The Role of the Granuloma in Expansion and Dissemination of Early Tuberculous Infection

Davis, J.M. and Ramakrishnan L. Cell 2009; 136: 37-49

Speaker: 陳倩怡                                   Time: 15:00-16:00, March 25, 2009

Commentator: 謝奇璋老師                  Place: Room 601

Abstract:

At the outset of human pulmonary tuberculosis, infected macrophages recruit additional macrophages and other immune cells to form organized structures called granulomas, pathological hallmarks of tuberculosis. According to the classical model, granulomas are believed to benefit the host by containing and restricting mycobacteria. Studies in transparent zebrafish embryos infected with Mycobacterium marinum (Mm), a system which recapitulates the earliest stages of tuberculosis, refute the classical model of granuloma initiation as a host-protective event in fundamental ways. In this study, the authors sought to determine the mechanisms by which mycobacteria might take advantage of such a widely used host-protective response as granuloma formation. By comparing virulent and ∆RD1 Mm infection, the authors developed the Hoechst recruitment assay for macrophage arrival at granulomas. They induced brain granulomas by hindbrain ventricle infection and then injected the nuclear dye Hoechst 33342 into the circulation via the caudal vein. Individual infected macrophages promote extravasation and tissue migration of uninfected macrophages to form granulomas in an RD1-dependent fashion. They also constructed a simple mathematical model of granuloma expansion. In summary, the authors proposed that the pathway of granuloma formation and subsequent bacterial dissemination is based upon macrophage responses (recruitment, phagocytosis, and apoptosis) that are of themselves generally protective and that work reasonably well against less virulent (i.e., RD1-deficient) infection. RD1-competent mycobacteria appear to accelerate them to turn the granuloma response into an effective tool for pathogenesis. The initiation of the adaptive immune response then may halt bacterial expansion not by forming granulomas as suggested by the classical model, but by altering the early granuloma into a form of stalemate between host and pathogen.

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