Toxoplasma gondii infection continues to be problem for immunocompromised individuals, especially those afflicted with AIDS. Although HAART therapy has improved survival, the deficits continue to be presented in these patients. Moreover, many amongst the AIDS population do not take HAART and toxoplasmic encephalitis is manifestation of their HIV infection. An understanding of host immune mechanisms responsible for protection against this parasite in immunocompetent individuals is essential for the development of immunotherapeutic agents for immunocompromised hosts like those suffering from AIDS. In addition to their protective role during acute infection, innate immune factors like DC and NK cells are important for optimal induction of CD8+ T cell immunity against infection. Role of CD8+ T cell immunity in long-term protection against T.gondii infection is well documented. Preliminary studies from my laboratory have demonstrated that oral Toxoplasma challenge results in strong dendritic cell (DC) response in the gut, which may be a key for launching a primary CD8+ T cell response against the parasite in this tissue. Understanding the development of CD8+ T cell immunity during natural (per-oral) route of infection is the main focus of this proposal. The proposal is comprised of three specific aims. In the first specific aim the induction of different subsets of DC in response to oral T.gondii infection and their cytokine (IL-12, IL-15 and IFN3) production will be assayed. The role of DC as major IL-15 producers (a cytokine essential for maintenance memory CD8+ T cells) during T.gondii infection will be evaluated. Finally the experiments will be performed to determine the DC subset involved in the priming of CD8+ T cell response against the parasite. Recent studies from our laboratory have shown that NK-DC interaction via the NKG2D molecule is essential for priming of robust CD8+ T cell immunity against T.gondii. In the second specific aim DC population responsible for the NK-DC interaction will be identified and signaling events following this NKG2D mediated event analyzed. The role of NKG2D on the CD8+ T cell immunity during secondary or long- term infection will be assayed. In the third specific aim importance of IL-7 and IL-15 in the generation and maintenance of CD8+ T cell effector memory (TEM) and central memory (TCM) will be studied. The mechanism by which CD4+ T cells control the long-term maintenance of CD8+ T cell response against the parasite will be analyzed. Finally the strategies, which can lead to the development and long-term survival of immune, CD8+ T cells in an immunocompromised situation will be evaluated.

Public Health Relevance

Toxoplasma gondii infection is a major problem for HIV-infected subjects. Development of immunotherapeutic agents against this pathogen would reduce the complications in these high-risk individuals.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
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Wali, Tonu M
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George Washington University
Schools of Medicine
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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
Bhadra, Rajarshi; Gigley, Jason P; Khan, Imtiaz A (2011) Cutting edge: CD40-CD40 ligand pathway plays a critical CD8-intrinsic and -extrinsic role during rescue of exhausted CD8 T cells. J Immunol 187:4421-5

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