Journal
PLOS ONE
Volume 9, Issue 4, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0094418
Keywords
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Categories
Funding
- National Natural Science Foundation [81371851, 81071316, 81271882]
- National Megaprojects for Key Infectious Diseases [2008ZX10003-006, 2012ZX10003-003]
- New Century Excellent Talents in Universities [NCET-11-0703]
- Southwest University [kb2010017, ky2011003]
- Fundamental Research Funds for the Central Universities [XDJK2011D006, XDJK2012D011, XDJK2012D007, XDJK2013D003]
- Natural Science Foundation Project of CQ CSTC [CSTC 2010BB5002]
- Chongqing Municipal Committee of Education for postgraduates excellence program [YJG123104]
- undergraduates teaching reform program [2011JY052]
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Intracellular survival plays a central role in the pathogenesis of Mycobacterium tuberculosis, a process which depends on an array of virulence factors to colonize and replicate within the host. The M. tuberculosis iron regulated open reading frame (ORF) rv3402c, encoding a conserved hypothetical protein, was shown to be up-regulated upon infection in both human and mice macrophages. To explore the function of this ORF, we heterologously expressed the rv3402c gene in the nonpathogenic fast-growing Mycobacterium smegmatis strain, and demonstrated that Rv3402c, a cell envelope-associated protein, was able to enhance the intracellular survival of recombinant M. smegmatis. Enhanced growth was not found to be the result of an increased resistance to intracellular stresses, as growth of the Rv3402c expressing strain was unaffected by iron depletion, H2O2 exposure, or acidic conditions. Colonization of macrophages by M. smegmatis expressing Rv3402c was associated with substantial cell death and significantly greater amount of TNF-alpha and IL-1 beta compared with controls. Rv3402c-induced TNF-alpha and IL-1 beta production was found to be mediated by NF-kappa B, ERK and p38 pathway in macrophages. In summary, our study suggests that Rv3402c delivered in a live M. smegmatis vehicle can modify the cytokines profile of macrophage, promote host cell death and enhance the persistence of mycobacterium within host cells.
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