Infection with Toxoplasma gondii continues to be a serious cause of morbidity and mortality in newborns and immunosuppressed individuals, especially those infected with AIDS. Cell mediated immunity is critical for the host defense, both during acute and chronic infection with the parasite. Amongst the T cell subtypes, CD8+T cells are important mediators of long-term immune response against the infection. The effector/memoryCD8+ T cells play a dominant role in the protection against both challenge infection and reactivation of latent disease. The understanding of the mechanisms involved in the generation and the maintenance of robust CD8+ T cell immunity against T.gondii may enable to generate novel therapeutic or prophylactic agents against the parasite. In the first specific aim we plan to evaluate the development of CD8+ T cell immunity against T.gondii. The role of NK cells in the induction of CD8+ T cell response in the absence of CD4+ T cells will be assayed. The quality of CD8+ T cell response in the presence of overwhelming TH-2 cytokine environment will be determined. The preliminary studies suggest that although primary CD8+ T cell response against T.gondii infection in the CD4-/- mice can be induced these animals are susceptible to repeat infection due to the poor development of memory CD8+ T cell immunity against the parasite. In this specific aim the mechanism of CD4 CD8 T cell interaction during long-term T.gondii infection will be understood. The second specific aim will entail the study of the role of host IL-15 in the maintenance of CD8+ T cell memory response against T.gondii. The maintenance of CD8+ memory T cells in the IL-15 receptor a knock out mice will be studied and the mechanistic role of IL-15 in the survival of memory CD8+ T cell response will be determined. ? ? ?

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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AIDS and Related Research 8 (AARR)
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Wali, Tonu M
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Louisiana State University Hsc New Orleans
Schools of Medicine
New Orleans
United States
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Moretto, Magali M; Hwang, SuJin; Khan, Imtiaz A (2017) Downregulated IL-21 Response and T Follicular Helper Cell Exhaustion Correlate with Compromised CD8 T Cell Immunity during Chronic Toxoplasmosis. Front Immunol 8:1436
Hwang, SuJin; Cobb, Dustin A; Bhadra, Rajarshi et al. (2016) Blimp-1-mediated CD4 T cell exhaustion causes CD8 T cell dysfunction during chronic toxoplasmosis. J Exp Med 213:1799-818
Hwang, SuJin; Khan, Imtiaz A (2015) CD8+ T cell immunity in an encephalitis model of Toxoplasma gondii infection. Semin Immunopathol 37:271-9
Bhadra, Rajarshi; Cobb, Dustin A; Weiss, Louis M et al. (2013) Psychiatric disorders in toxoplasma seropositive patients--the CD8 connection. Schizophr Bull 39:485-9
Bhadra, Rajarshi; Cobb, Dustin A; Khan, Imtiaz A (2013) Donor CD8+ T cells prevent Toxoplasma gondii de-encystation but fail to rescue the exhausted endogenous CD8+ T cell population. Infect Immun 81:3414-25
Bhadra, Rajarshi; Cobb, Dustin A; Khan, Imtiaz A (2013) CD40 signaling to the rescue: A CD8 exhaustion perspective in chronic infectious diseases. Crit Rev Immunol 33:361-78
Bhadra, Rajarshi; Khan, Imtiaz A (2012) Redefining chronic toxoplasmosis--a T cell exhaustion perspective. PLoS Pathog 8:e1002903
Gigley, Jason P; Bhadra, Rajarshi; Moretto, Magali M et al. (2012) T cell exhaustion in protozoan disease. Trends Parasitol 28:377-84
Bhadra, Rajarshi; Khan, Imtiaz A (2012) IL-7 and IL-15 do not synergize during CD8 T cell recall response against an obligate intracellular parasite. Microbes Infect 14:1160-8
Bhadra, Rajarshi; Gigley, Jason P; Khan, Imtiaz A (2012) PD-1-mediated attrition of polyfunctional memory CD8+ T cells in chronic toxoplasma infection. J Infect Dis 206:125-34

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