| Autor(es): |
Franco, Luis H.
;
Fleuri, Anna K. A.
;
Pellison, Natalia C.
;
Quirino, Gustavo F. S.
;
Horta, Catarina V.
;
de Carvalho, Renan V. H.
;
Oliveira, Sergio C.
;
Zamboni, Dario S.
Número total de Autores: 8
|
Leishmaniasis is caused by protozoan parasites of the genus Leishmania. 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 Leishmania major in vivo. For example, mice in the resistant C57BL/6 genetic background that are triple-deficient for TLR3, -7, and -9 (Tlr3/7/9(-/-)) are highly susceptible to L. major infection. Tlr3/7/9(-/-) 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 L. major 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 L. major-induced autophagy. We also confirmed that Myd88(-/-), Tlr3/7/9(-/-), and Unc93b1(-/-) cells were highly permissive to L. major replication. Accordingly, shRNA-mediated suppression of Atg5, an E3 ubiquitin ligase essential for autophagosome elongation, in macrophages impaired the restriction of L. major replication in C57BL/6, but did not affect parasite replication in Myd88(-/-) or Unc93b1(-/-) macrophages. Rapamycin treatment reduced inflammatory lesions formed in the ears of Leishmania-infected C57BL/6 and Tlr3/7/9(-/-) mice, indicating that autophagy operates downstream of TLR signaling and is relevant for disease development in vivo. Collectively, our results indicate that autophagy contributes to macrophage resistance to L. major replication, and mechanistically explain the previously described endosomal TLR-mediated resistance to L. major infection. (AU) |