Project 3

"Macaque T cell signatures of Mtb control"

Project-3

Co-Principle Investigators: Deepak Kaushal, PhD and Francois Villinger, PhD

How a majority of individuals infected with Mycobacterium tuberculosis (Mtb) control the infection in a state referred to as latent Mtb infection (LTBI), is not well understood. Asymptomatic individuals with LTBI can progress to clinically active TB disease due to the ability of Mtb to persist in vivo and reactivate when the host is immune-compromised. Antigen-specific T cell responses, particularly CD4 T cell responses, are crucial to the control of Mtb infection in humans and in experimental animal models.

However, the characteristics of Mtb-specific T cell responses that control Mtb infection and/or confer protective immunity have not been identified. Moreover, as infection with Mtb can result in a spectrum of outcomes, ranging from resolution of infection, asymptomatic LTBI with persisting bacteria, active TB disease, and reactivation of LTBI, it is important to identify antigen-specific T cell responses that are associated with distinct outcomes of Mtb infection: clearance, persistence, and progression to active disease.

Due to their genomic, physiological and immunological similarities to humans, nonhuman primates (NHPs) are attractive experimental models of TB. Low-dose aerosol infection of NHPs recapitulates the spectrum of lung pathological lesions observed in humans, including LTBI and its reactivation by co-infection with Simian Immunodeficiency Virus (SIV). In Project 3, we will focus on identifying Mtb-specific T cell responses in Rhesus macaques associated with resolved and persistent Mtb infection, which integrates into the overall TBRU ASTRa application. The objectives of Project 3 are highly complementary to those of Project 1 and Project 2. The NHP model will contribute data that cannot be readily obtained in human studies, including profiling immune responses in infected tissue, experimental verification of bacterial presence/absence and longitudinal sampling of blood and tissue. Thus, our studies on persistently infected and resolved animals will be performed in the light of bacteriological evidence of persistence or clearance. Project 3 will both benefit from the human-specific data and contribute overlapping data including tissue responses from an excellent experimental model. Project 3 will synergize with Project 1 to study antigen-specific T-cell responses that allow immunocompetent hosts to maintain or resolve LTBI and with Project 2 to study the impact of re-exposure on these responses. We will work closely with the Immunology Core to develop tools and methodologies for studying CD4 and CD8 T cells responses to multiple Mtb antigens in rhesus macaques with LTBI and characterize their phenotypes and functions before and after chemotherapy-mediated clearance of Mtb infection.