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Πέμπτη 24 Αυγούστου 2017

Phenolic Glycolipid Facilitates Mycobacterial Escape from Microbicidal Tissue-Resident Macrophages

Publication date: Available online 24 August 2017
Source:Immunity
Author(s): C.J. Cambier, Seónadh M. O'Leary, Mary P. O'Sullivan, Joseph Keane, Lalita Ramakrishnan
Mycobacterium tuberculosis (Mtb) enters the host in aerosol droplets deposited in lung alveoli, where the bacteria first encounter lung-resident alveolar macrophages. We studied the earliest mycobacterium-macrophage interactions in the optically transparent zebrafish. First-responding resident macrophages phagocytosed and eradicated infecting mycobacteria, suggesting that to establish a successful infection, mycobacteria must escape out of the initially infected resident macrophage into growth-permissive monocytes. We defined a critical role for mycobacterial membrane phenolic glycolipid (PGL) in engineering this transition. PGL activated the STING cytosolic sensing pathway in resident macrophages, inducing the production of the chemokine CCL2, which in turn recruited circulating CCR2+ monocytes toward infection. Transient fusion of infected macrophages with CCR2+ monocytes enabled bacterial transfer and subsequent dissemination, and interrupting this transfer so as to prolong mycobacterial sojourn in resident macrophages promoted clearing of infection. Human alveolar macrophages produced CCL2 in a PGL-dependent fashion following infection, arguing for the potential of PGL-blocking interventions or PGL-targeting vaccine strategies in the prevention of tuberculosis.Video Abstract

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Teaser

Cambier et al. find that activation of the STING pathway in lung-resident microbicidal macrophages by the mycobacterial surface lipid PGL enables bacterial escape by inducing the recruitment of mycobacterium-permissive monocytes via the CCL2-CCR2 chemokine axis. Their findings reveal a relocation strategy that enables mycobacterial dissemination, and argue for the potential of interventions targeting PGL in the prevention of tuberculosis.


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