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

Abstract

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