Editors' ChoiceHost-Pathogen Interactions

Pathogen-driven vascularization

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Science Signaling  30 Oct 2018:
Vol. 11, Issue 554, eaav8424
DOI: 10.1126/scisignal.aav8424

A cell wall component of mycobacteria stimulates vascularization of granulomas.

Mycobacterium tuberculosis that enter the lung are phagocytosed by macrophages that aggregate to form granulomas. These structures benefit the host by confining the pathogen to a localized area where the immune system can keep bacterial proliferation in check, resulting in latent infection. Granulomas also benefit the pathogen by protecting it from complete destruction by the host and by serving as a reservoir of bacteria that can be reactivated to establish an active infection. The vascularization of granulomas also benefits the pathogen and promotes Mycobacterium growth in animal models. The vascularization of Mycobacterium-containing granulomas has been thought to depend only on hypoxia in the granuloma, but Walton et al. found that mycobacteria actively promote this process. Using a model of M. marinum infection in zebrafish larvae characterized by granulomas analogous to those formed by M. tuberculosis in the human lung, the authors found that M. marinum proximal cyclopropane synthase of alpha-mycolates (PcaA) was required for the formation of vascularized granulomas. PcaA modifies the alpha class of mycolic acids, which are long-chain fatty acids unique to the cell walls of mycobacteria. Mycolic acids are incorporated into lipids, most notably trehalose-6,6-dimycolate (TDM), which is critical for mycobacterial viability. Injecting wild-type M. marinum, purified TDM, or mycolic acid–containing lipids from wild-type M. marinum into zebrafish larvae induced angiogenesis and the expression of a transcriptional reporter of vegfaa, which encodes a vascular endothelial growth factor (VEGF) homologous to human VEGFA. In contrast, pcaA mutant bacteria or mycolic acid–containing lipids derived from them did not stimulate angiogenesis or vegfaa reporter expression. Genetic or pharmacological inhibition of VEGF signaling prevented TDM-induced angiogenesis. The pcaA mutants exhibited reduced growth in vivo, but this defect was rescued by co-infection with wild-type bacteria. Thus, vascularization of mycobacterium-containing granulomas is an active process driven by a component of the bacterial cell wall. These findings also suggest possible targets for interfering with granuloma vascularization to combat latent M. tuberculosis infections (see Uusi-Mäkelä and Rämet).

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