Natural immunity refers to the ability of pre-existing or rapidly- inducible host effector systems to combat infectious agents to which the host has not previously been immunized. Understanding how the natural immune system functions may provide us with strategies that would increase one's resistance to infectious agents and to tumor development. Natural killer (NK) cells are an important component of the this natural immune system, as they can mediate immunoregulatory functions and resistance to infections and tumor growth. My laboratory has shown that cytokines, most notably interferons (IFN), induced during viral infections elicit the activation and proliferation of natural killer (NK) cells, which infiltrate areas of virus-infected tissue. These NK cells are profound mediators of natural resistance against certain viruses, such as murine cytomegalovirus (MCMV), but not others, such as lymphocytic choriomeningitis virus (LCMV). Recently we have isolated NK- sensitive and -resistant variants of the arenavirus, Pichinde (PV), and have discovered that natural resistance to infection may also be mediated by T cells expressing gamma delta T cell receptors (TcR) and by remotely crossreactive memory alpha beta T cells specific for other viruses.
The specific aims of this proposal are the following: 1. to examine the mechanism of the antiviral effect of NK cells in vivo; 2. to determine whether there are redundancies in the mechanisms of natural resistance to viruses; 3. to determine whether selected NK cell subsets have distinct antiviral activities; and 4. to do a molecular analysis of NK- sensitive and NK-resistant variants of PV, in order to determine which viral gene product confers the phenotype of NK-sensitivity.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA034461-13
Application #
2088683
Study Section
Special Emphasis Panel (ZRG5-EI (03))
Project Start
1983-05-01
Project End
2000-03-31
Budget Start
1995-06-01
Budget End
1996-03-31
Support Year
13
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Pathology
Type
Schools of Medicine
DUNS #
660735098
City
Worcester
State
MA
Country
United States
Zip Code
01655
Waggoner, Stephen N; Daniels, Keith A; Welsh, Raymond M (2014) Therapeutic depletion of natural killer cells controls persistent infection. J Virol 88:1953-60
Mishra, Rabinarayan; Welsh, Raymond; Szomolanyi-Tsuda, Eva (2014) NK cells and virus-related cancers. Crit Rev Oncog 19:107-19
Rodriguez, Idalia A; Welsh, Raymond M (2013) Possible role of a cell surface carbohydrate in evolution of resistance to viral infections in old world primates. J Virol 87:8317-26
Welsh, Raymond M; Waggoner, Stephen N (2013) NK cells controlling virus-specific T cells: Rheostats for acute vs. persistent infections. Virology 435:37-45
Cornberg, Markus; Kenney, Laurie L; Chen, Alex T et al. (2013) Clonal exhaustion as a mechanism to protect against severe immunopathology and death from an overwhelming CD8 T cell response. Front Immunol 4:475
Waggoner, Stephen N; Cornberg, Markus; Selin, Liisa K et al. (2012) Natural killer cells act as rheostats modulating antiviral T cells. Nature 481:394-8
Waggoner, Stephen N; Taniguchi, Ruth T; Mathew, Porunelloor A et al. (2010) Absence of mouse 2B4 promotes NK cell-mediated killing of activated CD8+ T cells, leading to prolonged viral persistence and altered pathogenesis. J Clin Invest 120:1925-38
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
Mathurin, Keisha S; Martens, Gregory W; Kornfeld, Hardy et al. (2009) CD4 T-cell-mediated heterologous immunity between mycobacteria and poxviruses. J Virol 83:3528-39

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