My major goal is to elucidate host mechanisms involved in the efficient control of virus infections, studying as a model the natural host-virus relationship of polyomavirus (PyV)-infected mice. We previously reported that PyV, a DNA tumor virus, induced protective antiviral antibody responses in the absence of T lymphocytes in T cell-deficient (TCR?x? KO) mice. This was the first report of T cell-independent (Tl), protective IgG responses to a virus. Subsequent studies with other viruses suggested that the ability to elicit Tl antibody responses may be a general phenomenon for viruses. We characterized the Tl antibody responses to PyV and mechanisms involved in their induction and showed that Tl type 2 IgG responses were induced, but only by live PyV infection, not by immunization with viral proteins or virus-like particles. Investigating how the innate immune system may collaborate with B cells to generate these responses, we have made two novel observations: (i) T cell-depleted MyD88 KO spleen cells fail to generate PyV-specific Tl IgG responses in vivo, although they respond with antiviral IgM secretion, suggesting a dependence of Tl isotype switching on innate toll-like receptor (TLR)-derived signals;(ii) long-term antiviral antibody responses were impaired in MyD88 KO mice, suggesting that T cell-dependent (TD) antiviral B cell memory to PyV infection also required MyD88-dependent signals. Based on these observations we propose to test the hypothesis that innate immune signals mediated by MyD88 are essential for the generation of antiviral Tl isotype-switched IgG responses and for long-term TD B cell responses to PyV infection. I propose to determine in which cell type(s) the MyD88-mediated signals are required for these processes, which innate receptors are involved, and investigate some of the underlying mechanisms. In addition, I plan to determine the biological consequences of impaired innate immune signaling in normal and T cell-deficient PyV-infected host by testing virus load, pathology, and possible effects on NK and ?? T cell responses. The new information generated by these studies is relevant to basic problems of viral pathogenesis that have clinical importance, such as the control of persistent virus infections (e.g. JC and BK human polyomavirus infections), particularly in hosts with partial immunodeficiency. Moreover, the proposed project will address for the first time the role of innate immune receptors in the regulation of protective antiviral Tl and long-term TD memory B cell responses in vivo, and the mechanisms involved. These basic questions are important for the design of vaccines with high efficacy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA066644-13
Application #
8015362
Study Section
Virology - B Study Section (VIRB)
Program Officer
Blair, Donald G
Project Start
1997-05-01
Project End
2012-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
13
Fiscal Year
2011
Total Cost
$253,225
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Pathology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
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
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
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
Erickson, Kimberly D; Bouchet-Marquis, Cedric; Heiser, Katie et al. (2012) Virion assembly factories in the nucleus of polyomavirus-infected cells. PLoS Pathog 8:e1002630
Fang, C-M; Roy, S; Nielsen, E et al. (2012) Unique contribution of IRF-5-Ikaros axis to the B-cell IgG2a response. Genes Immun 13:421-30
Wigglesworth, Kim M; Racki, Waldemar J; Mishra, Rabinarayan et al. (2011) Rapid recruitment and activation of macrophages by anti-Gal/α-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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