RT Journal Article SR Electronic T1 Phenolic glycolipid facilitates mycobacterial escape from a microbicidal population of tissue-resident macrophages JF bioRxiv FD Cold Spring Harbor Laboratory SP 147421 DO 10.1101/147421 A1 C.J. Cambier A1 Seónadh M. O’Leary A1 Mary P. O’Sullivan A1 Joseph Keane A1 Lalita Ramakrishnan YR 2017 UL http://biorxiv.org/content/early/2017/06/07/147421.abstract AB Mycobacterium tuberculosis 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. We find that the first-responding resident macrophages can phagocytose and eradicate infecting mycobacteria. So, to establish a successful infection, mycobacteria must escape out of the initial resident macrophage into growth-permissive monocytes. We define a critical role for the membrane phenolic glycolipid (PGL) in engineering this transition to a permissive niche. PGL activates the STING cytosolic sensing pathway, thereby inducing the chemokine CCL2 that recruits permissive peripheral monocytes. The bacteria then transfer from resident macrophage to recruited monocyte via transient fusion of the two immune cells. We show that interrupting this bacterial strategy so as to prolong the mycobacterial sojourn in resident macrophages promotes clearing of infection. Because PGL-dependent CCL2 induction is conserved in human alveolar macrophages, our findings suggest the potential of immunological or pharmacological PGL-blocking interventions to prevent tuberculosis.