMP-13, and MMP-14 are involved, suggesting a key role for CTSK. We confirmed the importance of CTSK upregulation in human lung specimens, using immunohistochemical analysis, which revealed perigranulomatous staining for CTSK, and we showed that CTSK levels were increased in the serum of patients with tuberculosis, compared with those in controls (3.3 vs 0.3 ng/mL; P = .005).

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

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

  • 19.
    Larsson, Christer
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Andersson, Marie
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Guo, Betty P
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Nordstrand, Annika
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hägerstrand, Inga
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Carlsson, Sara
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Complications of pregnancy and transplacental transmission of relapsing-fever borreliosis2006In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 194, no 10, p. 1367-1374Article in journal (Refereed)
    Abstract [en]

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

  • 20.
    Linderholm, Mats
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Settergren, Bo
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Waage, A
    Tärnvik, Arne
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Elevated plasma levels of tumor necrosis factor (TNF)-alpha, soluble TNF receptors, interleukin (IL)-6, and IL-10 in patients with hemorrhagic fever with renal syndrome.1996In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 173, no 1, p. 38-43Article in journal (Refereed)
    Abstract [en]

    Plasma levels of cytokines were measured by EIA in 15 subjects hospitalized with nephropathia epidemica, a European form of hantavirus-induced hemorrhagic fever with renal syndrome. Concentrations of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 were increased in all patients at admission, and the concentration of IL-10 was increased in most. TNF-alpha concentrations were still increased 1 week after onset of disease; levels of IL-6 and IL-10 were normalized. TNF-alpha was undetectable by the WEHI cell assay in serum samples obtained throughout the acute phase of disease. Serum levels of the two soluble TNF receptors p55 and p75 correlated with levels of the cytokine, indicating that receptor binding may be the reason for lack of bioactivity in vitro. TNF-alpha is known to induce pathophysiologic and clinical changes similar to those seen in nephropathia epidemica and in diseases caused by other hantaviruses.

  • 21. Moyes, Jocelyn
    et al.
    Cohen, Cheryl
    Pretorius, Marthi
    Groome, Michelle
    von Gottberg, Anne
    Wolter, Nicole
    Walaza, Sibongile
    Haffejee, Sumayya
    Chhagan, Meera
    Naby, Fathima
    Cohen, Adam L.
    Tempia, Stefano
    Kahn, Kathleen
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. INDEPTH network, Accra, Ghana.
    Dawood, Halima
    Venter, Marietjie
    Madhi, Shabir A.
    Epidemiology of Respiratory Syncytial Virus-Associated Acute Lower Respiratory Tract Infection Hospitalizations Among HIV-Infected and HIV-Uninfected South African Children, 2010-20112013In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 208, no Supplement: 3, p. S217-S226Article in journal (Refereed)
    Abstract [en]

    Background. There are limited data on respiratory syncytial virus (RSV) infection among children in settings with a high prevalence of human immunodeficiency virus (HIV). We studied the epidemiology of RSV-associated acute lower respiratory tract infection (ALRTI) hospitalizations among HIV-infected and HIV-uninfected children in South Africa. Methods. Children aged <5 years admitted to sentinel surveillance hospitals with physician-diagnosed neonatal sepsis or ALRTI were enrolled. Nasopharyngeal aspirates were tested by multiplex real-time polymerase chain reaction assays for RSV and other viruses. Associations between possible risk factors and severe outcomes for RSV infection among HIV-infected and uninfected children were examined. The relative risk of hospitalization in HIV-infected and HIV-uninfected children was calculated in 1 site with population denominators. Results. Of 4489 participants, 4293 (96%) were tested for RSV, of whom 1157 (27%) tested positive. With adjustment for age, HIV-infected children had a 3-5-fold increased risk of hospitalization with RSV-associated ALRTI (2010 relative risk, 5.6; [95% confidence interval (CI), 4.5-6.4]; 2011 relative risk, 3.1 [ 95% CI, 2.6-3.6]). On multivariable analysis, HIV-infected children with RSV-associated ALRTI had higher odds of death (adjusted odds ratio. 31.1; 95% CI, 5.4-179.8) and hospitalization for >5 days (adjusted odds ratio, 4.0; 95% CI, 1.5-10.6) than HIV-uninfected children. Conclusion. HIV-infected children have a higher risk of hospitalization with RSV-associated ALRTI and a poorer outcome than HIV-uninfected children. These children should be targeted for interventions aimed at preventing severe RSV disease.

