Abstract
Mycobacterium tuberculosis when phagocytosed by macrophages is not cleared completely and many of the bacteria remain in phagosomes indefinitely. In this study we considered abnormal retention of filamentous actin on early phagosomes contributing to defective phagosome acidification. Phosphocofilin1, the inactive form of actin depolymerizing protein cofilin1, which leads to retention of filamentous actin, and the total filamentous actin itself were found upregulated in macrophages infected with virulent M. tuberculosis. Over expression of constitutively active cofilin1 in macrophages was found to increase phagosome acidification when infected with virulent M. tuberculosis. The anticancer drug sorafenib which activates cofilin1 in PI3K dependent manner was also found to increase phagosome acidification. Cofilin1, known to be positively regulated by superoxide was found to be downregulated by ESAT-6 of M. tuberculosis where the latter is known to reduce ROS in macrophages. Ectopic expression of ESAT-6 in macrophages was found to increase filamentous actin and to transform the macrophages more spindle shaped. ESAT-6 was also found to decrease phagosome acidification in macrophages infected with an avirulent M. tuberculosis strain. Finally, this study proposes a role for the amino acid methionine in resisting ROS by creating M93 mutants of ESAT-6.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Email: ppmahesh1982{at}gmail.com, retnakumarrj{at}rgcb.res.in, sivakumar{at}rgcb.res.in