The outcome of virus infections is determined by the interaction of viral gene products with the host immune system. The major goal of these studies is to better understand this process, and polyomavirus (PyV) infection in mice offers an excellent model. Recently, the applicant reported that polyoma infection of severe combined immunodeficient (SCID) mice, which do not have functional T and B cells, induced an acute hematological disorder with 100% mortality. This pathology is very different from the tumor profiles induced by infection of newborn or adult mice. The applicant has shown that in mice deficient for T cells but retaining B cells, T-cell independent (TI) polyoma specific antibodies predominantly of the IgG2a isotype, protected mice from acute hematological disease. This was accompanied by a reduction of polyoma virus titers in all major organs tested. This is the first report of a protective antiviral TI antibody response in vivo. Recent data show that polyoma infected mice lacking T and NK cells produce IgG2b but not IgG2a suggesting an important role for NK cells in isotype regulation. These mice do not get acute disease but later develop tumors. The applicant proposes to use poloyma infected T-cell deficient mice as a model to study in vivo antibody response to a biologically relevant antigen, a tumor virus. It is hypothesized that during virus infection several factors might contribute to efficient B cell activation, isotype switching and antibody production in the absence of T cells. These include the repetitive nature of viral antigens, activation of non-T cells, and the production of cytokines. The role of these factors and their mechanisms of action will be investigated. The proposed experiments may elucidate fundamental T-independent mechanisms operating in vivo during virus infections. Studies are also planned to examine the kinetics of polyoma virus clearance in different organs by the TI antibodies. Polyoma is non-pathogenic in its immunocompetant natural host. Studying its pathogenesis in immunodeficient hosts can provide basic information which can help to understand processes induced by viruses in immunocompromised individuals.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Experimental Virology Study Section (EVR)
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Wong, May
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University of Massachusetts Medical School Worcester
Schools of Medicine
United States
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Tipper, Donald J; Szomolanyi-Tsuda, Eva (2016) Scaffolded Antigens in Yeast Cell Particle Vaccines Provide Protection against Systemic Polyoma Virus Infection. J Immunol Res 2016:2743292
Mishra, Rabinarayan; Welsh, Raymond; Szomolanyi-Tsuda, Eva (2014) NK cells and virus-related cancers. Crit Rev Oncog 19:107-19
Raval, Forum M; Mishra, Rabinarayan; Garcea, Robert L et al. (2013) Long-lasting T cell-independent IgG responses require MyD88-mediated pathways and are maintained by high levels of virus persistence. MBio 4:e00812-13
Mishra, Rabinarayan; Polic, Bojan; Welsh, Raymond M et al. (2013) Inflammatory cytokine-mediated evasion of virus-induced tumors from NK cell control. J Immunol 191:961-70
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Wigglesworth, Kim M; Racki, Waldemar J; Mishra, Rabinarayan et al. (2011) Rapid recruitment and activation of macrophages by anti-Gal/?-Gal liposome interaction accelerates wound healing. J Immunol 186:4422-32
Guikema, Jeroen E J; Schrader, Carol E; Brodsky, Michael H et al. (2010) p53 represses class switch recombination to IgG2a through its antioxidant function. J Immunol 184:6177-87
Mishra, Rabinarayan; Chen, Alex T; Welsh, Raymond M et al. (2010) NK cells and gammadelta T cells mediate resistance to polyomavirus-induced tumors. PLoS Pathog 6:e1000924
Rathinam, Vijay A K; Jiang, Zhaozhao; Waggoner, Stephen N et al. (2010) The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nat Immunol 11:395-402

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