Acute infection and macrophage subversion by Mycobacterium tuberculosis require a specialized secretion system.
Although many bacterial pathogens use specialized secretion systems for virulence, no such systems have been described for Mycobacterium tuberculosis, a major pathogen of humans that proliferates in host macrophages. In a screen to identify genes required for virulence of M. tuberculosis, we have discovered three components and two substrates of the first Sec-independent secretion pathway described in M. tuberculosis, which we designate the Snm pathway. Here we demonstrate that the proteins Snm1, -2, and -4 are required for the secretion of ESAT-6 and CFP-10, small proteins previously identified as major T cell antigens. Snm2, a member of the AAA ATPase family, interacts with substrates and with Snm1, another AAA ATPase. We show that M. tuberculosis mutants lacking either the Snm system or these substrates exhibit defects in bacterial growth during the acute phase of a mouse infection and are attenuated for virulence. Strikingly, snm mutants fail to replicate in cultured macrophages and to inhibit macrophage inflammatory responses, two well established activities of wild-type M. tuberculosis bacilli. Thus, the Snm secretion pathway works to subvert normal macrophage responses and is a major determinant of M. tuberculosis virulence.
Stanley
Sarah A
SA
Department of Microbiology and Immunology, G. W. Hooper Foundation, University of California, 513 Parnassus Avenue, San Francisco, CA 94143, USA.
Raghavan
Sridharan
S
Hwang
William W
WW
Cox
Jeffery S
JS
D000818:Animals; D002478:Cells, Cultured; D017124:Conserved Sequence; D004195:Disease Models, Animal; D008264:Macrophages / Q000382:microbiology*; D051379:Mice; D008954:Models, Biological; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000254:growth & development / Q000472:pathogenicity*; D010957:Plasmids; D021381:Protein Transport; D014376:Tuberculosis / Q000473:pathology*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D014774:Virulence / Q000235:genetics*
D014764:Viral Proteins