  • 22. Ohno, Tomoyuki
    et al.
    Vallström, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Department of Odontology, Oral Microbiology. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Rugge, Massimo
    Ota, Hiroyoshi
    Graham, David Y
    Arnqvist, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Yamaoka, Yoshio
    Effects of blood group antigen-binding adhesin expression during Helicobacter pylori infection of Mongolian gerbils2011In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 203, no 5, p. 726-735Article in journal (Refereed)
    Abstract [en]

    Helicobacter pylori outer membrane proteins, such as the blood group antigen-binding adhesin (BabA), are associated with severe pathological outcomes. However, the in vivo role of BabA during long-term infection is not clear. In this study, Mongolian gerbils were infected with H. pylori and necropsied continuously during 18 months. Bacterial clones were recovered and analyzed for BabA expression, Leb-binding activity, and adhesion to gastric mucosa. BabA expression was completely absent by 6 months post-infection. Loss of BabA expression was attributable to nucleotide changes within the babA gene that resulted in a truncated BabA. In response to the infection, changes in the epithelial glycosylation pattern were observed that were similar to responses observed in humans and monkeys. Furthermore, infections with BabA-expressing and BabA-nonexpressing H. pylori showed no differences in colonization, but infection with the BabA-expressing strain exhibited histological changes and increased inflammatory cell infiltration. This suggests that BabA expression contributes to severe mucosal injury.

  • 23.
    Pettersson-Kymmer, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hanson, Aimee L
    Madeleine, Margaret M
    Wang, Sophia S
    Schwartz, Stephen M
    Newell, Felicity
    Pettersson-Kymmer, Ulrika
    Hemminki, Kari
    Tiews, Sven
    Steinberg, Winfried
    Rader, Janet S
    Castro, Felipe
    Safaeian, Mahboobeh
    Franco, Eduardo L
    Coutlée, François
    Ohlsson, Claes
    Cortes, Adrian
    Marshall, Mhairi
    Mukhopadhyay, Pamela
    Cremin, Katie
    Johnson, Lisa G
    Garland, Suzanne M
    Tabrizi, Sepehr N
    Wentzensen, Nicolas
    Sitas, Freddy
    Trimble, Cornelia
    Little, Julian
    Cruickshank, Maggie
    Frazer, Ian H
    Hildesheim, Allan
    Brown, Matthew A
    Duncan, Emma L
    Sun, YingPu
    Leo, Paul J
    HLA and KIR Associations of Cervical Neoplasia2018In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 218, no 12, p. 2006-2015Article in journal (Refereed)
    Abstract [en]

    Background: Cervical cancer is the fourth most common cancer in women, and we recently reported human leukocyte antigen (HLA) alleles showing strong associations with cervical neoplasia risk and protection. HLA ligands are recognised by killer immunoglobulin-like receptors (KIRs) expressed on a range of immune cell subsets, governing their proinflammatory activity. We hypothesized that the inheritance of particular HLA-KIR combinations would increase cervical neoplasia risk.

    Methods: Here, we used HLA and KIR dosages imputed from SNP genotype data from 2,143 cervical neoplasia cases and 13,858 healthy controls of European decent.

