Mycobacterium tuberculosis exploits FIP200 regulated cell-death pathways to promote replication

Abstract Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is a leading health concern. The rise in antibacterial resistance has steered focus to developing host directed therapies, which requires an in-depth understanding of Mtb interactions with the immune system. Xenophagy, targeting autophagosomes within infected cells, not effective at controlling replication vivo, however, we have discovered that autophagy proteins function outside xenophagy impact pathogenesis. FIP200 pathway protein required for autophagosome formation. In this study, identified unique promoting infection mice independent its role autophagy. We show loss Fip200, but other genes, LysM +innate cells results lower burden lungs 7 dpi. Fip200 fl/fl-LysM-Cre harbor higher numbers neutrophils, macrophages, dendritic (DCs), and activated CD4 +T relative fl/flmice. Depletion either neutrophils or T did revert bacterial burdens, showing these do contribute enhanced control Mtb. specifically CD11c +macrophages and/or DCs during infection. been reported regulate several signaling pathways suppress apoptosis promote cell survival. observed increased macrophage airways compared fl/flcontrols response Based on our data, propose model where FIP200, proteins, leads better replication. NIH NIAID R01 #AI132697 U19 #AI142784 ND supported Alexander & Gertrude Berg Fellow