Despite many advances in biomedical research, viral infections remain a major threat to human health. In the past 20 years we have witnessed either the emergence or the definition of acute and persistent viral infections caused by agents such as HIV, HTLV, hepatitis viruses, ebola virus, hantavirus, papillomavirus, herpesviruses 6-8, the SARS coronavirus, and monkeypox, and we continue to live with the specter of the re-emergence of a 1918-like strain of influenza virus or the release of variola (small pox) virus by bioterrorism. There are few effective antiviral drugs to combat these viruses, and protection from these agents mainly rests on public health containment measures and on the use and development of vaccines. It is now thought that attenuated viruses which induce CD8 T cell responses, as well as antibody, make better, longer lasting vaccines. Thus, it is important to understand factors contributing to the maintenance or loss of CD8 memory in an environment in which a host is continually challenged by pathogens that may sometimes become persistent. The CD8 T cell response to viral infections is highly dynamic, beginning with a cytokine driven apoptotic loss (lymphopenia) in memory CD8 T cell number in the early stages of infection, followed by a dramatic expansion in number of virus-specific T cells and then by a second decline or silencing phase, associated with T cell apoptosis and dissemination into peripheral tissues. The activated CD8 T cells during the acute response also become sensitized to undergo Fas/FasL-mediated activation-induced cell death (AICD) on strong signaling through their TCR, and this may contribute to the transient immune deficiencies seen during viral infections and to the clonal exhaustion of T cells under conditions of antigen excess. My lab has made the unique observations that (1) there is a cytokine-driven apoptosis early in infection, that (2) apoptosis of CD8 T cells is differentially regulated, dependent on the tissue site, and that (3) there is substantial attrition of memory CD8 T cells occurring as a consequence of acute or persistent infections with unrelated viruses. Here we propose to continue our studies on CD8 T cell apoptosis in mice infected with LCMV, Pichinde, and vaccinia viruses, and determine (1) the mechanism and significance of the early cytokine-induced lymphopenia and apoptosis of memory CD8 T cells during viral infections, (2) the mechanisms regulating the tissue-dependent differences in apoptosis of virus-specific CD8 T cells, and (3) the mechanism and significance of memory T cell attrition following acute and persistent viral infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37AI017672-25
Application #
6771604
Study Section
Special Emphasis Panel (ZRG1-EVR (01))
Program Officer
Park, Eun-Chung
Project Start
1980-07-01
Project End
2009-03-31
Budget Start
2004-04-15
Budget End
2005-03-31
Support Year
25
Fiscal Year
2004
Total Cost
$403,125
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
Che, Jenny W; Daniels, Keith A; Selin, Liisa K et al. (2017) Heterologous Immunity and Persistent Murine Cytomegalovirus Infection. J Virol 91:
Che, Jenny W; Kraft, Anke R M; Selin, Liisa K et al. (2015) Regulatory T cells resist virus infection-induced apoptosis. J Virol 89:2112-20
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
Che, Jenny W; Selin, Liisa K; Welsh, Raymond M (2015) Evaluation of non-reciprocal heterologous immunity between unrelated viruses. Virology 482:89-97
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

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