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Single nucleotide polymorphism in Ag85 genes of Mycobacterium tuberculosis complex: analysis of 178 clinical isolates from China and 13 BCG strains.

ABSTRACT: Host immune pressure and associated immune evasion of pathogenic bacteria are key features of host-pathogen co-evolution. Human T-cell epitopes of Mycobacterium tuberculosis (M. tuberculosis) were evolutionarily hyperconserved and thus it was deduced that M. tuberculosis lacks antigenic variation and immune evasion. However, in our previous studies, proteins MPT64, PstS1, Rv0309 and Rv2945c all harbored higher numbers of amino acid substitutions in their T cell epitopes, which suggests their roles in ongoing immune evasion. Here, we used the same set of 180 clinical M. tuberculosis complex (MTBC) isolates from China, amplified the genes encoding Ag85 complex, and compared the sequences. The results showed that Ag85 were hyperconserved in T/B cell epitopes and the genes were more likely to be under purifying selection. The divergence of host immune selection on different proteins may result from different function of the proteins. In addition, A312G of Ag85A and T418C of Ag85B may represent special mutations in BCG strains, which may be used to differentiate M.bovis and BCG strains from MTB strains. Also, C714A in Ag85B seems to be a valuable phylogenetic marker for Beijing strains.

SUBMITTER: Jiang Y

PROVIDER: S-EPMC4293177 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Single nucleotide polymorphism in Ag85 genes of Mycobacterium tuberculosis complex: analysis of 178 clinical isolates from China and 13 BCG strains.

Jiang Yi Y Liu Haican H Li Machao M Li Guilian G Pang Hui H Dou Xiangfeng X Zhao Xiuqin X Wan Kanglin K

International journal of medical sciences 20150105 2

Host immune pressure and associated immune evasion of pathogenic bacteria are key features of host-pathogen co-evolution. Human T-cell epitopes of Mycobacterium tuberculosis (M. tuberculosis) were evolutionarily hyperconserved and thus it was deduced that M. tuberculosis lacks antigenic variation and immune evasion. However, in our previous studies, proteins MPT64, PstS1, Rv0309 and Rv2945c all harbored higher numbers of amino acid substitutions in their T cell epitopes, which suggests their rol ...[more]

PMID: 25589888

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Project description:BackgroundThe presence of four mammalian cell entry (mce) operons in Mycobacterium tuberculosis suggests the essentiality of the functions of the genes in these operons. The differential expression of the four mce operons in different phases of in vitro growth and in infected animals reported earlier from our laboratory further justifies the apparent redundancy for these genes in the genome.Here we investigate the extent of polymorphism in eight genes in the mce1 and mce4 operons of M. tuberculosis from four standard reference strains (H37Rv, H37Ra, LVS (Low Virulent Strain) and BCG) and 112 clinical isolates varying in their drug susceptibility profile, analysed by direct sequencing and Sequenom MassARRAY platform.ResultsWe discovered 20 single nucleotide polymorphisms (SNPs) in the two operons. The comparative analysis of the genes of mce1 and mce4 operons revealed that yrbE1A [Rv0167] was most polymorphic in mce1 operon while yrbE4A [Rv3501c] and lprN [Rv3495c] had the highest number of SNPs in the mce4 operon. Of 20 SNPs, 12 were found to be nonsynonymous and were further analysed for their pathological relevance to M. tuberculosis using web servers PolyPhen and PMut, which predicted five deleterious nonsynonymous SNPs. A mutation from proline to serine at position 359 of the native Mce1A protein was most deleterious as predicted by both PolyPhen and PMut servers. Energy minimization of the structure of native Mce1A protein and mutated protein was performed using InsightII. The mutated Mce1A protein showed structural changes that could account for the effects of this mutation.ConclusionsOur results show that SNPs in the coding sequences of mce1 and mce4 operons in clinical isolates can be significantly high. Moreover, mce4 operon is significantly more polymorphic than mce1 operon (p < 0.001). However, the frequency of nonsynonymous substitutions is higher in mce1 operon and synonymous substitutions are more in mce4 operon. In silico modeling predict that nonsynonymous SNP at mce1A [Rv0169], a virulence gene could play a pivotal role in causing functional changes in M. tuberculosis that may reflect upon the biology of the bacteria.

Project description:Background:Mycobacterium tuberculosis Complex (MTBC) is a group of Mycobacterium that causes tuberculosis (TB). TB is an infectious disease that remains a global health problem. Indonesia is one of the five countries in the world where TB is the most prevalent and became the country with tle second largest rate of TB in 2014 and 2015. MTBC has high pathogenicity that can cause infections in animals and humans. The most common route of transmission is via airborne droplet nuclei and contact with animals or humans infected with TB. MTBC has many virulence factors. One of these factors is EccB5 that is encoded by eccB5 gene. EccB5 is a transmembrane protein-conserved membrane protein and could play a role in inducing damage in host cells, macrophage infection, and may correlate with active disease. The characterization of eccB5 gene needs to be studied to determine the nucleotide sequences, which may be associated with active disease. The aim of this research was to analyze the nuclotide sequences of eccB5 gene of MTBC from suspected pulmonary tuberculosis patients, SNPs of eccB5 gene and possible correlation with the disease, especially in Indonesia. Materials and Methods:Samples were collected from the Tuberculosis Laboratory, Clinical Microbiology of Dr. Soetomo Hospital Surabaya Indonesia. DNA extraction used boiling extraction method and continued nucleic acid amplification using PCR techniques. Primer pairs used eccB5 SK.. The positivity of DNA specific revealed amplicon in 1592 bp. PCR product was sequenced by 1st Base (First BASE Laboratories Sdn Bhd, Selangor, Malaysia). The sequence analysis used Genetyx-Win version 10.0 (Genetyx Corporation, Tokyo, Japan). Results:Total isolates of Mycobacterium spp. were 28 and those that showed positive MTBC were 24 isolates and 4 nontuberculosis mycobacteria (NTM) using immunochromatographic test (ICT). The amount of homology from MTBC using blast NCBI was 99%-100%. Two SNPs were found in position c.1277 which revealed replacement of amino acid in 426 of codon position. Conclusion:The sequence of eccB5 gene of MTBC showed high significant homology, while proposed non-synoymous single nucleotide polymorphisms (nsSNP) may associated with clinical outcomes.

Dataset Information

Single nucleotide polymorphism in Ag85 genes of Mycobacterium tuberculosis complex: analysis of 178 clinical isolates from China and 13 BCG strains.

Publications

Single nucleotide polymorphism in Ag85 genes of Mycobacterium tuberculosis complex: analysis of 178 clinical isolates from China and 13 BCG strains.

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