title: Insights on the virulence of swine respiratory tract mycoplasmas through genome-scale metabolic modeling.
abstract: The respiratory tract of swine is colonized by several bacteria among which are three Mycoplasma species: Mycoplasma flocculare, Mycoplasma hyopneumoniae and Mycoplasma hyorhinis. While colonization by M. flocculare is virtually asymptomatic, M. hyopneumoniae is the causative agent of enzootic pneumonia and M. hyorhinis is present in cases of pneumonia, polyserositis and arthritis. The genomic resemblance among these three Mycoplasma species combined with their different levels of pathogenicity is an indication that they have unknown mechanisms of virulence and differential expression, as for most mycoplasmas.
  
  
  
  In this work, we performed whole-genome metabolic network reconstructions for these three mycoplasmas. Cultivation tests and metabolomic experiments through nuclear magnetic resonance spectroscopy (NMR) were also performed to acquire experimental data and further refine the models reconstructed in silico.
  
  
  
  Even though the refined models have similar metabolic capabilities, interesting differences include a wider range of carbohydrate uptake in M. hyorhinis, which in turn may also explain why this species is a widely contaminant in cell cultures. In addition, the myo-inositol catabolism is exclusive to M. hyopneumoniae and may be an important trait for virulence. However, the most important difference seems to be related to glycerol conversion to dihydroxyacetone-phosphate, which produces toxic hydrogen peroxide. This activity, missing only in M. flocculare, may be directly involved in cytotoxicity, as already described for two lung pathogenic mycoplasmas, namely Mycoplasma pneumoniae in human and Mycoplasma mycoides subsp. mycoides in ruminants. Metabolomic data suggest that even though these mycoplasmas are extremely similar in terms of genome and metabolism, distinct products and reaction rates may be the result of differential expression throughout the species.
  
  
  
  We were able to infer from the reconstructed networks that the lack of pathogenicity of M. flocculare if compared to the highly pathogenic M. hyopneumoniae may be related to its incapacity to produce cytotoxic hydrogen peroxide. Moreover, the ability of M. hyorhinis to grow in diverse sites and even in different hosts may be a reflection of its enhanced and wider carbohydrate uptake. Altogether, the metabolic differences highlighted in silico and in vitro provide important insights to the different levels of pathogenicity observed in each of the studied species.
authors.affiliation: ERABLE, Inria, 43, Bd du 11 Novembre 1918, Villeurbanne, France.|CBiot, UFRGS, Av Bento Gon'calves, Porto Alegre, 9500, Brazil.|Laboratoire de Biométrie et Biologie Évolutive, Université de Lyon, 43, Bd du 11 Novembre 1918, Villeurbanne, France.
authors.forename: Mariana G
authors.initials: MG
authors.lastname: Ferrarini
authors.affiliation: CBiot, UFRGS, Av Bento Gon'calves, Porto Alegre, 9500, Brazil.
authors.forename: Franciele M
authors.initials: FM
authors.lastname: Siqueira
authors.affiliation: CBiot, UFRGS, Av Bento Gon'calves, Porto Alegre, 9500, Brazil.
authors.forename: Scheila G
authors.initials: SG
authors.lastname: Mucha
authors.affiliation: Université de Lyon, Institut des Sciences Analytiques (CNRS, ENS Lyon, Université Lyon 1), 5, Rue de la Doua, Villeurbanne, France.|Current address: LISBP - INSA Toulouse, Toulouse, France.
authors.forename: Tony L
authors.initials: TL
authors.lastname: Palama
authors.affiliation: Université de Lyon, Institut des Sciences Analytiques (CNRS, ENS Lyon, Université Lyon 1), 5, Rue de la Doua, Villeurbanne, France.
authors.forename: Élodie
authors.initials: É
authors.lastname: Jobard
authors.affiliation: Université de Lyon, Institut des Sciences Analytiques (CNRS, ENS Lyon, Université Lyon 1), 5, Rue de la Doua, Villeurbanne, France.|Université de Lyon, Centre Léon Bérard, Département d'oncologie médicale, 28, rue Laënnec, Lyon, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Elena-Herrmann
authors.affiliation: Laboratório Nacional de Computaćão Científica, Av. Getúlio Vargas, 333, Petrópolis, Brazil.
authors.forename: Ana T
authors.initials: AT
authors.lastname: R Vasconcelos
authors.affiliation: Anses, Laboratoire de Lyon, UMR Mycoplasmoses des Ruminants, 31, Av Tony Garnier, Lyon, France.|Université de Lyon, VetAgro Sup, UMR Mycoplasmoses des Ruminants, 1 Avenue Bourgelat, Marcy L'Étoile, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Tardy
authors.affiliation: CBiot, UFRGS, Av Bento Gon'calves, Porto Alegre, 9500, Brazil.
authors.forename: Irene S
authors.initials: IS
authors.lastname: Schrank
authors.affiliation: CBiot, UFRGS, Av Bento Gon'calves, Porto Alegre, 9500, Brazil.
authors.forename: Arnaldo
authors.initials: A
authors.lastname: Zaha
authors.affiliation: ERABLE, Inria, 43, Bd du 11 Novembre 1918, Villeurbanne, France. marie-france.sagot@inria.fr.|Laboratoire de Biométrie et Biologie Évolutive, Université de Lyon, 43, Bd du 11 Novembre 1918, Villeurbanne, France. marie-france.sagot@inria.fr.
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Sagot
mesh_terms: D000818:Animals; D058491:Bacterial Load; D018533:Biomass; D019295:Computational Biology / Q000379:methods; D004734:Energy Metabolism; D063990:Gene Ontology; D016680:Genome, Bacterial; D023281:Genomics / Q000379:methods; D009682:Magnetic Resonance Spectroscopy; D053858:Metabolic Networks and Pathways; D055432:Metabolomics / Q000379:methods; D050296:Microbial Viability; D008954:Models, Biological; D045705:Mycoplasma hyopneumoniae / Q000472:pathogenicity / Q000502:physiology*; D045729:Pneumonia of Swine, Mycoplasmal / Q000382:microbiology*; D013552:Swine; D014774:Virulence / Q000235:genetics*
keywords: Hydrogen peroxide; Metabolic network; Metabolism; Mollicutes; Mycoplasma; Whole-genome metabolic reconstruction