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 #
1R01AI072060-01A2
Application #
7466453
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Repik, Patricia M
Project Start
2008-02-01
Project End
2008-11-14
Budget Start
2008-02-01
Budget End
2008-11-14
Support Year
1
Fiscal Year
2008
Total Cost
$217,505
Indirect Cost
Name
Colorado State University-Fort Collins
Department
Microbiology/Immun/Virology
Type
Schools of Veterinary Medicine
DUNS #
785979618
City
Fort Collins
State
CO
Country
United States
Zip Code
80523
McGruder, Brenna; Saxena, Vandana; Wang, Tian (2016) Lessons from the Murine Models of West Nile Virus Infection. Methods Mol Biol 1435:61-9
Xie, Guorui; Luo, Huanle; Tian, Bing et al. (2015) A West Nile virus NS4B-P38G mutant strain induces cell intrinsic innate cytokine responses in human monocytic and macrophage cells. Vaccine 33:869-78
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; 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
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
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; Welte, Thomas; Bao, Xiaoyong et al. (2012) A hamster-derived West Nile virus strain is highly attenuated and induces a differential proinflammatory cytokine response in two murine cell lines. Virus Res 167:179-87
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
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

Showing the most recent 10 out of 16 publications