title: Evolutionary history of tuberculosis shaped by conserved mutations in the PhoPR virulence regulator.
abstract: 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 IS6110 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.
authors: Grupo de Genética de Micobacterias, Facultad de Medicina, Universidad de Zaragoza, 50009 Zaragoza, Spain;Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Instituto de Salud Carlos III, 28029 Madrid, Spain;
authors: Jesús
authors: http://orcid.org/0000-0001-8841-6593
authors: J
authors: Gonzalo-Asensio
authors: Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, 31000 Toulouse, France;Université de Toulouse, Université Paul Sabatier, Institut de Pharmacologie et de Biologie Structurale, 31000 Toulouse, France;
authors: Wladimir
authors: W
authors: Malaga
authors: Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, 75015 Paris, France; and.
authors: Alexandre
authors: A
authors: Pawlik
authors: Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, 31000 Toulouse, France;Université de Toulouse, Université Paul Sabatier, Institut de Pharmacologie et de Biologie Structurale, 31000 Toulouse, France;
authors: Catherine
authors: C
authors: Astarie-Dequeker
authors: Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, 31000 Toulouse, France;Université de Toulouse, Université Paul Sabatier, Institut de Pharmacologie et de Biologie Structurale, 31000 Toulouse, France;
authors: Charlotte
authors: C
authors: Passemar
authors: Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, 31000 Toulouse, France;Université de Toulouse, Université Paul Sabatier, Institut de Pharmacologie et de Biologie Structurale, 31000 Toulouse, France;
authors: Flavie
authors: F
authors: Moreau
authors: Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, 31000 Toulouse, France;Université de Toulouse, Université Paul Sabatier, Institut de Pharmacologie et de Biologie Structurale, 31000 Toulouse, France;
authors: Françoise
authors: F
authors: Laval
authors: Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, 31000 Toulouse, France;Université de Toulouse, Université Paul Sabatier, Institut de Pharmacologie et de Biologie Structurale, 31000 Toulouse, France;
authors: Mamadou
authors: M
authors: Daffé
authors: Grupo de Genética de Micobacterias, Facultad de Medicina, Universidad de Zaragoza, 50009 Zaragoza, Spain;Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Instituto de Salud Carlos III, 28029 Madrid, Spain;Servicio de Microbiología, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Aragón, 50009 Zaragoza, Spain.
authors: Carlos
authors: C
authors: Martin
authors: Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, 75015 Paris, France; and roland.brosch@pasteur.fr Christophe.Guilhot@ipbs.fr.
authors: Roland
authors: R
authors: Brosch
authors: Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, 31000 Toulouse, France;Université de Toulouse, Université Paul Sabatier, Institut de Pharmacologie et de Biologie Structurale, 31000 Toulouse, France; roland.brosch@pasteur.fr Christophe.Guilhot@ipbs.fr.
authors: Christophe
authors: C
authors: Guilhot
mesh_terms: D000483:Alleles; D000818:Animals; D000942:Antigens, Bacterial; D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism; D005075:Biological Evolution; D002417:Cattle; D017124:Conserved Sequence / Q000235:genetics; D017353:Gene Deletion; D054884:Host-Pathogen Interactions; D006801:Humans; D016254:Mutagenesis, Insertional; D009154:Mutation / Q000235:genetics*; D009161:Mycobacterium / Q000235:genetics; D009163:Mycobacterium bovis / Q000235:genetics / Q000472:pathogenicity; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000472:pathogenicity*; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D014376:Tuberculosis / Q000235:genetics / Q000382:microbiology*; D014774:Virulence / Q000235:genetics
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C093276:ESAT-6 protein, Mycobacterium tuberculosis; C061279:PhoR protein, Bacteria; C061064:PhoP protein, Bacteria
keywords: adaptation; evolution; phylogeny; zoonosis