Complement C3 Drives Autophagy-Dependent Restriction of Cyto-invasive Bacteria

In physiological settings, the complement protein C3 is deposited on all bacteria, including invasive pathogens. However, because experimental host-bacteria systems typically use decomplemented serum to avoid the lytic action of complement, the impact of C3 coating on epithelial cell responses to invasive bacteria remains unexplored. Here, we demonstrate that following invasion, intracellular C3-positive Listeria monocytogenes is targeted by autophagy through a direct C3/ATG16L1 interaction, resulting in autophagy-dependent bacterial growth restriction. In contrast, Shigella flexneri and Salmonella Typhimurium escape autophagy-mediated growth restriction in part through the action of bacterial outer membrane proteases that cleave bound C3. Upon oral infection with Listeria, C3-deficient mice displayed defective clearance at the intestinal mucosa. Together, these results demonstrate an intracellular role of complement in triggering antibacterial autophagy and immunity against intracellular pathogens. Since C3 indiscriminately associates with foreign surfaces, the C3-ATG16L1 interaction may provide a universal mechanism of xenophagy initiation. [Display omitted] •Complement C3 interacts directly with the autophagy protein ATG16L1•C3 coating of invasive bacteria increases autophagy targeting and restricts replication•Shigella/Salmonella use proteases to shed C3 and escape C3-dependent growth restriction•C3−/− mice have altered autophagy responses to infection and increased Listeria invasion Complement C3 activation and opsonization is a critical part of the host response to infection in the extracellular environment. Sorbara et al. report that C3 can also be carried into cells by invasive bacteria, where it promotes autophagy-dependent restriction of the bacterium through an interaction with the autophagy protein ATG16L1.