Abstract
The genome sequencing of Mycobacterium tuberculosis, the causative organism of tuberculosis, has significantly improved our understanding of the mechanisms that drive the establishment of infection and disease progression. Several clinical strains of M. tuberculosis exhibit single-nucleotide polymorphisms (SNPs), the implications of which are only beginning to be understood. Here, we examined the impact of a specific polymorphism in PhoR, the sensor kinase of the PhoPR two-component system. Biochemical analysis revealed reduced autophosphatase/ATPase activity, which led to enhanced downstream gene expression. We complemented M. tuberculosis H37Ra with the wild-type and mutant phoPR genes and characterized the strains in a cell line infection model. We provide an explanation for the low prevalence of the SNP in clinical strains (∼1%), as the mutation causes a survival disadvantage in the host cells. The study provides a rare example of selection of a signaling node under competing evolutionary forces, wherein a biochemically superior mutation aids bacterial adaptation within-host but has low fitness for infection and hence is not selected. Our study highlights the importance of accounting for such SNPs to test therapeutic and co-therapeutic methods to combat TB.
Highlights
Sequencing of Mycobacterium tuberculosis H37Rv genome, a virulent laboratory strain, has revolutionized the research done on this pathogen world over (Cole et al, 1998)
We analyzed the sequences of several clinical strains and sought single-nucleotide polymorphisms (SNPs) primarily in TCS genes to understand the evolutionary pressures subjected to TCSs
We analyzed the sequence of phoR in 242 mycobacterial strains from BioProject PRJNA235851 in National Center for Biotechnology Information (NCBI) (Ramaiah et al, 2019) with a combination of drug-sensitive/resistant, polydrug- and multidrug-resistant cohort of a South Indian population (Ramaiah et al, 2019) with H37Rv as the reference sequence to identify various SNPs, and we found one that translated into a non-synonymous, missense mutation in the protein
Summary
Sequencing of Mycobacterium tuberculosis H37Rv genome, a virulent laboratory strain, has revolutionized the research done on this pathogen world over (Cole et al, 1998). It revealed the presence of sizeable unknown gene sets, like serine–threonine protein kinases (STPKs) and other relatively small groups of typical bacterial signaling systems, the two-component systems. To adapt and survive in changing environmental conditions, it uses signaling systems called TCSs, which regulate the expression of many genes in response to various environmental stimuli (Pang et al, 2007). We analyzed the sequences of several clinical strains and sought single-nucleotide polymorphisms (SNPs) primarily in TCS genes to understand the evolutionary pressures subjected to TCSs
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