Clinical Microbiology: Open Access

HIV infection and impaired innate and adaptive immune responses against Mycobacterium tuberculosis

3^rd International Conference on Clinical Microbiology & Microbial Genomics

September 24-26, 2014 Valencia Convention Centre, Spain

Vishwanath Venketaraman

Accepted Abstracts: Clin Microbial

Abstract:

Glutathione (GSH), a tripeptide antioxidant, is essential for cellular homeostasis and plays a vital role in diverse cellular functions. Individuals who are infected with HIV are known to be susceptible to M. tb infection. We reported that by enhancing the levels of GSH, T-cells are able to inhibit the growth of M. tb inside macrophages (Mφ). In addition, those GSHreplenished T cell cultures produced increased levels of IL-2, IL-12, and IFN-γ, cytokines, which are known to be crucial for the control of intracellular pathogens. Our study reveals that T lymphocytes that are derived from HIV infected individuals are deficient in GSH, and that this deficiency correlates with decreased levels of Th1 cytokines and enhanced growth of M. tb inside human Mφ. We also characterized the underlying mechanisms by which GSH-enhanced natural killer (NK) cells inhibit the growth of M. tb inside human Mφ. We observed that in healthy individuals, treatment of NK cells with N-acetyl cysteine (NAC), a GSH pro-drug in conjunction with cytokines such as IL-2+IL-12, resulted in enhanced expression of NK cytotoxic ligands (FasL and CD40L) with concomitant stasis in the intracellular growth of M. tb. Neutralization of FasL and CD40L in IL- 2+IL-12+NAC-treated NK cells resulted in abrogation in the growth inhibition of M. tb inside Mφ. Importantly, we observed that the levels of GSH are decreased significantly in NK cells derived from individuals with HIV infection, and this decrease correlated with a several-fold increase in the growth of M. tb inside Mφ. We also observed lower levels of intracellular GSH in Mφ from individuals with HIV and this decrease correlated with an increase in the growth of M. tb in Mφ. Finally, we examined the causes for decreased GSH in individuals with HIV infection. We found that the GSH composition found in Mφ from individuals with HIV infection heavily favours oxidized glutathione (GSSG) which lacks antioxidant and immune enhancing activities, over free or reduced GSH (rGSH), which is responsible for GSH's antioxidant and immune enhancing properties. In addition, we observed increased levels of free radicals, IL-1, IL-17 and TGF-β in plasma samples derived from individuals with HIV infection. We observed decreased expression of the genes coding for enzymes responsible for de novo synthesis of GSH in Mφ derived from individuals with HIV infection using quantitative PCR. Our results indicate that overproduction of pro-inflammatory cytokines in individuals with HIV infection lead to increased production of free radicals. This combined with the decreased expression of GSH synthesis enzymes leads to a depletion of free GSH and may lead in part to the loss of immune function observed in HIV patients. Our findings represent a novel mechanism for control of M. tb infection, and a possible supplement to current HIV treatments.

Biography :

Vishwanath Venketaraman is an Associate Professor at the College of Osteopathic Medicine of the Pacific, Western University of Health Sciences CA. He has published 33 papers in reputable journals and serves on the editorial board of several journals. He received his PhD in 1996 and is actively involved in research on infectious diseases with major focus on tuberculosis and HIV.