Due to their ability to produce cytokines and exhibit cytolytic activity against infected targets, CD8+ T cells are critical role for protection against number of intracellular pathogens. Since last few years it has been reported that superior control of replication of these infectious agents is dependent on the ability of these cells to display multiple functions. Many of these studies have been carried out with HIV infected individuals and it has been demonstrated that non-progressors (those who do not develop symptomatic infection) maintain high levels of multifunctional response, which is not the case in the subjects where infection progresses. Moreover, the success of vaccine regimens against viral infection has also been linked to its ability to induce robust multifunctional CD8+ T cell response. Recent data from our laboratory suggests that importance of multifunctional cells cannot be restricted to viral infections and can be extended to fungal pathogens like microsporidia an important opportunistic pathogen that causes morbidity/ mortality in HIV infected population. Preliminary data for the proposal demonstrates that host protection is strongly dependent on its ability to develop a strong polyfunctional CD8+ T cell response. However, factor (s) responsible for the development of robust polyfunctional SLEC (short-lived effector cell) and MPEC (memory precursor effector cell) response has not been well studied and cytokine responsible for their induction has not been identified. Preliminary studies from our laboratory suggest that FTH (Follicular T helper cells) subset of CD4+ T cells, main producers of IL- 21 play a pivotal role in the induction of thi response to microsporidial infection. In this proposal we plan to study the induction of FTH immunity against the microsporidial infection and their importance and mechanism in the development of multifunctional SLEC/ MPEC response. Moreover, in an immune-compromised situation like HIV infection, when CD4+ T cell responses are severely down-regulated alternate mechanism(s) that can be explored to induce and maintain the multifunctional ability of these cells will be tested. The proposal comprises of three specific aims. In the first specific aim kinetics, induction and mechanism of induction of FTH response against microsporidial infection will be determined. Further their role in the development of multifunctional SLEC and MPEC response will be assayed. The second specific aim will involve the role of FTH/IL-21 in the transition of multifunctional SLEC and MPEC population to memory response. Further, importance of FTH/IL-21 in maintenance of long-term memory response will be assayed. Finally in the third specific aim role of gd T cells in the development of functional SLEC and MPEC response in the absence of optimal CD4+ T cell immunity, like during HIV infection will be determined.

Public Health Relevance

Microsporidial infection poses a problem for immunocompromised patients like those carrying HIV infection and elderly immuno-competent individuals. Gut immune response is critical for protection against this oral pathogen. The goal of this proposal is to evaluate the strategies which can protect immunocompromised individuals against the infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56AI102711-01A1
Application #
8698505
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Duncan, Rory A
Project Start
2013-08-06
Project End
2014-07-31
Budget Start
2013-08-06
Budget End
2014-07-31
Support Year
1
Fiscal Year
2013
Total Cost
$389,019
Indirect Cost
$131,976
Name
George Washington University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
043990498
City
Washington
State
DC
Country
United States
Zip Code
20052