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Here we report a novel regulatory mechanism for autophagy-mediated degradation of  Mycobacterium tuberculosis (Mtb)  and specific strategy exploited by the virulent  Mtb  to evade it. We show while both avirulent (H37Ra) and virulent (H37Rv) mycobacteria could readily localize to autophagosomes, their maturation into autolysosomes (flux) was significantly inhibited by the latter strain. The inhibition of autophagy flux by the virulent strain was highly selective, as it did not perturb the basal autophagy flux in the macrophages. Selective inhibition of flux of  Mtb- containing autophagosomes required virulence regulators PhoP and ESAT-6. We show that the maturation of  Mtb -containing autophagosomes into autolysosomes required recruitment of the late endosome marker RAB7, forming the intermediate compartment amphisomes. Virulent  Mtb  selectively evaded their targeting to the amphisomes. Thus we report a crosstalk between autophagy and phagosome maturation pathway and highlight the adaptability of  Mtb,  manifested by selective regulation of autophagy flux.

Mycobacterium tuberculosis Inhibits RAB7 Recruitment to Selectively Modulate Autophagy Flux in Macrophages