Tuberculous Granuloma Formation Is Enhanced by a Mycobacterium Virulence Determinant

TLDR

Granulomas are organized immune structures that contain mycobacterial infection but are not always fully effective, and the Mycobacterium RD1 locus encodes a secretion system that enhances virulence through an unknown mechanism. The study used transparent zebrafish embryos to show that RD1‑deficient mycobacteria cannot efficiently trigger granuloma formation while still replicating within macrophages. Virulent mycobacteria secrete an RD1‑dependent signal that drives macrophage aggregation into granulomas, promoting bacterial dissemination and growth, thereby co‑opting granulomas for virulence.

Abstract

Granulomas are organized host immune structures composed of tightly interposed macrophages and other cells that form in response to a variety of persistent stimuli, both infectious and noninfectious. The tuberculous granuloma is essential for host containment of mycobacterial infection, although it does not always eradicate it. Therefore, it is considered a host-beneficial, if incompletely efficacious, immune response. The Mycobacterium RD1 locus encodes a specialized secretion system that promotes mycobacterial virulence by an unknown mechanism. Using transparent zebrafish embryos to monitor the infection process in real time, we found that RD1-deficient bacteria fail to elicit efficient granuloma formation despite their ability to grow inside of infected macrophages. We showed that macrophages infected with virulent mycobacteria produce an RD1-dependent signal that directs macrophages to aggregate into granulomas. This Mycobacterium-induced macrophage aggregation in turn is tightly linked to intercellular bacterial dissemination and increased bacterial numbers. Thus, mycobacteria co-opt host granulomas for their virulence.