    Results: Four novel HLA alleles were identified in association with cervical neoplasia: HLA-DRB3*9901 (OR=1.24, P=2.49×10-9), HLA-DRB5*0101 (OR=1.29, P=2.26×10-8), HLA-DRB5*9901 (OR=0.77, P=1.90×10-9) and HLA-DRB3*0301 (OR=0.63, P=4.06×10-5), due to their linkage disequilibrium with known cervical neoplasia-associated HLA-DRB1 alleles. We also found homozygosity of HLA-C1 group alleles is a protective factor for HPV16-related cervical neoplasia (C1/C1, OR=0.79, P=0.005). This protective association was restricted to carriers of either KIR2DL2 (OR=0.67, P=0.00045) or KIR2DS2 (OR=0.69, P=0.0006).

    Conclusions: Our findings suggest that HLA-C1 group alleles play a role in protecting against HPV16-related cervical neoplasia, mainly through a KIR-mediated mechanism.

  • 24. Ryan, M
    et al.
    Murphy, G
    Gothefors, Leif
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Nilsson, L
    Storsaeter, J
    Mills, K H
    Bordetella pertussis respiratory infection in children is associated with preferential activation of type 1 T helper cells.1997In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 175, no 5, p. 1246-50Article in journal (Refereed)
    Abstract [en]

    The mechanism of protective immunity against Bordetella pertussis generated following recovery from whooping cough in childhood has not yet been elucidated. Studies with a murine respiratory infection model have indicated that cellular immunity, mediated by Th1 cells, plays a role in the clearance of a primary infection with B. pertussis and in protection against subsequent challenge. In the present study, the induction of B. pertussis-specific Th cell subsets in children was examined. Peripheral blood mononuclear cells from B. pertussis-infected or convalescent children proliferated and secreted cytokines following antigen stimulation in vitro. In contrast, responses were weak or undetectable in the majority of children who had not been infected or vaccinated. In all cases, responding T cells produced interferon-gamma but low or undetectable interleukin-5. The findings suggest that Th1 cells may play a role in protective immunity generated following infection with B. pertussis in children.

  • 25.
    Rydén, Patrik
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Björk, Rafael
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Schäfer, Martina L
    Lundström, Jan O
    Petersén, Bodil
    Lindblom, Anders
    Forsman, Mats
    Sjöstedt, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Outbreaks of tularemia in a boreal forest region depends on mosquito prevalence2012In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 205, no 2, p. 297-304Article in journal (Refereed)
    Abstract [en]

    Background. We aimed to evaluate the potential association of mosquito prevalence in a boreal forest area with transmission of the bacterial disease tularemia to humans, and model the annual variation of disease using local weather data.

    Methods. A prediction model for mosquito abundance was built using weather and mosquito catch data. Then a negative binomial regression model based on the predicted mosquito abundance and local weather data was built to predict annual numbers of humans contracting tularemia in Dalarna County, Sweden.

    Results. Three hundred seventy humans were diagnosed with tularemia between 1981 and 2007, 94% of them during 7 summer outbreaks. Disease transmission was concentrated along rivers in the area. The predicted mosquito abundance was correlated (0.41, P < .05) with the annual number of human cases. The predicted mosquito peaks consistently preceded the median onset time of human tularemia (temporal correlation, 0.76; P < .05). Our final predictive model included 5 environmental variables and identified 6 of the 7 outbreaks.

    Conclusions. This work suggests that a high prevalence of mosquitoes in late summer is a prerequisite for outbreaks of tularemia in a tularemia-endemic boreal forest area of Sweden and that environmental variables can be used as risk indicators.

