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Evolutionary history of tuberculosis shaped by conserved mutations in the PhoPR virulence regulator
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Evolutionary history of tuberculosis shaped by conserved mutations in the PhoPR virulence regulator
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Evolutionary history of tuberculosis shaped by conserved mutations in the PhoPR virulence regulator
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Journal Article
Evolutionary history of tuberculosis shaped by conserved mutations in the PhoPR virulence regulator
2014
Overview
Although the bovine tuberculosis (TB) agent, Mycobacterium bovis , may infect humans and cause disease, long-term epidemiological data indicate that humans represent a spill-over host in which infection with M. bovis is not self-maintaining. Indeed, human-to-human transmission of M. bovis strains and other members of the animal lineage of the tubercle bacilli is very rare. Here, we report on three mutations affecting the two-component virulence regulation system PhoP/PhoR (PhoPR) in M. bovis and in the closely linked Mycobacterium africanum lineage 6 (L6) that likely account for this discrepancy. Genetic transfer of these mutations into the human TB agent, Mycobacterium tuberculosis , resulted in down-regulation of the PhoP regulon, with loss of biologically active lipids, reduced secretion of the 6-kDa early antigenic target (ESAT-6), and lower virulence. Remarkably, the deleterious effects of the phoPR mutations were partly compensated by a deletion, specific to the animal-adapted and M. africanum L6 lineages, that restores ESAT-6 secretion by a PhoPR-independent mechanism. Similarly, we also observed that insertion of an IS 6110 element upstream of the phoPR locus may completely revert the phoPR-bovis –associated fitness loss, which is the case for an exceptional M. bovis human outbreak strain from Spain. Our findings ultimately explain the long-term epidemiological data, suggesting that M. bovis and related phoPR -mutated strains pose a lower risk for progression to overt human TB, with major impact on the evolutionary history of TB.
Publisher
National Academy of Sciences,National Acad Sciences
Subject
/ Animals
/ Bacterial Proteins - genetics
/ Bacterial Proteins - secretion
/ Bacterial Proteins / metabolism
/ Cattle
/ Conserved Sequence - genetics
/ Genetics
/ Humans
/ Lipids
/ loci
/ Microbiology and Parasitology
/ Mutation
/ Mycobacterium bovis - genetics
/ Mycobacterium bovis - pathogenicity
/ Mycobacterium tuberculosis - genetics
/ Mycobacterium tuberculosis - pathogenicity
/ Polymorphism, Single Nucleotide - genetics
/ regulon
/ risk
/ Spain
