Autophagy Is an Innate Mechanism Associated with Leprosy Polarization

Abstract

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.

Macrophages in the Pathogenesis of Leprosy

“…As mentioned earlier, the paucibacillary tuberculoid skin macrophages activate the vitamin D pathway and produce antimicrobial peptides that could be involved in autophagy induction. In addition, Silva and colleagues [58] demonstrated that autophagy is differentially regulated between leprosy polar forms. In paucibacillary tuberculoid skin lesion macrophages, IFN-γ/beclin 1-induced autophagy contributes for M. leprae control, whereas in lepromatous macrophages B cell lymphoma 2 (BCL2)-mediated blockade of beclin 1 autophagic pathway promotes mycobacterial persistence [58].…”

“…In addition, Silva and colleagues [58] demonstrated that autophagy is differentially regulated between leprosy polar forms. In paucibacillary tuberculoid skin lesion macrophages, IFN-γ/beclin 1-induced autophagy contributes for M. leprae control, whereas in lepromatous macrophages B cell lymphoma 2 (BCL2)-mediated blockade of beclin 1 autophagic pathway promotes mycobacterial persistence [58]. Indeed, the M. leprae can take advantage of host antiviral protein 2′-5′-oligoadenylate synthetase like (OASL) to inhibit autophagy and promote its own survival through a stimulator of interferon genes (STING)-mediated type I IFN response [60].…”

“…In addition to the role of autophagy in the elimination of potentially toxic protein aggregates and in the prevention of neurodegeneration [56], autophagy plays a key role in the host's response to mycobacterial infection, because it is able to reverse the blockade of phagosome maturation, inhibiting the intracellular survival of the pathogen [57]. It has been shown that autophagy is an important innate mechanism associated with leprosy immunopathogenesis [58]. Recently, it was demonstrated that autophagy enhances the ability of M. leprae-infected Langerhans cells to present antigens to CD1a T cells [59].…”

“…Despite the effectiveness of MDT in controlling the polar forms of the disease, limitations in terms of persistent activity in paucibacillary patients, in combination with the persistence of live and/or dead bacilli in multibacillary patients, have been observed, which has repercussions on the frequency of relapses and reactional episodes after treatment [71,72]. Recent studies have demonstrated that autophagy is an important molecular mechanism for controlling the viability of mycobacteria in the host cell and of the bacillary load in patients with leprosy [58][59][60]. Autophagy can be induced by oxidative stress or by an infectious agent and is closely associated with the immune response and host defense [73,74].…”

“…The molecular regulators interconnecting autophagy and apoptosis, including BCL2, BCL2associated X protein (BAX), and beclin 1, have been suggested to act as switching points that are critical for the outcome of tumor cells, and lysosomes have been reported to initiate the cell death pathway in autophagic cells [77,78]. Regarding leprosy, it was observed that in skin cells of patients with the lepromatous form of the disease there is a blockade of the autophagic flux that can be attributed to the increased expression of the antiapoptotic protein BCL2, which inhibits autophagy mediated by beclin 1 [58]. Blockade of the autophagic machinery in lepromatous cells may contribute to the persistence of mycobacteria in host cells.…”