  • 26. Schmitz, Franz-Josef
    et al.
    Beyer, Andreas
    Charpentier, Emmanuelle
    Normark, Birgitta Henriques
    Schade, Marc
    Fluit, Ad C
    Hafner, Dieter
    Novak, Rodger
    Toxin-gene profile heterogeneity among endemic invasive European group A streptococcal isolates.2003In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 188, no 10, p. 1578-1586Article in journal (Refereed)
    Abstract [en]

    We determined the toxin-gene profiles of 239 endemic, invasive group A streptococcal (GAS) isolates that circulated, within a 5-year period, in European university hospitals. Profiling was performed by use of multiplex polymerase chain reaction that screened for 9 streptococcal pyrogenic exotoxins (speA, speB, speC, speF, speG, speH, speJ, ssa, and smeZ). Analysis revealed that invasive GAS isolates do not share a common toxin-gene profile. Although all emm types were characterized by several different toxin-gene profiles, a predominance of 1 or 2 toxin-gene profiles could be observed, reflecting that a few invasive clones have spread successfully throughout the world. Remarkably, statistical pair-wise analysis of individual toxin genes revealed that strains that did not share the predominant profile still showed a nonrandom distribution of key toxin genes characteristic of the specific emm type. This could indicate that M proteins function, directly or indirectly, as barriers for horizontal gene exchange.

  • 27. Slepenkin, Anatoly
    et al.
    Chu, Hencelyn
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Keyser, Pia
    Peterson, Ellena M
    Protection of mice from a chlamydia trachomatis vaginal infection using a salicylidene acylhydrazide, a potential Mmcrobicide2011In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 204, no 9, p. 1314-1320Article in journal (Refereed)
    Abstract [en]

    The salicylidene acylhydrazide INP0341 inhibits growth of Chlamydia in HeLa cells, has negligible cell toxicity, and does not inhibit the growth of lactobacilli. The antichlamydial activity of INP0341 was retained when tested in vaginal and semen simulants. Vaginal tissue from INP0341-treated mice appeared similar to control sham-treated mice. To determine whether INP0341 can protect mice from a vaginal challenge, C3H/HeJ mice were either sham or INP0341 treated intravaginally pre- and postinoculation with 5 × 10(2) inclusion-forming units (IFUs) of Chlamydia trachomatis serovar D. Vaginal cultures taken over a month-long period showed a significant difference in the number of control mice that were culture positive versus the number in the INP0341-treated group, 100% (25/25) and 31% (8/26), respectively (P < .05). The quantity of IFUs shed and antibody titers to Chlamydia were significantly higher for the control group (P < .05). In summary, INP0341 is a promising compound to be considered for formulation as a vaginal microbicide.

  • 28. Stoll, B J
    et al.
    Svennerholm, A M
    Gothefors, Leif
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Barua, D
    Huda, S
    Holmgren, J
    Local and systemic antibody responses to naturally acquired enterotoxigenic Escherichia coli diarrhea in an endemic area.1986In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 153, no 3, p. 527-34Article in journal (Refereed)
    Abstract [en]

    Fifteen patients hospitalized with acute, watery diarrhea and with enterotoxigenic Escherichia coli (ETEC) detected from stool samples were studied to evaluate the extent to which natural ETEC diarrhea induces local and systemic antibody responses to E. coli heat-labile toxin (LT), homologous lipopolysaccharide (LPS), and colonization factors (CFA/I and CFA/II). Specific IgA and IgG antibodies to LT, CFA I and II, and each patient's homologous LPS were determined by ELISA in serum, saliva, breastmilk, and intestinal lavage fluid. The majority of patients had greater than a twofold rise in local levels of IgA antibodies in the intestine: 80% of LT+ patients responded to LT, 63% of CFA+ patients responded to CFA, and 78% of all toxin-positive patients responded to the LPS of their infecting strain. Local antibody responses in the intestine were associated with responses in breastmilk and saliva, but relationships were not clear-cut, and the usefulness of these secretions as proxy measures of local intestinal antibody production remains unclear. Antibody responses in serum also occurred in most patients and were significantly more frequent in cases than in controls. This study demonstrates that natural ETEC disease results in local IgA responses to LT, CFA, and LPS in the gut and also in immune responses in breastmilk, saliva, and serum.

