Mycobacterium tuberculosis PPE25 and PPE26 proteins expressed in Mycobacterium smegmatis modulate cytokine secretion in mouse macrophages and enhance mycobacterial survival

PPE25 and PPE26, the Mycobacterium tuberculosis proline-proline-glutamic acid (PPE) family proteins, are members of the M. tuberculosis ESX-5 system associated with virulence of M. tuberculosis. To investigate the roles of PPE25 and PPE26 during M. tuberculosis infection, we expressed them in non-pathogenic fast-growing Mycobacterium smegmatis, respectively, and used these recombinant strains to infect ANA-1 macrophages and BALB/c mice. We observed that both PPE25 and PPE26 enhanced survival of M. smegmatis in ANA-1 macrophages, and prolonged the persistence of M. smegmatis in mouse tissues. M. smegmatis-expressed PPE25 and PPE26 induced a significantly higher level of TNF-alpha and a slightly higher amount of IL-1 beta, which was found to be mediated by the NF-kappa B, ERK and p38 pathways in ANA-1 macrophages. In addition, M. smegmatis-expressed PPE26 inhibited synthase of inducible nitric oxide and induced stronger cell necrosis. In summary, our data suggest that PPE25 and PPE26 enhance non-pathogenic M. smegmatis to survive in ANA-1 macrophages and persistence in mice, modify expression of multiple cytokines and affect host cell necrosis. Our results could help to understand the complex interactions between the host and M. tuberculosis. (C) 2016 Published by Elsevier Masson SAS on behalf of Institut Pasteur.