Approximately one-fourth of the world's population is latently infected (LTBI) with Mycobacterium tuberculosis (Mtb) and those infected have a 10% lifetime risk of developing clinical pulmonary TB (PTB) disease over their lifetime. Global efforts to combat TB are hampered by the emergence of extensively drug-resistant and multidrug- resistant strains and the variable efficacy of the currently available vaccine, M. bovis Bacille Calmette Guerin. Unfortunately, the immune mechanisms that govern progression from LTBI to PTB are poorly defined, preventing rational design of treatments or vaccines that stimulate immune control of TB. Thus, there is an urgent need to better understand the immune parameters that contribute to Mtb control. The tubercle granuloma is a hallmark of TB and is important for the immune control of Mtb infection. However, not all granulomas effectively control TB, as they are seen both during LTBI and during TB reactivation (TB-R) and PTB. During the previous R01 funding period, we used human TB samples and non-human primate (NHP) and mouse models of TB to demonstrate an unequivocal protective role for inducible bronchus-associated lymphoid tissue (iBALT) containing clearly defined B-cell follicles during both primary and vaccine-induced responses to Mtb infection. Additionally, we determined that a dominant feature of granulomas during PTB is the accumulation of neutrophils that produce proinflammatory molecules such as S100A8/A9 proteins and limit iBALT formation. Our long-term goal is to develop clinical strategies to restrain Mtb growth and prevent progression from LTBI to TB disease. Based on work from this funded R01, the objective of this R01 renewal is to identify the roles of granuloma- associated B cells and neutrophils in TB infection and disease progression and to determine if iBALT is an effective target for preventing TB progression. Towards this overall goal, we propose to use both small animal and large animal models to address the following specific aims:
In Specific Aim 1 we will investigate the role of iBALT-residing B cells in protecting against TB;
In Specific Aim 2, we will evaluate the role of neutrophilic proteins such as S100A8/A9 in limiting iBALT during PTB, and to determine if targeting S100A8/A9 pathways will reduce TB disease and improve Mtb control; Finally, in Specific Aim 3, we will determine if iBALT structures can be targeted to prevent TB progression in Mtb-infected hosts. The knowledge to be gained from these studies is significant, as it will directly advance the development of new therapeutics and vaccine strategies for limiting TB-R and progression to TB.
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 1.6 million deaths each year. 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. The work proposed in this R01 renewal will further elucidate the mechanisms by which inducible Bronchus Associated Lymphoid Tissue (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 and progression to TB.
Showing the most recent 10 out of 11 publications
