Study of the immune mechanisms that control tuberculosis infection in the human host

GARCIA VE

Congreso; SLAM TB. REUNION DE LA SOCIEDAD LATINOAMERICANA DE TUBERCULOSIS Y OTRAS MICOBACTERIOSIS; 2016

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 IL-17 and IFNG expression in lymphocytes from tuberculosis patients correlates with disease severity. Here we investigate the role of IFNG and IL-17A 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. IL-17A augmented autophagy in infected monocytes from HR patients through a mechanism that activated ERK but, during infection of monocytes from LR patients, IL-17A had no effect on the autophagic response. In contrast, addition of IFNG to infected monocytes, increased autophagy by activating p38 MAPK both in HR and LR patients. Interestingly, proteins codified in the RD1 region did not interfere with IFNG and IL-17A autophagy induction. Therefore, in severe tuberculosis patients? monocytes, IL-17A was unable to augment autophagy because of a defect in the ERK signaling pathway. In contrast, both IFNG and IL-17A 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.