  • 29. Svennerholm, A M
    et al.
    Jertborn, M
    Gothefors, Leif
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Karim, A M
    Sack, D A
    Holmgren, J
    Mucosal antitoxic and antibacterial immunity after cholera disease and after immunization with a combined B subunit-whole cell vaccine.1984In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 149, no 6, p. 884-93Article in journal (Refereed)
    Abstract [en]

    Mucosal and systemic immune responses to a new oral cholera vaccine, consisting of the B subunit plus killed vibrios, were studied in Bangladeshi volunteers and compared with those to clinical cholera. A single peroral dose of vaccine induced a local IgA antitoxin response in intestinal-lavage fluid of seven of eight vaccinees; the response closely mimicked that of patients convalescing from cholera, and evidence of the induction of local immunologic memory was found as well. Two peroral doses were needed for stimulation of an intestinal IgA immune response to the lipopolysaccharide of Vibrio cholerae that was comparable to the response obtained after clinical cholera. This response to peroral immunization was considerably stronger than that to parenteral vaccination, although the intramuscular route gave rise to the strongest IgG antitoxin and antilipolysaccharide responses in serum. The results suggest that B subunit-whole cell vaccine, when given in at least two oral doses, may be a good candidate for use in cholera prophylaxis.

  • 30. Tissera, Hasitha
    et al.
    Rathore, Abhay P. S.
    Leong, Wei Yee
    Pike, Brian L.
    Warkentien, Tyler E.
    Farouk, Farouk S.
    Syenina, Ayesa
    Ooi, Eng Eong
    Gubler, Duane J.
    Wilder-Smith, Annelies
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
    John, Ashley L. St.
    Chymase Level Is a Predictive Biomarker of Dengue Hemorrhagic Fever in Pediatric and Adult Patients2017In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 216, no 9, p. 1112-1121Article in journal (Refereed)
    Abstract [en]

    Background. Most patients with dengue experience mild disease, dengue fever (DF), while few develop the life-threatening diseases dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). No laboratory tests predict DHF or DSS. We evaluated whether the serum chymase level can predict DHF or DSS in adult and pediatric patients and the influence of preexisting conditions (PECs) on chymase levels. Methods. Serum chymase levels were measured in patients presenting with undifferentiated fever to hospitals in Colombo District, Sri Lanka. The value of serum the chymase concentration and clinical signs and symptoms as predictors of DHF and/or DSS was evaluated by multivariate analysis. We assessed the influence of age, PECs, and day after fever onset on the robustness of the chymase level as a biomarker for DHF and/or DSS. Results. An elevated chymase level in acute phase blood samples was highly indicative of later diagnosis of DHF or DSS for pediatric and adult patients with dengue. No recorded PECs prevented an increase in the chymase level during DHF. However, certain PECs (obesity and cardiac or lung-associated diseases) resulted in a concomitant increase in chymase levels among adult patients with DHF. Conclusions. These results show that patients with acute dengue who present with high levels of serum chymase consistently are at greater risk of DHF. The chymase level is a robust prognostic biomarker of severe dengue for adult and pediatric patients.

  • 31. Vojtek, Ivo
    et al.
    Pirzada, Zaid A
    Henriques-Normark, Birgitta
    Mastny, Markus
    Janapatla, Rajendra P
    Charpentier, Emmanuelle
    Lysogenic transfer of group A Streptococcus superantigen gene among Streptococci.2008In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 197, no 2, p. 225-34Article in journal (Refereed)
    Abstract [en]

    A group A Streptococcus (GAS) isolate, serotype M12, recovered from a patient with streptococcal toxic shock syndrome was analyzed for superantigen-carrying prophages, revealing phi149, which encodes superantigen SSA. Sequence analysis of the att-L proximal region of phi149 showed that the phage had a mosaic nature. Remarkably, we successfully obtained lysogenic conversion of GAS clinical isolates of various M serotypes (M1, M3, M5, M12, M19, M28, and M94), as well as of group C Streptococcus equisimilis (GCSE) clinical isolates, via transfer of a recombinant phage phi149::Km(r). Phage phi149::Km(r) from selected lysogenized GAS and GCSE strains could be transferred back to M12 GAS strains. Our data indicate that horizontal transfer of lysogenic phages among GAS can occur across the M-type barrier; these data also provide further support for the hypothesis that toxigenic conversion can occur via lysogeny between species. Streptococci might employ this mechanism specifically to allow more efficient adaptation to changing host challenges, potentially leading to fitter and more virulent clones.

