Editors' ChoiceInfectious Disease

Macrophages build a wall and the host pays for it

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Science Translational Medicine  09 Nov 2016:
Vol. 8, Issue 364, pp. 364ec178
DOI: 10.1126/scitranslmed.aal0066

Tuberculosis (TB) is an age-old scourge. It has long been known that the mycobacteria that cause TB are surrounded by macrophages in structures known as granulomas. These macrophages are described as epithelioid because they resemble epithelial cells: They have elongated nuclei, abundant cytoplasm, and extensive contacts with other macrophages. The significance of these epithelioid macrophages, however, remains a mystery.

In a new study, Cronan et al. shed light on these epithelioid macrophages using zebrafish infected with Mycobacterium marinum. In this model, bacilli become localized to granulomas similar to the granulomas observed in TB patients infected with Mycobacterium tuberculosis. Using lineage labeling of macrophages, the authors observed expression of the epithelial adhesion protein E-cadherin in macrophages associated with granulomas but not in those at other sites. These macrophages also expressed catenins and cortical actin and exhibited other characteristic epithelial structures, such as tight junctions and desmosomes. Likewise, RNA-seq analysis of the granuloma-associated macrophages revealed epithelial junction and polarity markers, in addition to expression of macrophage-specific genes.

In order to probe the functional significance of this epithelial switch in granuloma-associated macrophages in zebrafish infected with M. marinum, the authors expressed a dominant-negative, truncated E-cadherin in the macrophages and observed suppression of adherens junction formation. Interestingly, mycobacterial burden was decreased in granulomas formed from these mutant macrophages, and survival of zebrafish was prolonged. Examination of the granulomas from zebrafish expressing the dominant-negative E-cadherin revealed increased numbers of neutrophils. These data suggest that, normally, granuloma-associated macrophages with their epithelioid junction contacts effectively wall off the mycobacteria preventing effective immune clearance of the pathogen by neutrophils.

Taking a step toward human disease, the authors report E-cadherin staining of granuloma-associated macrophages in samples from patients infected with M. tuberculosis or M. avium-intracellulare. They also found similar staining patterns in the granulomas of mice infected with M. tuberculosis. It has long been debated whether formation of granulomas by the host to wall off M. tuberculosis is beneficial or detrimental. The new data from Cronan et al. now suggest that the epithelioid morphology and associated barrier function of host macrophages associated with granulomas may prevent effective immune clearance of mycobacteria. Future studies should determine what signals—from the host or the pathogen—stimulate macrophages to become epithelioid and whether disrupting this transition could be a potential therapeutic approach to clearing M. tuberculosis infection.

M. R. Cronan et al., Macrophage epithelial reprogramming underlies mycobacterial granuloma formation and promotes infection. Immunity 45, 861–876 (2016). [Abstract]

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