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    Pathogenic Old World Arenaviruses inhibit the TLR2-dependent activation of innate immune responses in vitro

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    Author
    Hayes, Melissa Ann Wright
    Advisor
    Lukashevich, Igor S.
    Date
    2012
    Type
    dissertation
    
    Metadata
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    Abstract
    Lymphocytic chorimeningitis virus (LCMV), the prototype arenavirus, and Lassa virus (LASV), causative agent of Lassa fever (LF), have extensive strain diversity and significant variations in pathogenicity for man and experimental animals. LCMV strain WE, but not the Armstrong (ARM) strain, induces a fatal LF-like disease in rhesus macaques. LASV infection of human macrophages and endothelial cells results in reduced levels of proinflammatory cytokines. LCMV was recently shown to be detected by TLR2, but it was unclear whether this was a general innate sensor mechanism to elicit host defense against arenaviruses with different degrees of pathogenicity. Doing pair-wise comparisons of virus strains with different degrees of pathogenicity, we have shown that non-pathogenic, but not pathogenic strains of Old World arenaviruses elicit TLR2/6-dependent proinflammatory responses. In contrast to infection with non-pathogenic strains, cells infected with LASV or with LCMV-WE demonstrated attenuated TLR2/6-dependent proinflammatory cytokine responses. Immunosuppressive LCMV Clone 13 also failed to stimulate IL-6 in macrophages. In contrast, non-pathogenic Mopeia virus (MOPV), a genetic relative of LASV, and LCMV-ARM, induced robust responses that were TLR2/Mal-dependent, required virus replication, and were enhanced by CD14. LCMV-ARM, but not LCMV-WE or Clone 13 strains, induced activation of NFκB, and super-infection experiments revealed that the WE strain inhibited the ARM-mediated IL-8 response during the early stage of infection while allowing exogenous signaling via TLR2. The results suggest that pathogenic arenaviruses suppress NFκB-mediated pro-inflammatory cytokine responses in infected cells. Thus, arenavirus-induced TLR2/6-dependent proinflammatory responses are elicited by non-pathogenic strains and the ability to inhibit these responses could contribute to pathogenicity.
    Description
    University of Maryland in Baltimore. Molecular Microbiology and Immunology. Ph.D. 2012
    Keyword
    proinflammatory
    TLR2
    Arenavirus
    Cytokines
    Immunity, Innate
    Toll-Like Receptor 2
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/1687
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    Theses and Dissertations All Schools

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