Recently we made the surprising observations that a subpopulation of Mycobacterium tuberculosis (M. tb)-expanded human CD4+CD25+FoxP3+ cells produce Rho GDP dissociation inhibitor (D4GDI), which inhibits M. tb growth in monocyte-derived macrophages (MDMs). Based on our data, we hypothesize that defective D4GDI production by a subpopulation of CD4+CD25+FoxP3+ cells and enhanced production of IL-10 and TGF- by CD4+CD25+FoxP3+ cells in HIV-infected persons with LTBI contribute to enhanced M. tb growth in their macrophages and increasing the risk for progression to active TB.
In aim 1 we will test this hypothesis by comparing the number of FOXP3+D4GDI+ cells and their effect on virulent M. tb growth in MDMs of HIV-LTBI+ and HIV+LTBI+ persons. We will also use siRNA to D4GDI and recombinant D4GDI to determine the role of FOXP3+D4GDI+ cells in the progression to active TB.
In aim 2 we will characterize the phenotype and function of D4GDI-producing FoxP3+ cells in HIV-LTBI+ and HIV+LTBI+ persons and HIV+TB patients with low CD4 count (<100) and with high CD4 count (>100). These studies will improve our understanding of the mechanisms that mediate susceptibility to TB in HIV+ persons, and facilitate development of interventions to improve Foxp3+D4GDI+ cell function and prevent progression of LTBI in HIV-infected persons.
Mycobacterium tuberculosis infects one-third of the world's population and causes almost 2 million deaths per year. HIV infection markedly increases susceptibility to TB, and HIV-infected persons with latent tuberculosis infection (LTBI) have an 800-fold greater risk of developing active TB. The proposed studies will improve our understanding of the mechanisms that mediate susceptibility to TB in HIV+ persons, and facilitate development of interventions to improve D4GDI+FoxP3+ cell function and prevent progression of LTBI in HIV-infected persons.
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| Venkatasubramanian, S; Cheekatla, S; Paidipally, P et al. (2017) IL-21-dependent expansion of memory-like NK cells enhances protective immune responses against Mycobacterium tuberculosis. Mucosal Immunol 10:1031-1042 |
| Cheekatla, Satyanarayana Swamy; Tripathi, Deepak; Venkatasubramanian, Sambasivan et al. (2017) IL-21 Receptor Signaling Is Essential for Optimal CD4+ T Cell Function and Control of Mycobacterium tuberculosis Infection in Mice. J Immunol 199:2815-2822 |
