Mycobacterium tuberculosisComplex Exhibits Lineage-Specific Variations Affecting Protein Ductility and Epitope Recognition

Abstract

The advent of whole-genome sequencing has provided an unprecedented detail about the evolution and genetic significance of species-specific variations across the whole Mycobacterium tuberculosis Complex. However, little attention has been focused on understanding the functional roles of these variations in the protein coding sequences. In this work, we compare the coding sequences from 74 sequenced mycobacterial species including M. africanum, M. bovis, M. canettii, M. caprae, M. orygis, and M. tuberculosis. Results show that albeit protein variations affect all functional classes, those proteins involved in lipid and intermediary metabolism and respiration have accumulated mutations during evolution. To understand the impact of these mutations on protein functionality, we explored their implications on protein ductility/disorder, a yet unexplored feature of mycobacterial proteomes. In agreement with previous studies, we found that a Gly71Ile substitution in the PhoPR virulence system severely affects the ductility of its nearby region in M. africanum and animal-adapted species. In the same line of evidence, the SmtB transcriptional regulator shows amino acid variations specific to the Beijing lineage, which affects the flexibility of the N-terminal trans-activation domain. Furthermore, despite the fact that MTBC epitopes are evolutionary hyperconserved, we identify strain- and lineage-specific amino acid mutations affecting previously known T-cell epitopes such as EsxH and FbpA (Ag85A). Interestingly, in silico studies reveal that these variations result in differential interaction of epitopes with the main HLA haplogroups.

Accurate Phylogenetic Relationships Among Mycobacterium bovis Strains Circulating in France Based on Whole Genome Sequencing and Single Nucleotide Polymorphism Analysis

“…The non-synonymous SNP detected in virulence genes are most likely to impact on protein function and contribute to phenotypic variation. Further investigations on secreted proteins, epitope recognition, or pattern of outer membrane lipids (Yruela et al, 2016; Jankute et al, 2017; Ates et al, 2018) are needed to address the consequence of these mutations in order to define phenotypic differences across the main M. bovis groups still responsible for the persistence of outbreaks in cattle and wild life.…”

Tuberculosis outbreak investigation using phylodynamic analysis

“…Our estimates of the epidemiological parameters, particularly R e , are in line with previous estimates obtained from different M. tuberculosis data sets ( Tanaka et al, 2006 ; Sanchez and Blower, 1997 ). However, due to the chronic nature of tuberculosis and the many factors influencing the transmission potential of individual patients ( Brites and Gagneux, 2015 ; Coscolla et al, 2015b ; Yruela et al, 2016 ), more work is needed to understand the complex dynamics influencing these parameters in different epidemiological settings.…”

The Troika Host–Pathogen–Extrinsic Factors in Tuberculosis: Modulating Inflammation and Clinical Outcomes

“…Ensuring conservation of T cell responses could thus be a mechanism explored by M. tuberculosis to ensure transmission. Nonetheless, outlier epitopes to the general rule of hyperconservation have been described both in previously known and newly identified antigenic regions ( 89 , 91 ). Moreover, amino acid substitutions in these variable epitopes were shown to impact the host response with some patients responding only to the wild-type epitope variant and others only to the mutated forms ( 89 ).…”