  • 32. Wang, Z H
    et al.
    Kjellberg, L
    Abdalla, H
    Wiklund, F
    Eklund, C
    Knekt, P
    Lehtinen, M
    Kallings, I
    Lenner, P
    Hallmans, G
    Mählck, C G
    Wadell, G
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Schiller, J
    Dillner, J
    Type specificity and significance of different isotypes of serum antibodies to human papillomavirus capsids.2000In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 181, no 2, p. 456-62Article in journal (Refereed)
    Abstract [en]

    Isotype-specific serum antibody responses against human papillomavirus (HPV) type 16 were evaluated by use of cross-sectional, prospective, and population-based seroepidemiologic studies. IgG1 and IgA were the most abundant isotypes. No sample contained IgG2, and <25 samples contained IgG3 or IgM. Total IgG, IgA, and IgG1 were HPV type specific and were associated with HPV-16 DNA (odds ratios [ORs], 5.4, 5.0, and 5.9, respectively; P<.001) but not with other HPV DNA (ORs, 1.2, 1.2, and 0.8, respectively; P value was not significant). Total IgG and IgG1 were strongly associated with number of lifetime sex partners (P<.001); IgA was only associated with number of recent sex partners and lifetime sex partners among younger women. Total IgG, IgG1, and IgA were associated with cervical intraepithelial neoplasia type III and also predicted risk of future cervical neoplasia. IgG and IgG1 appeared to mark lifetime cumulative exposure, whereas IgA may mark recent or ongoing infection.

  • 33.
    Wilder-Smith, Annelies
    et al.
    Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; Institute of Public Health, University of Heidelberg, Germany.
    Vannice, Kirsten S.
    Hombach, Joachim
    Farrar, Jeremy
    Nolan, Terry
    Population Perspectives and World Health Organization Recommendations for CYD-TDV Dengue Vaccine2016In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 214, no 12, p. 1796-1799Article in journal (Refereed)
  • 34. Wolter, Nicole
    et al.
    Cohen, Cheryl
    Tempia, Stefano
    Madhi, Shabir A.
    Venter, Marietjie
    Moyes, Jocelyn
    Walaza, Sibongile
    Kgokong, Babatyi Malope
    Groome, Michelle
    du Plessis, Mignon
    Pretorius, Marthi
    Dawood, Halima
    Kahn, Kathleen
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Center for Global Health Research.
    Variava, Ebrahim
    Klugman, Keith P.
    von Gottberg, Anne
    HIV and Influenza Virus Infections Are Associated With Increased Blood Pneumococcal Load: A Prospective, Hospital-Based Observational Study in South Africa, 2009-20112014In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 209, no 1, p. 56-65Article in journal (Refereed)
    Abstract [en]

