title: Tuberculous granuloma formation is enhanced by a mycobacterium virulence determinant.
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.
authors.affiliation: Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, Washington, USA.
authors.forename: Hannah E
authors.initials: HE
authors.lastname: Volkman
authors.forename: Hilary
authors.initials: H
authors.lastname: Clay
authors.forename: Dana
authors.initials: D
authors.lastname: Beery
authors.forename: Jennifer C W
authors.initials: JC
authors.lastname: Chang
authors.forename: David R
authors.initials: DR
authors.lastname: Sherman
authors.forename: Lalita
authors.initials: L
authors.lastname: Ramakrishnan
mesh_terms: D000818:Animals; D016923:Cell Death; D002460:Cell Line; D002478:Cells, Cultured; D002633:Chemotaxis; D006099:Granuloma / Q000382:microbiology; D020287:In Situ Nick-End Labeling; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D018715:Microscopy, Video; D009154:Mutation; D009164:Mycobacterium Infections / Q000382:microbiology* / Q000473:pathology; D009169:Mycobacterium tuberculosis / Q000472:pathogenicity*; D011898:Ranidae / Q000382:microbiology*; D013997:Time Factors; D014375:Tuberculoma / Q000382:microbiology*; D014376:Tuberculosis / Q000382:microbiology*; D014774:Virulence; D015027:Zebrafish