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| ISV Paper of the Month |
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March 2011 |
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Rv3615c is a highly immunodominant RD1 (Region
of Difference 1)-dependent secreted antigen specific for Mycobacterium tuberculosis
infection |
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Kerry A. Millington, Sarah M. Fortune, Jeffrey Low, Alejandra
Garces, Suzanne M. Hingley- Wilson, Melissa Wickremasinghe, Onn M. Kon, and Ajit
Lalvania |
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Proceedings of the National Academy of Sciences of the United States of America, 2011 Apr 5; 108(14):5730-5 |
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The 6-kDa early secretory antigenic target of Mycobacterium
tuberculosis (ESAT-6) and the 10- kDa culture filtrate antigen (CFP-10), encoded
in region of difference 1 (RD1) and secreted by the ESAT-6 system 1 (Esx-1) secretion
system, are the most immunodominant and highly M. tuberculosis (MTB)-specific antigens.
These attributes are responsible for their primary importance in tuberculosis (TB)
immunodiagnosis and vaccine development. Rv3615c [Esx-1 substrate protein C (EspC)],
encoded outside RD1, is similar in size and sequence homology to CFP-10 and ESAT-6,
suggesting it might be a target of cellular immunity in TB. Using ex vivo enzyme-linked
immunospot- and flow cytometry-based cytokine-secretion assay, we comprehensively
assessed cellular immune responses to EspC in patients with active TB, latently
infected persons, and uninfected bacillus Calmette-Guerin (BCG)-vaccinated controls.
EspC was at least as immunodominant as ESAT-6 and CFP-10 in both active and latent
TB infection. EspC contained broadly recognized CD4(+) and CD8(+) epitopes, inducing
a predominantly CD4(+) T-cell response that comprised functional T-cell subsets
secreting both IFN-gamma and IL-2 as well as functional T-cell subsets secreting
only IFN-gamma. Surprisingly, T-cell responses to EspC were as highly specific (93%)
for MTB infection as responses to ESAT-6 and CFP-10, with only 2 of 27 BCG-vaccinated
controls responding to each antigen. Using quantitative proteomics and metabolically
labeled mutant and genetically complemented MTB strains, we identified the mechanism
of the specificity of anti-EspC immunity as the Esx-1 dependence of EspC secretion.
The high immunodominance of EspC, equivalent to that of ESAT-6 and CFP-10, makes
it a TB vaccine candidate, and its high specificity confers strong potential for
T-cell-based immunodiagnosis. |
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