Autophagy downstream of endosomal Toll-like receptor signaling in macrophages is a key mechanism for resistance to infection.

Leishmaniasis is caused by protozoan parasites of the genus In mammalians, these parasites survive and replicate in macrophages and parasite elimination by macrophages is critical for host resistance. Endosomal Toll-like receptors (TLRs) have been shown to be crucial for resistance to For example, mice in the resistant C57BL/6 genetic background that are triple-deficient for TLR3, -7, and -9 () are highly susceptible to infection. mice are as susceptible as mice deficient in MyD88 or UNC93B1, a chaperone required for appropriate localization of endosomal TLRs, but the mechanisms are unknown. Here we found that macrophages infected with undergo autophagy, which effectively accounted for restriction of parasite replication. Signaling via endosomal TLRs was required for autophagy because macrophages deficient for TLR3, -7, and 9, UNC93B1, or MyD88 failed to undergo -induced autophagy. We also confirmed that , , and cells were highly permissive to replication. Accordingly, shRNA-mediated suppression of Atg5, an E3 ubiquitin ligase essential for autophagosome elongation, in macrophages impaired the restriction of replication in C57BL/6, but did not affect parasite replication in or macrophages. Rapamycin treatment reduced inflammatory lesions formed in the ears of -infected C57BL/6 and mice, indicating that autophagy operates downstream of TLR signaling and is relevant for disease development Collectively, our results indicate that autophagy contributes to macrophage resistance to replication, and mechanistically explain the previously described endosomal TLR-mediated resistance to infection.