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Phenolic Glycolipid Facilitates Mycobacterial Escape from Microbicidal Tissue-Resident Macrophages

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Cambier, CJ 
O'Leary, SM 
O'Sullivan, MP 
Keane, J 
Ramakrishnan, Lalita  ORCID logo


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 towards 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 upon Mtb infection, arguing for the potential of PGL-blocking interventions or PGL-targeting vaccine strategies in the prevention of tuberculosis.



Animals, Chemokine CCL2, Chemotaxis, Cytokines, Disease Models, Animal, Gene Knockout Techniques, Glycolipids, Humans, Inflammation Mediators, Macrophages, Macrophages, Alveolar, Membrane Proteins, Monocytes, Mutation, Mycobacterium tuberculosis, Organ Specificity, Tuberculosis, Zebrafish

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Wellcome Trust (103950/Z/14/Z)
This work was supported by the NIH Director’s Pioneer Award, NIH grant R37AI054503, and a Wellcome Trust Principal Research Fellowship (L.R.), NIH training grant T32 AI55396 and a Damon Runyon Postdoctoral Fellowship (C.J.C.), the Health Research Board of Ireland (S.M.O., M.P.O., and J.K.), and The Royal City of Dublin Hospital Trust (J.K.).