Mycobacterium tuberculosis nuoG is a virulence gene that inhibits apoptosis of infected host cells.
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.
Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, United States of America.
Kamalakannan
K
Velmurugan
Bing
B
Chen
Jessica L
JL
Miller
Sharon
S
Azogue
Serdar
S
Gurses
Tsungda
T
Hsu
Michael
M
Glickman
William R
WR
Jacobs
Steven A
SA
Porcelli
Volker
V
Briken
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001483:Base Sequence; D002460:Cell Line; D005260:Female; D015964:Gene Expression Regulation, Bacterial; D020868:Gene Silencing; D005798:Genes, Bacterial; D054884:Host-Pathogen Interactions; D006801:Humans; D008264:Macrophages / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009000:Monocytes / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D009169:Mycobacterium tuberculosis / Q000201:enzymology / Q000235:genetics* / Q000472:pathogenicity; D009245:NADH Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D009252:NADPH Dehydrogenase / Q000378:metabolism; D014774:Virulence
D009252:NADPH Dehydrogenase; D009245:NADH Dehydrogenase