Diagnostic and Vaccine Potentials of ESAT-6 Family Proteins encoded by M. tuberculosis genomic regions absent in M. bovis BCG

Abstract

Tuberculosis is a major international health problem and its control requires cost-effective diagnostic reagents and protective vaccines. Among the candidates advocated for both applications is the immunodominant 6 kDa early secreted antigenic target (ESAT-6) of M. tuberculosis. The esat6 gene is located in the M. tuberculosis-specific genomic region of difference 1 (RD1), which is absent in all vaccine strains of M. bovis BCG. In addition to ESAT6, RD1 contains the gene for another immunodominant low molecular weight culture filtrate protein 10 (CFP-10). Both ESAT-6 (ESXA) and CFP10 (ESXB) belong to the ESAT-6 family. The sequences of ESXA and ESXB lack significant homology with each other and any other member of ESAT-6 family. Furthermore, four additional immune dominant proteins belonging to ESAT-6 family have been identified, whose genes are present in M. tuberculosis-specific genomic regions absent in M. bovis BCG, i.e. Rv2346c/ESXO and Rv2347c/ESXP in RD7, and Rv3619c/ESXV and Rv3620c/ESXW in RD9. ESXO and ESXV belong to ESAT-6 subfamily-1 and ESXP and ESXW to ESAT-6 subfamily 2. Each subfamily contains five members and has orthologs in M. bovis BCG. Although, members of subfamily 1 lack sequence identity with members of subfamily 2, each of the five members within a given family share >92% sequence identity. Immunization with RD proteins of ESAT-6 family protects animals against challenge with M. tuberculosis, but due to the immunodominant recognition by the majority of TB-infected and exposed individuals, and the absence in M. bovis BCG, ESXA and ESXB should be reserved for diagnostic applications, and the ESAT-6 subfamily 1 and 2 proteins deserve to be considered as subunit vaccine candidates.