Date Published: January 5, 2017
Publisher: Public Library of Science
Author(s): Bruno Jorge de Andrade Silva, Mayara Garcia de Mattos Barbosa, Priscila Ribeiro Andrade, Helen Ferreira, José Augusto da Costa Nery, Suzana Côrte-Real, Gilberto Marcelo Sperandio da Silva, Patricia Sammarco Rosa, Mario Fabri, Euzenir Nunes Sarno, Roberta Olmo Pinheiro, Padmini Salgame.
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.
Leprosy is a chronic infectious disease that is gradually decreasing in many countries; however rates of new case detection remain at almost the same level globally and in different regions . It is caused by Mycobacterium leprae, an intracellular pathogen that preferentially infects macrophages (MΦs) and Schwann cells . Ridley and Jopling described a spectrum in which clinical manifestations correlate with the type of immune response . At one end of the spectrum, tuberculoid leprosy (T-lep) is characterized by a strong cellular immune response to the pathogen, few skin lesions presenting well-formed granulomas and well-differentiated type 1 MΦs, and only rare mycobacteria. At the opposite end of the spectrum, lepromatous leprosy (L-lep) patients have a disseminated form, with several skin lesions, absence of granuloma formation, high amounts of type 2 foamy MΦs loaded with bacilli, and anti-M. leprae antibodies [2–4]. The existence of both poles is a direct reflection of the cytokine patterns found in their respective skin lesions. Whereas T-lep patients show a strong Th1 profile, including IFN-γ, TNF, and IL-15, L-lep patients have a predominantly Th2 type response, typical of IL-4, IL-10, and IL-13 cytokines [5–7].
The present study details the enrollment of autophagy in the immunopathogenesis of leprosy. We demonstrated that in the multibacillary form of the disease the impairment of the autophagy pathway may significantly contribute to the survival of the bacilli inside the host cells, and it was reversed during T1R episodes.