02653nas a2200265   4500000000100000008004100001653001200042100002100054700001600075700001400091700001500105700001800120700001800138700001400156700001100170700001200181700001200193700001500205245007500220856010300295300001300398490000700411520195500418022001402373       2017                            d10aleprosy1 aAndrade Silva BJ1 aBarbosa MGM1 aAndrade P1 aFerreira H1 aCosta Nery JA1 aCôrte-Real S1 aSilva GMS1 aRosa P1 aFabri M1 aSarno E1 aPinheiro R00aAutophagy Is an Innate Mechanism Associated with Leprosy Polarization.  uhttp://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1006103&type=printable  ae10061030 v133 a<p>Leprosy is a chronic infectious disease that may present different clinical forms according to the immune response of the host. Levels of IFN-γ are significantly raised in paucibacillary tuberculoid (T-lep) when compared with multibacillary lepromatous (L-lep) patients. IFN-γ primes macrophages for inflammatory activation and induces the autophagy antimicrobial mechanism. The involvement of autophagy in the immune response against Mycobacterium leprae remains unexplored. Here, we demonstrated by different autophagic assays that LC3-positive autophagosomes were predominantly observed in T-lep when compared with L-lep lesions and skin-derived macrophages. Accumulation of the autophagic receptors SQSTM1/p62 and NBR1, expression of lysosomal antimicrobial peptides and colocalization analysis of autolysosomes revealed an impairment of the autophagic flux in L-lep cells, which was restored by IFN-γ or rapamycin treatment. Autophagy PCR array gene-expression analysis revealed a significantly upregulation of autophagy genes (BECN1, GPSM3, ATG14, APOL1, and TPR) in T-lep cells. Furthermore, an upregulation of autophagy genes (TPR, GFI1B and GNAI3) as well as LC3 levels was observed in cells of L-lep patients that developed type 1 reaction (T1R) episodes, an acute inflammatory condition associated with increased IFN-γ levels. Finally, we observed increased BCL2 expression in L-lep cells that could be responsible for the blockage of BECN1-mediated autophagy. In addition, in vitro studies demonstrated that dead, but not live M. leprae can induce autophagy in primary and lineage human monocytes, and that live mycobacteria can reduce the autophagy activation triggered by dead mycobacteria, suggesting that M. leprae may hamper the autophagic machinery as an immune escape mechanism. Together, these results indicate that autophagy is an important innate mechanism associated with the M. leprae control in skin macrophages.</p>
  a1553-7374