Research Areas
Host-Directed Therapy (HDT) for TB
Drugs conventionally used to treat TB requires longer duration of treatment that often results in low compliance and leads to the development of drug resistant strains of Mtb. Also, it is known that effective immune responses are disrupted during TB. Recently host-directed therapies that either improves the efficiency of host immune responses to effectively eliminate Mtb or minimize the excessive inflammatory damage seems promising. Indolamine-2,3-dioxygenase (IDO) is a key enzyme that mediates the catabolism of Tryptophan which is an essential amino acid resulting in the starvation of many intracellular pathogen leading to an effective innate immune control. As Mtb residing in the granuloma can synthesize its own tryptophan the host mechanism of starvation is not effective against M.tb. Moreover, the IDO mediated catabolism of tryptophan results in the formation of metabolites like Kynurenine which are highly immunosuppressive and results in inhibition of T cell responses. Therefore Mtb can modulate host immune responses for its long term persistence in the TB granuloma via IDO1. We hypothesize that targeting IDO1 can substantially improve the immune responses in the TB granuloma enabling the immune system to better kill Mtb.
Chronic immune activation in TB/HIV
About one quarter of the world’s population is latently infected with TB. These individuals serve as an important reservoir for the reactivation of disease. Immunocompromised conditions such as co-infection with HIV leads to the development of disease in such individuals. In NHP models of latent TB infection, HIV/SIV co-infection results in a state of chronic immune activation and also leads to the disruption of effective anti-Mtb immunity, which is not fully restored after treatment with anti-retroviral therapy alone. This leads to the reactivation of TB. We hypothesize that the chronic immune activation leads to immune dysfunction and reactivation of LTBI in Mtb/SIV co-infected rhesus macaques. One major outcome has been shown to be dysregulated IDO signaling. Inhibiting the IDO activity could be a critical target to control the chronic immune activation and resulting reactivation of TB.
Effect of Cigarette smoking on progression of TB
Cigarette smoking has been long associated with TB but is not very well characterized. Along with increased susceptibility, smoking is associated with poor treatment outcomes, increased TB recurrence, and mortality rates. Cigarette smoke impacts Mtb virulence and pathogenesis by invoking bacillary factors which scavenge stress present in the macrophage, potentially enhancing pathogen survival. We hypothesize that exposure to cigarette smoke impairs key macrophage functions required for the innate control of M.tb. We are interested to identify if cigarette smoke offers survival advantage to Mtb during infection in macrophages and the underlying immune mechanisms of this phenomenon. This is critical for the development of new approaches to control TB infection in individuals exposed to cigarette smoke.
