Molecular mechanism of T cell evasion by Mycobacterium tuberculosis



 DESCRIPTION (provided by applicant): Approximately one-third of the world's population is infected with Mycobacterium tuberculosis (Mtb), and the World Health Organization estimates that in 2012 there were 8.6 million new cases and more than one million deaths. Mtb is able to establish this enormous worldwide burden of disease by subverting innate and adaptive defenses of the host. One way in which it does this is by impairing key cellular functions of macrophages and dendritic cells (DCs), undermining degradation of the bacilli and presentation of antigens to T cells. Antigen presentation is critical both for priming naïve T cells and for recognition of infected macrophages by effector T cells. Thus, by inhibiting antigen presentation, Mtb prevents effective clearance and promotes persistent infection. Despite its clear importance in Mtb pathogenesis and implications for vaccine development, we lack a comprehensive understanding of how Mtb inhibits antigen presentation. Our group recently found that to promote its intracellular survival, Mtb secretes EsxH, which inhibits the endosomal sorting complex required for transport (ESCRT), a cellular machinery of the host involved in protein trafficking. We hypothesize that by targeting ESCRT, EsxH also impairs MHC-II antigen presentation. Consistent with this idea, my preliminary data demonstrates that ESCRT is required for Mtb-infected macrophages to activate effector CD4+ T cells. Correspondingly, macrophages infected with an Mtb strain lacking EsxH elicited better activation of CD4+ T cells than macrophages infected with wild type Mtb, whereas overexpression of EsxH impairs T cell activation. In this application, I seek to extend these preliminary studies. My aims are to: 1) to define the mechanism by which EsxH and ESCRT modulate antigen presentation in both macrophages and DCs, and 2) to determine their contribution to T cell evasion in vivo. These studies will significantly augment our understanding of the mechanisms employed by Mtb to evade the immune response. Our findings may provide an explanation for the delay in the initiation of an adaptive immune response seen during Mtb infection. In addition, our studies may provide a molecular explanation for how Mtb prevents effector CD4+ T cells from directly recognizing infected cells. Thus, targeting this host-pathogen interaction might promote host clearance of Mtb by restoring macrophage function and T cell activation.