Acute infection and macrophage subversion by Mycobacterium tuberculosis require a specialized secretion system
Open accessAbstract
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.
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The two FtsK/SpoIIIE-like proteins of the ESX-1 system form a functional unit.
“Since these gene products clearly form a functional unit, as has also been shown for the two FtsK/SpoIIIE-like proteins of the ESX-1 system [14], the split genes will get a lower case alphabetic suffix, i.e., eccCa1 and eccCb1 for the ESX-1 system of M. tuberculosis (Figure 1 and Table 2).”
From Systematic Genetic Nomenclature for Type VII Secretion Systems (2009) · cites this paper as [14]
M. tuberculosis and M. marinum mutants with deletion of ESX-1 are attenuated in their respective hosts.
“M. tuberculosis and M. marinum mutants with deletion of ESX-1 are attenuated in their respective hosts (61)(62)(63)(64), which is in line with the attenuation of”
From ESX/Type VII Secretion Systems—An Important Way Out for Mycobacterial Proteins (2019) · cites this paper as [63]
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- Authors
- Stanley, S. A., Raghavan, S., Hwang, W. W., & Cox, J. S.
- Affiliations
- University of California, San Francisco (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2003-10-13
- Volume
- 100
- Issue
- 22
- Pages
- 13001-13006
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC240734
- OpenAlex
- W2141681443
- Cited by
- 570
- References
- 32
- Citations by year
- 2026: 17 · 2025: 24 · 2024: 20 · 2023: 19 · 2022: 19 · 2021: 23 · 2020: 24 · 2019: 35 · 2018: 21 · 2017: 26 · 2016: 47 · 2015: 24 · 2014: 32 · 2013: 24 · 2012: 29
- FWCI
- 11.84
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Université de Genève
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (AI 68540)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Health Sciences › Medicine › Epidemiology › Mycobacterium research and diagnosis
- Keywords
- Mycobacterium tuberculosis, ESAT-6, CFP-10, AAA+ ATPase, virulence factors, macrophage evasion, T cell antigens, mouse infection model
- MeSH terms
- Animals, Cells, Cultured, Disease Models, Animal, Macrophages, Models, Biological, Mycobacterium tuberculosis, Plasmids, Tuberculosis, Viral Proteins, Virulence, Conserved Sequence, Protein Transport, Mice
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