    Background. Increased pneumococcal loads are associated with severe outcomes. We determined the prevalence of pneumococcal DNA in blood specimens from patients hospitalized with acute lower respiratory tract infection and identified factors associated with invasive pneumococcal pneumonia, bacterial loads, and death. Methods. A total of 8523 patients were enrolled as part of prospective hospital-based surveillance. Blood was collected for quantitative pneumococcal (tytA) detection, and nasopharyngeal specimens were collected for detection of influenza virus and other respiratory viruses by real-time polymerase chain reaction. Results. Of 6396 cases (75%) with /ytA results, 422 (7%) were positive for pneumococcal DNA. The prevalences of human immunodeficiency virus (HIV) and influenza virus were 51% (2965/5855) and 8% (485/6358), respectively. On multivariable analysis, HIV infection (adjusted odds ratio [aOR], 2.4; 95% confidence interval [CI], 1.6-3.6), influenza virus coinfection (aOR, 1.4; 95% CI, 1.2-2.1), oxygen therapy during admission (a0R, 1.6; 95% CI, 1.1-2.3) and in-hospital death (aOR, 2.1; 95% CI, 1.1-4.0) were significantly associated with increased pneumococcal load. Among /ytA-positive patients, after adjustment for length of hospitalization, duration of symptoms, and oxygen therapy during admission, pneumococcal loads >= 10,000 DNA copies/mi. (a0R, 3.6; 95% CI, 1.8-7.2) were associated with increased risk of death. Conclusions. HIV and influenza virus infections were associated with elevated pneumococcal loads, which, in turn, were associated with increased risk of death.

  • 35. Wolter, Nicole
    et al.
    Tempia, Stefano
    Cohen, Cheryl
    Madhi, Shabir A.
    Venter, Marietjie
    Moyes, Jocelyn
    Walaza, Sibongile
    Malope-Kgokong, Babatyi
    Groome, Michelle
    du Plessis, Mignon
    Magomani, Victoria
    Pretorius, Marthi
    Hellferscee, Orienka
    Dawood, Halima
    Kahn, Kathleen
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. MRC/Wits Rural Public Health and Health Transition Research Unit Research Unit (Agincourt), Faculty of Health Sciences, University of the Witwatersrand, Johannesburg ; INDEPTH Network, Accra, Ghana.
    Variava, Ebrahim
    Klugman, Keith P.
    von Gottberg, Anne
    High nasopharyngeal pneumococcal density, increased by viral coinfection, is associated with invasive pneumococcal pneumonia2014In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 210, no 10, p. 1649-1657Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: We identified factors associated with pneumococcal colonization, high colonization density, and invasive pneumococcal pneumonia among patients hospitalized with acute lower respiratory tract infections (ALRTIs). METHODS: In 2010, 4025 cases were enrolled in surveillance in South Africa. A total of 969 of 4025 systematically selected nasopharyngeal-oropharyngeal specimens (24%) were tested for respiratory viruses and Streptococcus pneumoniae by real-time polymerase chain reaction. Of these, 749 (77%) had blood tested for S. pneumoniae. RESULTS: Pneumococcal colonization was detected in 55% of cases (534 of 969). On multivariable analysis that controlled for age and tuberculosis treatment, infection with influenza virus (adjusted odds ratio [OR], 2.2; 95% confidence interval [CI], 1.1-4.5), adenovirus (adjusted OR, 1.7; 95% CI, 1.1-2.7), rhinovirus (adjusted OR, 1.6; 95% CI, 1.1-2.3), and human immunodeficiency virus (HIV; adjusted OR, 1.6; 95% CI, 1.1-2.4) were associated with pneumococcal colonization. High colonization density was associated with respiratory virus coinfection (adjusted OR, 1.7; 95% CI, 1.1-2.6) and invasive pneumococcal pneumonia (adjusted OR, 2.3; 95% CI, 1.3-4.0), after adjustment for age and sex. Seven percent (52 of 749) had pneumococci detected in blood. On multivariable analysis among colonized cases, invasive pneumococcal pneumonia was associated with HIV (adjusted OR, 3.2; 95% CI, 1.4-7.5), influenza virus (adjusted OR, 8.2; 95% CI, 2.7-25.0), high colonization density (adjusted OR, 18.7; 95% CI, 2.3-155.1), and >= 5 days of hospitalization (adjusted OR, 3.7; 95% CI, 1.7-8.2). CONCLUSIONS: Respiratory virus infection was associated with elevated colonization density and, in turn, invasive pneumococcal pneumonia.

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