The goal of this proposal is to evaluate the role of programmed cell death in the control of viral infections, in the down-regulation or silencing of the immune response and conversion into memory, and in the development of the transient immune deficiency that is characteristic of most acute systemic viral infections. The lymphocytic choriomeningitis virus (LCMV) infection of mice will be used as a model system to generate activated natural killer (NK) cells and cytotoxic T lymphocytes (CTL). The first specific aim evaluates the role of cell quiescence on the ability of NK cells and CTL to induce apoptosis in target cells, as we have shown that quiescent cells don't fragment their DNA during CTL attack. The effects of infections with viruses such as herpes simplex, vaccinia, and murine cytomegalo on the susceptibility of the targets to apoptosis will be studied. Analyses will be made concerning whether viral DNA fragments in cells attacked by CTL and whether quiescent cells in vivo fragment their DNA. The second specific aim deals with an analysis of programmed cell death in vivo during LCMV infection and in vitro upon T cell receptor stimulation of LCMV-induced T cells, which we have shown rapidly undergo apoptosis during a window of time in which there is immune deficiency. A variety of genes shown to be involved in apoptotic pathways in other systems will be examined, using in situ hybridization and transgenic mice techniques. The third specific aim focuses on the phenotype of virus- induced memory T cells and the hypothesis that memory T cell responses to unrelated antigens are compromised by acute viral infections due to an out of sequence stimulation of the memory cells with growth factors before exposure to antigen. The significance of this work is that it will contribute to an understanding of what may be a universal mechanism of virus-induced immune deficiency.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Experimental Virology Study Section (EVR)
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University of Massachusetts Medical School Worcester
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Che, Jenny W; Daniels, Keith A; Selin, Liisa K et al. (2017) Heterologous Immunity and Persistent Murine Cytomegalovirus Infection. J Virol 91:
Nayar, Ribhu; Schutten, Elizabeth; Jangalwe, Sonal et al. (2015) IRF4 Regulates the Ratio of T-Bet to Eomesodermin in CD8+ T Cells Responding to Persistent LCMV Infection. PLoS One 10:e0144826
Rydyznski, Carolyn; Daniels, Keith A; Karmele, Erik P et al. (2015) Generation of cellular immune memory and B-cell immunity is impaired by natural killer cells. Nat Commun 6:6375
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
Kapoor, Varun N; Shin, Hyun Mu; Cho, Ok Hyun et al. (2014) Regulation of tissue-dependent differences in CD8+ T cell apoptosis during viral infection. J Virol 88:9490-503
Nayar, Ribhu; Schutten, Elizabeth; Bautista, Bianca et al. (2014) Graded levels of IRF4 regulate CD8+ T cell differentiation and expansion, but not attrition, in response to acute virus infection. J Immunol 192:5881-93
Urban, Stina L; Welsh, Raymond M (2014) Out-of-sequence signal 3 as a mechanism for virus-induced immune suppression of CD8 T cell responses. PLoS Pathog 10:e1004357
Welsh, Raymond M; Waggoner, Stephen N (2013) NK cells controlling virus-specific T cells: Rheostats for acute vs. persistent infections. Virology 435:37-45
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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