Evaluate potential novel vaccines for their safety and efficacy
Infection with Mycobacterium tuberculosis (Mtb) causes tuberculosis (TB) disease. As many as ~ 9 million new cases and ~ 1.5 million deaths globally, every year are reported. This global pandemic is made worse by widespread incidences of drug-resistance. The problem is compounded by the spectacular failure of BCG, the vaccine in use for a century to protect against TB. The development of one or more efficacious vaccines against TB, including one that can prevent the transmission of MDR-TB is of the utmost priority. We use a highly faithful nonhuman primate (NHP) model of TB to study the protective efficacy of a series of mycobacterial strains based on the sigH deletion. Preliminary data shows that the Mtb:D-sigH mutant, an avirulent, BSL2 strain, is able to protect against lethal Mtb challenge in NHPs, especially when delivered directly to the lungs. We are pursuing the development of an anti-TB vaccine candidate based on sigH deletion.
Study the role of host negative regulators of T cell function
IDO (IDO1), which encodes the tryptophan-degrading enzyme Indoleamine 2,3 dioxygenase, is a powerful immunosuppressant and may play a key role in modulating immune responses to TB. Its expression is highly induced in the lungs of NHPs and Kramnik mice with acute but not latent infection. It is expression is highly induced in cultured macrophages. Its presence is limited to the macrophage rich ring structure, adjoining the caseum. Thus, Mtb infection-mediated IDO induction may suppress the function of activated, interferon gamma producing CD4+ T cells and prevent them from accessing the center of the lesion. This could potentially facilitate the persistent survival of Mtb. We propose experiments to conclusively test the hypothesis that IDO expression in the inner ring of a TB granuloma modulates T cell function, thus aiding Mtb in its persistence.
Granuloma Mechanisms of Protection from Tuberculosis
We utilize the nonhuman primate model of inhalation TB, to study Mtb-specific mechanisms of granuloma persistence and modulation of immune responses. We propose to characterize mechanisms that allows granulomas to control Mtb infection and identify events, which cause this control to dissipate. Our studies have the potential to inform fundamental aspects of the latent control of Mtb within granulomatous lesions.
