West Nile virus (WNV), a vector-borne pathogen, has resulted in annual outbreaks of viral encephalitis in North America since 1999. Severe neurological disease (encephalitis or death) has been observed in over 30% of the confirmed WNV cases with a higher frequency in the elderly and immunocompromised patients. Human vaccines are not available yet. Thus, it is important to understand factors contributing to the development of long-lasting protective immunity, especially in the potentially susceptible host. 34 T cells, the non-classical T cell subsets, are involved in the early control of microbial infection. In two recently published studies, we have shown that 1) 34 T cells are important for early control of WNV dissemination and that 2) TCR4 / (34 T cell deficient) mice have reduced CD8+ T cell memory response and are more susceptible to secondary WNV infection. Moreover, our preliminary data show that aged mice are more susceptible to WNV induced encephalitis than young mice. 34 T cells of aged mice respond to WNV infection in a much slower and reduced manner than those of young mice. This suggests that the dysfunction of 34 T cells in aged mice contributes to the enhanced host susceptibility to WNV induced encephalitis. The decline in immunity in the elderly is a significant contributor to the increased risk of pathogen infection. The overall goal of this application is to examine the role of 34 T cells in host adaptive immunity against WNV. Specifically, we hypothesize that 34 T cells are crucial for the development of memory T cells following WNV challenge;dysfunction of 34 T cells in aged mice leads to a defective adaptive immunity against WNV.
In Specific aim 1, we will further define the role of 34 T cells in host adaptive immunity against WNV. We will characterize CD8+ T cell response at different stages of development and assess CD4+ T cell memory response in TCR4-/- mice.
In Specific aim 2, we will attempt to dissect the underlying mechanisms by which 34 T cells regulate host adaptive immunity. The interactions between 34 T cells and other immune cells during WNV infection will be examined.
In Specific aim 3, we will determine whether the dysfunction of 34 T cells in aged mice leads to a defective adaptive immunity against WNV. Information obtained from this study will not only enhance our understanding of host immunity against WNV;but also will provide critical basic insights for new strategies in flavivirus vaccine development. PUBLIC HEALTH REVELENCE: West Nile virus (WNV) has become an increasing public health concern. Severe neurological disease (encephalitis or death) has been observed in over 30% of the confirmed WNV cases with a higher frequency in the elderly and immunocompromised patients. Human vaccines are not available yet. It is important to understand factors contributing to the development of long-lasting protective immunity, especially in the potentially susceptible host. The overall goal of this application is to examine the role of 34 T cells in adaptive immunity against WNV. We anticipate information obtained from this study will not only enhance our understanding of host immunity against WNV;but also will provide critical basic insights for new strategies in flavivirus vaccine development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI072060-06
Application #
8211016
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Repik, Patricia M
Project Start
2008-02-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
6
Fiscal Year
2012
Total Cost
$367,864
Indirect Cost
$122,839
Name
University of Texas Medical Br Galveston
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Xie, Guorui; Whiteman, Melissa C; Wicker, Jason A et al. (2014) In vitro analysis of MyD88-mediated cellular immune response to West Nile virus mutant strain infection. J Vis Exp :e52121
Zhang, Jinping; Wang, Jia; Pang, Lan et al. (2014) The co-stimulatory effects of MyD88-dependent Toll-like receptor signaling on activation of murine ?? T cells. PLoS One 9:e108156
Xie, Guorui; Welte, Thomas; Wang, Jia et al. (2013) A West Nile virus NS4B-P38G mutant strain induces adaptive immunity via TLR7-MyD88-dependent and independent signaling pathways. Vaccine 31:4143-51
Saxena, Vandana; Xie, Guorui; Li, Bei et al. (2013) A hamster-derived West Nile virus isolate induces persistent renal infection in mice. PLoS Negl Trop Dis 7:e2275
Wang, Tian; Welte, Thomas (2013) Role of natural killer and Gamma-delta T cells in West Nile virus infection. Viruses 5:2298-310
Welte, Thomas; Aronson, Judith; Gong, Bin et al. (2011) V?4+ T cells regulate host immune response to West Nile virus infection. FEMS Immunol Med Microbiol 63:183-92
Welte, Thomas; Xie, Guorui; Wicker, Jason A et al. (2011) Immune responses to an attenuated West Nile virus NS4B-P38G mutant strain. Vaccine 29:4853-61
Wang, Tian (2011) Role of ýýýý T cells in West Nile virus-induced encephalitis: friend or foe? J Neuroimmunol 240-241:22-7
Fang, Hao; Welte, Thomas; Zheng, Xin et al. (2010) gammadelta T cells promote the maturation of dendritic cells during West Nile virus infection. FEMS Immunol Med Microbiol 59:71-80
Wang, Shuhui; Welte, Thomas; Fang, Hao et al. (2009) Oral administration of active hexose correlated compound enhances host resistance to West Nile encephalitis in mice. J Nutr 139:598-602

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