Abstract
SummaryMycobacterium 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
Highlights
When M. tuberculosis (Mtb) is aerosolized into the lower lung, it first encounters lung-resident alveolar macrophages that patrol the air-lung epithelium interface (Srivastava et al, 2014)
Directly posterior to the hindbrain ventricle infection site (Figure 1A), is the brain which, like most organs, has a population of resident macrophages (Herbomel et al, 2001). We asked whether these brain-resident macrophages or microglia, analogous to the resident macrophages of the mammalian lung, participated in the immune response to mycobacterial infection
We found that resident macrophages were the first-responders in bacterial infections wherein overall myeloid cell recruitment is dependent on Toll-like receptor (TLR-MyD88) signaling rather than the CCL2-CCR2 axis (Cambier et al, 2014b), such as in the case of phthiocerol dimycoceroserate (PDIM)-deficient Mm (DmmpL7) and the mucosal commensal-pathogens Staphylococcus aureus and Pseudomonas aeruginosa (Figures 1F–1H)
Summary
When M. tuberculosis (Mtb) is aerosolized into the lower lung, it first encounters lung-resident alveolar macrophages that patrol the air-lung epithelium interface (Srivastava et al, 2014). We have exploited the optical transparency of the zebrafish larva to study the early mycobacterium-phagocyte interactions by infecting Mycobacterium marinum (Mm), a close genetic relative of Mtb, into the zebrafish larval hindbrain ventricle, an epithelium-lined cavity (Cambier et al, 2014b; Yang et al, 2012) In this model, pathogenic mycobacteria manipulate host responses immediately upon infection so as to inhibit the recruitment of neutrophils and microbicidal monocytes, and instead recruit and infect mycobacterium-permissive myeloid cells (Cambier et al, 2014b; Yang et al, 2012). PGL-deficient mycobacteria fail to recruit normal numbers of monocytes and their ability to establish infection is attenuated (Cambier et al, 2014b)
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