FIP200 promotes Mycobacterium tuberculosis pathogenesis independent of its role in autophagy

Abstract Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains a critical health issue. Xenophagy, the targeting of Mtb to autophagosomes within infected cells is ineffective at controlling Mtb replication in vivo. We discovered that autophagy-associated proteins function outside of xenophagy to impact Mtb pathogenesis. We reveal a distinct autophagy-independent function of FIP200 in CD11c+ alveolar macrophages (AMs) to control Mtb burden in mice lungs at 7 days post-infection. Intra-tracheal airway labelling shows that despite the abundance of inflammatory cells, including AMs, in airway and interstitium, airway resident AMs precisely exhibit better infection control in Fip200fl/fl-LysM-Cre mice lungs.FIP200, beyond its role in autophagy, is shown to regulate signaling pathways to suppress TNF-induced apoptosis and promote cell survival. Compared to flox control, loss of Fip200 resulted in significantly higher apoptosis in AMs, in the lungs of naïve mice, which is sustained during infection. We also observed higher reactive oxygen species production by the AMs in lungs. This observation extends to Streptococcus pneumoniae infection, where loss of FIP200 in CD11c+ AMs caused similar increase in apoptosis and ROS,with reduced bacterial burden in mouse lungs. Thus, we propose a model where the FIP200 inhibits the apoptosis and ROS production in AMs, which impairs the antimicrobial defense in these cells, thus promoting Mtb infection in the airways following infection.