Comparative in silico analyses reveal crucial factors for virulence, antigenicity, and evolution in m.tb

Abstract

The evolution of pathogenic mycobacteria includes not only loss of nonessential genes for survival in the host but also horizontal gene transfer-mediated gene acquisition critical for pathogenicity. Despite this pressure of reductive evolution, some multigene families have instead expanded down the evolution. In silico comparative analyses of these multigene families (mce, mmpL, sigma, TCSS, and PE/PPE) in the context of virulence in M.tb, i.e., phenotypic difference between H37Rv and H37Ra, have intensified the importance of PE/PPE gene family. Although Mycobacterium indicus pranii (MIP), a nonpathogenic soil mycobacterium, is positioned much above Mycobacterium tuberculosis in evolutionary line, it shares 75% of M.tb antigens. Upon comparing MIP with another vaccine candidate, M. vaccae, in terms of sharing antigens with M.tb, further highlighted the importance of PE/PPE proteins. This comparative antigenic analysis has also pointed to the PGRS domain acquisition by the PE proteins and further expansion through gene duplication events. These results have suggested gene co-option as another key player in mycobacterial evolution besides horizontal gene transfer and genomic reduction. In conclusion, this chapter is an attempt to use in silico methodology to uncover the importance of PE and PE_PGRS proteins in virulence, antigenicity, and host immunomodulation in tuberculosis.