Reactivation of latent toxoplasmosis leads to encephalitis (TE) and is one of the most common life threatening central nervous system infections in HIV infected patients. Although incidence as a result of cART therapy has decreased substantially, it continues to be a problem in countries with high prevalence of infection. It is believed that reactivation of latent toxoplasmosis occurs during advanced stages of HIV infection, when CD8 T cell response is compromised. In mouse model of encephalitis, we have reported severe dysfunctionality in memory CD8+ T cell population due to graded up- regulation of PD-1 (a well-known inhibitory molecule) expression on these cells. Although PD-1-PDL-1 blockade invigorated CD8+ T cell response, highly exhausted memory CD8+ T cells could not be rescued. Preliminary data for the proposal demonstrates that in addition to PD-1, CD8+ T cells from susceptible animals exhibited increased expression of other inhibitory molecules like LAG-3, 2B4 and CTLA-4. Thus blockade of multiple inhibitors may be needed to restore the functionality of memory CD8+ T cells. Further, to develop effective therapies against this chronic infection, mechanism responsible for CD8 dysfunction needs to be defined. The proposal has three specific aims.
In aim 1, kinetics and pattern of multiple inhibitory receptors expressed by memory CD8+ T cells from infected animals will be performed. This will provide important information about the antibody cocktail needed for reversing the dysfunctionality in this population.
In aim 2, the mechanism of memory CD8+ T cell dysfunction during chronic toxoplasma infection will be evaluated. Based on our preliminary findings, in this specific aim the mechanism involved in the IL-21 mediated maintenance of CD8+T functionality will be deciphered. Finally in the third aim, underlying causes responsible for decreased IL-21 response in animals susceptible to TE with reference to CD40 signaling will be performed. Information generated from these studies will be highly beneficial to develop therapeutic regimen that will enable to maintain robust CD8+T cell memory against chronic toxoplasma infection, which continues to be a serious problem for HIV, infected population.

Public Health Relevance

Toxoplasma encephalitis, due to reactivation of latent infection during advanced HIV infection poses a problem for these patients. The goal of this proposal is to determine the strategy, which will reinvigorate the CD8 T cell response, needed to maintain the chronicity of infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI033325-22
Application #
9173015
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Wali, Tonu M
Project Start
1992-07-01
Project End
2020-10-31
Budget Start
2016-11-01
Budget End
2017-10-31
Support Year
22
Fiscal Year
2017
Total Cost
Indirect Cost
Name
George Washington University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
043990498
City
Washington
State
DC
Country
United States
Zip Code
20052
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
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
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) Redefining chronic toxoplasmosis--a T cell exhaustion perspective. PLoS Pathog 8:e1002903
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) The CD8 T-cell road to immunotherapy of toxoplasmosis. Immunotherapy 3:789-801
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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