IL17A augments autophagy in Mycobacterium tuberculosis -infected monocytes from patients with active tuberculosis in association with the severity of the disease

AMIANO, NICOLÁS OSCAR; PALMERO, DOMINGO JUAN; PELLEGRINI, JOAQUÍN MIGUEL; CASCO, NICOLÁS; GARCÍA, VERÓNICA EDITH; TATEOSIAN, NANCY LILIANA; ROLANDELLI, AGUSTÍN; COLOMBO, MARÍA ISABEL

AUTOPHAGY

LANDES BIOSCIENCE

Lugar: Austin, Texas; Año: 2017 vol. 13 p. 1191 - 1204

1554-8627

During mycobacterial infection, autophagy, a process modulated by cytokines, is essential for mounting successful host responses. Autophagy collaborates with human immune responses against Mycobacterium tuberculosis (Mtb) in association with specific IFNG secreted against the pathogen. However, IFNG alone is not sufficient to the complete bacterial eradication, and other cytokines might be required. Actually, induction of Th1 and Th17 immune responses are required for protection against Mtb. Accordingly, we showed that IL17 and IFNG expression in lymphocytes from tuberculosis patients correlates with disease severity. Here we investigate the role of IFNG and IL17A during autophagy in monocytes infected with MtbH37Rv or the mutant MtbΔRD1. Patients with active disease were classified as high (HR) or low responder (LR) accordingly to their T cell responses against Mtb. IL17A augmented autophagy in infected monocytes from HR patients through a mechanism that activated MAPK1/2 (ERK) but, during infection of monocytes from LR patients, IL17A had no effect on the autophagic response. In contrast, addition of IFNG to infected monocytes, increased autophagy by activating MAPK14/p38 both in HR and LR patients. Interestingly, proteins codified in the RD1 region did not interfere with IFNG and IL17A autophagy induction. Therefore, in severe tuberculosis patients? monocytes, IL17A was unable to augment autophagy because of a defect in the ERK signaling pathway. In contrast, both IFNG and IL17A increased autophagy levels in patients with strong immunity to Mtb, promoting mycobacterial killing. Our findings might contribute to recognize new targets for the development of novel therapeutic tools to fight the pathogen.