title: pks5-recombination-mediated surface remodelling in Mycobacterium tuberculosis emergence.
abstract: Mycobacterium tuberculosis is a major, globally spread, aerosol-transmitted human pathogen, thought to have evolved by clonal expansion from a Mycobacterium canettii-like progenitor. In contrast, extant M. canettii strains are rare, genetically diverse, and geographically restricted mycobacteria of only marginal epidemiological importance. Here, we show that the contrasting evolutionary success of these two groups is linked to loss of lipooligosaccharide biosynthesis and subsequent morphotype changes. Spontaneous smooth-to-rough M. canettii variants were found to be mutated in the polyketide-synthase-encoding pks5 locus and deficient in lipooligosaccharide synthesis, a phenotype restored by complementation. Importantly, these rough variants showed an altered host-pathogen interaction and increased virulence in cellular- and animal-infection models. In one variant, lipooligosaccharide deficiency occurred via homologous recombination between two pks5 genes and removal of the intervening acyltransferase-encoding gene. The resulting single pks5 configuration is similar to that fixed in M. tuberculosis, which is known to lack lipooligosaccharides. Our results suggest that pks5-recombination-mediated bacterial surface remodelling increased virulence, driving evolution from putative generalist mycobacteria towards professional pathogens of mammalian hosts.
authors: Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris 75015, France.
authors: Eva C
authors: EC
authors: Boritsch
authors: Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris 75015, France.
authors: Wafa
authors: W
authors: Frigui
authors: Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris 75015, France.
authors: Alessandro
authors: A
authors: Cascioferro
authors: CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), Toulouse 31000, France.|Université de Toulouse, UPS, IPBS, Toulouse 31000, France.
authors: Wladimir
authors: W
authors: Malaga
authors: CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), Toulouse 31000, France.|Université de Toulouse, UPS, IPBS, Toulouse 31000, France.
authors: Gilles
authors: G
authors: Etienne
authors: CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), Toulouse 31000, France.|Université de Toulouse, UPS, IPBS, Toulouse 31000, France.
authors: Françoise
authors: F
authors: Laval
authors: Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris 75015, France.
authors: Alexandre
authors: A
authors: Pawlik
authors: Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris 75015, France.|University Paris Diderot, Sorbonne Paris Cité, Cellule Pasteur, Paris, France.
authors: Fabien
authors: F
authors: Le Chevalier
authors: Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris 75015, France.
authors: Mickael
authors: M
authors: Orgeur
authors: Institut Pasteur, PF1-Plate-Forme Génomique, Paris, France.
authors: Laurence
authors: L
authors: Ma
authors: Institut Pasteur, PF1-Plate-Forme Génomique, Paris, France.
authors: Christiane
authors: C
authors: Bouchier
authors: Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia.
authors: Timothy P
authors: http://orcid.org/0000-0003-0150-123X
authors: TP
authors: Stinear
authors: Inserm U1019, CNRS UMR8204, Université de Lille, Institut Pasteur de Lille, Center for Infection and Immunity, Lille 59000, France.
authors: Philip
authors: P
authors: Supply
authors: Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris 75015, France.
authors: Laleh
authors: L
authors: Majlessi
authors: CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), Toulouse 31000, France.|Université de Toulouse, UPS, IPBS, Toulouse 31000, France.
authors: Mamadou
authors: M
authors: Daffé
authors: CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), Toulouse 31000, France.|Université de Toulouse, UPS, IPBS, Toulouse 31000, France.
authors: Christophe
authors: C
authors: Guilhot
authors: Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris 75015, France.
authors: Roland
authors: http://orcid.org/0000-0003-2587-3863
authors: R
authors: Brosch
mesh_terms: D000818:Animals; D053898:Biosynthetic Pathways; D004195:Disease Models, Animal; D019143:Evolution, Molecular; D017353:Gene Deletion; D005816:Genetic Complementation Test; D059765:Homologous Recombination; D054884:Host-Pathogen Interactions; D006801:Humans; D008070:Lipopolysaccharides / Q000096:biosynthesis*; D051379:Mice; D009161:Mycobacterium / Q000235:genetics* / Q000472:pathogenicity*; D009164:Mycobacterium Infections / Q000382:microbiology / Q000473:pathology; D048630:Polyketide Synthases / Q000235:genetics* / Q000378:metabolism*; D014774:Virulence
chemical_list: D008070:Lipopolysaccharides; C023023:lipid-linked oligosaccharides; D048630:Polyketide Synthases