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Rv3615c is a highly immunodominant RD1 (Region of Difference 1)-dependent secreted antigen specific for Mycobacterium tuberculosis infection.

Millington, KA, Fortune, SM, Low, J, Garces, A, Hingley-Wilson, SM, Wickremasinghe, M, Kon, OM and Lalvani, A (2011) Rv3615c is a highly immunodominant RD1 (Region of Difference 1)-dependent secreted antigen specific for Mycobacterium tuberculosis infection. Proc Natl Acad Sci U S A, 108 (14). pp. 5730-5735.

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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-Guérin (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-γ and IL-2 as well as functional T-cell subsets secreting only IFN-γ. 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.

Item Type: Article
Divisions : Surrey research (other units)
Authors :
Millington, KA
Fortune, SM
Low, J
Garces, A
Wickremasinghe, M
Kon, OM
Lalvani, A
Date : 5 April 2011
DOI : 10.1073/pnas.1015153108
Uncontrolled Keywords : Antigens, Bacterial, BCG Vaccine, Bacterial Proteins, Enzyme-Linked Immunospot Assay, Flow Cytometry, Humans, Immunodominant Epitopes, Mycobacterium tuberculosis, Proteomics, T-Lymphocyte Subsets, Tuberculosis
Related URLs :
Depositing User : Symplectic Elements
Date Deposited : 17 May 2017 09:42
Last Modified : 24 Jan 2020 17:29

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