Mycobacterium tuberculosis (Mtb), the causative agent of the disease tuberculosis (TB), is estimated to infect one-fourth of the world’s population, resulting in approximately 1.5 million deaths each year. The emergence of multidrug- and extensively drug-resistant Mtb strains and the variable efficacy of the currently used vaccine, M. bovis Bacille Calmette Guerin (BCG), are barriers to the global control of TB. Thus, there is a critical need to better understand the mechanisms of TB immunopathogenesis, as such mechanisms can be targeted to improve host control of Mtb infection. Following inhalation of aerosolized Mtb, bacteria are phagocytosed by alveolar macrophages (AMs) and dendritic cells (DCs), resulting in the recruitment of immune cells to the lung and the formation of the tubercle granuloma. Although granulomas have long been considered a hallmark of both latent TB infection (LTBI) and clinical pulmonary TB (PTB), the immunological differences between protective granulomas and non-protective granulomas have only recently begun to emerge. Our recent data suggest that the presence of B-cell follicles in inducible bronchus-associated lymphoid tissue (iBALT)-containing granulomas is indicative of protective granulomas that mediate Mtb control during LTBI. In contrast, infiltrating neutrophils producing proinflammatory molecules are characteristic of non-protective granulomas during PTB. Our findings challenge the current paradigm that TB granulomas are generally protective and advocate a new model for TB immunopathogenesis in which protective granulomas contain iBALT whereas non-protective granulomas are neutrophilic or exhibit immune activation. We will further elucidate the mechanisms by which iBALT-containing granulomas confer protection against TB and will test approaches for clinically improving iBALT formation and limiting neutrophil accumulation. The knowledge to be gained from these studies is significant, as it will advance the development of new therapeutics and vaccine strategies for limiting TB-Reactivation (TB-R) and progression to PTB.

Role of B cells and T follicular helper cells in formation of iBALT and Mtb control

Role of Neutrophils in TB disease progression

Role of innate lymphoid cells (ILCs) in immunity to tuberculosis

Innate immunity

Novel Vaccines and Vaccination Strategies

Identification and characterization of immune correlates of tuberculosis disease and risk across species

Macrophage metabolic reprogramming in multidrug-resistant Mtb-infection