ATG9 inhibits rickettsia binding to the Host cell surface by blocking the rOmpB-XRCC6/KU70 interaction

Rickettsiae are tick-borne pathogens that infect human hosts through poorly characterized mechanisms. Herein, we report that ATG9 (autophagy related 9) plays a previously unrecognized role in inhibiting Rickettsia binding to the host cell surface. Unexpectedly, this new function of ATG9 is likely independent of macroautophagy/autophagy. Instead, ATG9 acts as a host defending factor by binding to XRCC6/KU70, a receptor of the Rickettsia outer-membrane protein rOmpB. Both ATG9 and rOmpB bind to the DNA-binding domain of XRCC6, suggesting a competitive role for ATG9 occupying the binding site of rOmpB to abrogate Rickettsia binding. Furthermore, we show that rapamycin transcriptionally activates ATG9 and inhibits rOmpB-mediated infection in a mouse model. Collectively, our study reveals a novel innate mechanism regulating Rickettsia infection and suggests that agonists of ATG9 May be useful for developing therapeutic strategies for the intervention of rickettsial diseases.