Defining Mechanisms for Plasmacytoid Dendritic Cell-driven Mycobacterium tuberculosis Susceptibility

Project Summary Mycobacterium tuberculosis (Mtb) is a major global health problem causing 1.6 million deaths a year worldwide. Options for tackling this scourge are limited as the only approved vaccine has little to no efficacy in adults and treatment involves a 4-6 month course of antibiotics. Host-directed therapies are an exciting alternative, but druggable pathways need to be identified for them to be a viable approach. Using a mouse model that recapitulates fundamental aspects of Mtb progression in humans, we demonstrated for the first time that plasmacytoid dendritic cells (pDCs) contribute to loss of Mtb control via their production of type I interferons. This proposal will build upon this finding to characterize pDC function during Mtb infection to identify pDC-specific therapeutic targets. Specific Aims: Aim 1) We identified that Mtb infection induces a 10- fold increase in lung pDCs at an early time point of infection. This aim will quantify pDC lung trafficking throughout the course of Mtb infection, identify the chemokine receptor required for the pDC lung honing, and define the contribution of pDCs at later time points of the infection. Aim 2) pDCs contribute to increased Mtb burden in a mouse model with a strong type I interferon response, but not in wild-type mice. We will test whether the difference in the effect of pDCs in these genotypes is due to differences in pDC localization within the lung or pDC activation state. Study Design: I will use our novel mouse model of Mtb infection that recapitulates the strong type I interferon response of human Mtb progressors to dissect pDC biology in response to a bacterial infection. This goal will be accomplished by leveraging flow cytometry, cutting-edge imaging approaches, single cell RNA-sequencing, and mouse genetics. Potential Impact: By characterizing pDC function during Mtb infection at the cellular level, we can identify pDC-specific targets that can serve as a basis for host-directed therapies to treat Mtb disease. Such therapeutics would constitute a major advance.