Chandra Pallavi, Ghanwat Swapnil, Matta Sumit Kumar, Yadav Swati Seth, Mehta Mansi, Siddiqui Zaved, Singh Amit, Kumar Dhiraj
Immunology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi, 110067, India.
Department of Microbiology and Cell Biology, Centre for Infectious Disease Research, Indian Institute of Sciences, Bangalore, 560012, India.
Sci Rep. 2015 Nov 6;5:16320. doi: 10.1038/srep16320.
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.
在此,我们报告了一种自噬介导的结核分枝杆菌(Mtb)降解的新型调控机制,以及毒力强的Mtb用于逃避该机制的特定策略。我们发现,无毒力的(H37Ra)和有毒力的(H37Rv)分枝杆菌都能很容易地定位于自噬体,但后者菌株显著抑制了它们成熟为自溶酶体(通量)的过程。毒力菌株对自噬通量的抑制具有高度选择性,因为它不会干扰巨噬细胞中的基础自噬通量。对含Mtb自噬体通量的选择性抑制需要毒力调节因子PhoP和ESAT-6。我们表明,含Mtb自噬体成熟为自溶酶体需要募集晚期内体标志物RAB7,形成中间隔室双膜体。毒力强的Mtb选择性地逃避了它们靶向双膜体的过程。因此,我们报告了自噬与吞噬体成熟途径之间的相互作用,并强调了Mtb的适应性,表现为对自噬通量的选择性调节。