Mycobacterium Tuberculosis NuoG is a Virulence Gene That Inhibits Apoptosis of Infected Host Cells

Overview

Journal PLoS Pathog

Specialty Microbiology

Date 2007 Jul 31

PMID 17658950

Citations 166

Authors

Kamalakannan Velmurugan

Bing Chen

Jessica L Miller

Sharon Azogue

Serdar Gurses

Tsungda Hsu

Michael Glickman

William R Jacobs Jr

Steven A Porcelli

Volker Briken

Affiliations

Soon will be listed here.

Abstract

The survival and persistence of Mycobacterium tuberculosis depends on its capacity to manipulate multiple host defense pathways, including the ability to actively inhibit the death by apoptosis of infected host cells. The genetic basis for this anti-apoptotic activity and its implication for mycobacterial virulence have not been demonstrated or elucidated. Using a novel gain-of-function genetic screen, we demonstrated that inhibition of infection-induced apoptosis of macrophages is controlled by multiple genetic loci in M. tuberculosis. Characterization of one of these loci in detail revealed that the anti-apoptosis activity was attributable to the type I NADH-dehydrogenase of M. tuberculosis, and was mainly due to the subunit of this multicomponent complex encoded by the nuoG gene. Expression of M. tuberculosis nuoG in nonpathogenic mycobacteria endowed them with the ability to inhibit apoptosis of infected human or mouse macrophages, and increased their virulence in a SCID mouse model. Conversely, deletion of nuoG in M. tuberculosis ablated its ability to inhibit macrophage apoptosis and significantly reduced its virulence in mice. These results identify a key component of the genetic basis for an important virulence trait of M. tuberculosis and support a direct causal relationship between virulence of pathogenic mycobacteria and their ability to inhibit macrophage apoptosis.

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