Immunological Characterization of Proteins Expressed by Genes Located in Mycobacterium tuberculosis-Specific Genomic Regions Encoding the ESAT6-like Proteins.

Abu Salim Mustafa

doi:10.3390/vaccines9010027

Abstract

The 6 kDa early secreted antigen target (ESAT6) is a low molecular weight and highly immunogenic protein of Mycobacterium tuberculosis with relevance in the diagnosis of tuberculosis and subunit vaccine development. The gene encoding the ESAT6 protein is located in the M. tuberculosis-specific genomic region known as the region of difference (RD)1. There are 11 M. tuberculosis-specific RDs absent in all of the vaccine strains of BCG, and three of them (RD1, RD7, and RD9) encode immunodominant proteins. Each of these RDs has genes for a pair of ESAT6-like proteins. The immunological characterizations of all the possible proteins encoded by genes in RD1, RD7 and RD9 have shown that, besides ESAT-6 like proteins, several other proteins are major antigens useful for the development of subunit vaccines to substitute or supplement BCG. Furthermore, some of these proteins may replace the purified protein derivative of M. tuberculosis in the specific diagnosis of tuberculosis by using interferon-gamma release assays and/or tuberculin-type skin tests. At least three subunit vaccine candidates containing ESAT6-like proteins as antigen components of multimeric proteins have shown efficacy in phase 1 and phase II clinical trials in humans.

Highlights

Using the Bacillus Calmette Guerin (BCG) vaccine against tuberculosis (TB) has shown variable protective efficacy in different parts of the world [1,2,3,4,5]
The results further showed that ESAT6 contained multiple T cell epitopes [62,63,64], which were recognized by T cells in association with several human leukocyte antigen (HLA) class II molecules that are frequently expressed in humans living in different countries and geographical locations [65,66]
The RD1 region contains the genes for EsxA (ESAT6) and EsxB (CFP10) along with 11 other M. tuberculosis-specific genes predicted by Robertson and Thole corresponding to the open reading frames (ORFs) known as ORF2 to ORF14 [120], seven genes predicted by Mahairas et al and designated as ORF1A to ORF1K [76], and nine genes predicted by Cole et al and designated as Rv3871 to Rv3879 in M. tuberculosis H37Rv genome [107] (Table 2)

Summary

Introduction

Using the Bacillus Calmette Guerin (BCG) vaccine against tuberculosis (TB) has shown variable protective efficacy in different parts of the world [1,2,3,4,5]. Immunological studies with ESAT6, biochemically purified from the short-term culture filtrates of M. tuberculosis, showed that it was a major antigen of M. tuberculosis recognized by T cells from mice infected with M. tuberculosis [49] These results were further confirmed by using the recombinant antigen and synthetic peptides of ESAT6 [50,51,52,53,54,55,56]. The results further showed that ESAT6 contained multiple T cell epitopes [62,63,64], which were recognized by T cells in association with several human leukocyte antigen (HLA) class II molecules that are frequently expressed in humans living in different countries and geographical locations [65,66] These results suggested that ESAT6 could be a universally useful antigen in a subunit vaccine development and/or in diagnostic applications, and its use will not be limited due to variations in the expression of HLA molecules in different population groups [65]. All the individual proteins encoded by the genes present in RD1, RD7, and RD9 have been identified and analyzed for their putative roles, including their immunological applications in the diagnosis of TB and vaccine developments

RD1 Genes and Encoded Proteins

RD7 Genes and Encoded Proteins

Findings

Summary