MODULATING L-ARGININE METABOLISM THROUGH ARG 2 AND INOS TO INHIBIT MTB GROWTH

Lsu Health Sciences Center, New Orleans LA

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), infects approximately one-third of the world population and is responsible for more adult deaths than any other disease caused by a single infectious agent. According to the WHO, approximately two million people die of this disease each year. Although TB occurs predominantly in undeveloped countries, it also occurs in the US were a resurgence of the disease has been seen during the last decade associated with the presence of multidrug-resistance TB (MDR-TB). The presence of MDR-TB and extensively drug-resistant TB (XDR-TB) are spreading globally (including the US), raising concerns of a future epidemic of virtually untreatable TB. Because XDR-TB is resistant to the most powerful first-line and second-line drugs, patients are left with treatment options that are much less effective and often have worse clinical outcomes. Even though, there is an urgent need to develop and test technologies to diagnose TB and identify drug resistance, more importantly there is a need to develop new and more reliable and efficient ways to control and treat MDR/XDR TB inside the host cell. Preliminary data shows that the amino acid L-arginine plays a key role in the survival as well as in the modulation of the host response to Mtb. L-arginine can be converted by inducible nitric oxide synthase (iNOS) to nitric oxide (NO), a cytotoxic agent for Mtb, or can be converted to L-ornithine by arginase, which may favor Mtb growth through the production of polyamines. We strongly believe that Mtb is capable to induce arginase to favor its survival within the macrophages. The mechanisms of arginase induction by Mtb appear to be regulated by cyclic adenosine monophosphate (cAMP). When macrophages are infected with Mtb, a burst of cAMP is induced, followed by increased levels of arginase production. Furthermore, blocking arginase production or increasing the production of iNOS/NO (by interferon-gamma) may enable us to manipulate the L-arginine pathway to develop more comprehensive and cost effective preventive and/or therapeutic TB regimens that could improved the effectiveness in the treatment and killing of MDR and XDR strains of TB to bypass TB drug resistance. In this proposal we are postulating that a better understanding of how Mtb modulates L-arginine metabolism within macrophages will lead to novel approaches to augment intracellular killing of MDR-TB and XDR-TB. We will test this hypothesis by manipulating in vitro, the L-arginine metabolic pathway by blocking arginase or increasing the production of iNOS/NO (by interferon-gamma) and determine the effect of these approaches in Mtb intracellular killing. We propose the following Specific Aims: 1) To test the concept that in macrophages, arginase induction is an important factor promoting intracellular Mtb growth. 2) To determine in macrophages the underlying mechanisms by which Mtb-cAMP induces arginase to promote and facilitate Mtb long-term survival. 3) To test alternative pathways to decrease mycobacterial survival and study the mechanisms by which Mtb induce host responses that reduce or bypass NO.