title: Single nucleotide polymorphisms may explain the contrasting phenotypes of two variants of a multidrug-resistant Mycobacterium tuberculosis strain.
abstract: Globally, about 4.5% of new tuberculosis (TB) cases are multi-drug-resistant (MDR), i.e. resistant to the two most powerful first-line anti-TB drugs. Indeed, 480,000 people developed MDR-TB in 2015 and 190,000 people died because of MDR-TB. The MDR Mycobacterium tuberculosis M family, which belongs to the Haarlem lineage, is highly prosperous in Argentina and capable of building up further drug resistance without impairing its ability to spread. In this study, we sequenced the whole genomes of a highly prosperous M-family strain (Mp) and its contemporary variant, strain 410, which produced only one recorded tuberculosis case in the last two decades. Previous reports have demonstrated that Mp induced dysfunctional CD8+cytotoxic T cell activity, suggesting that this strain has the ability to evade the immune response against M. tuberculosis. Comparative analysis of Mp and 410 genomes revealed non-synonymous polymorphisms in eleven genes and five intergenic regions with polymorphisms between both strains. Some of these genes and promoter regions are involved in the metabolism of cell wall components, others in drug resistance and a SNP in Rv1861, a gene encoding a putative transglycosylase that produces a truncated protein in Mp. The mutation in Rv3787c, a putative S-adenosyl-l-methionine-dependent methyltransferase, is conserved in all of the other prosperous M strains here analysed and absent in non-prosperous M strains. Remarkably, three polymorphic promoter regions displayed differential transcriptional activity between Mp and 410. We speculate that the observed mutations/polymorphisms are associated with the reported higher capacity of Mp for modulating the host's immune response.
authors.affiliation: Universidad de Buenos Aires, Facultad de Agronomía, Cátedra de Microbiología Agrícola.INBA-CONICET, Av. San Martín 4453, C1417DSE, Buenos Aires, Argentina. Electronic address: mebigi@hotmail.com.
authors.forename: María Mercedes
authors.initials: MM
authors.lastname: Bigi
authors.affiliation: Instituto Nacional de Enfermedades Infecciosas-ANLIS Carlos Malbrán, Av. Vélez Sarsfield 563, C1282AFF, Buenos Aires, Argentina. Electronic address: bealopez@anlis.gov.ar.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Lopez
authors.affiliation: Instituto de Biotecnología, Instituto Nacional de Tecnología Agropecuaria (INTA), N. Repetto and De los Reseros, Hurlingham, 1686, Buenos Aires, Argentina. Electronic address: blanco.federico@inta.gob.ar.
authors.forename: Federico Carlos
authors.initials: FC
authors.lastname: Blanco
authors.affiliation: IMEX-CONICET, Academia Nacional de Medicina, José Andrés Pacheco de Melo 3081, C1425AUM, Buenos Aires, Argentina. Electronic address: mariadelcarmen.sasiain@hotmail.com.
authors.forename: María Del Carmen
authors.initials: MD
authors.lastname: Sasiain
authors.affiliation: IMEX-CONICET, Academia Nacional de Medicina, José Andrés Pacheco de Melo 3081, C1425AUM, Buenos Aires, Argentina. Electronic address: sildelabar@gmail.com.
authors.forename: Silvia
authors.initials: S
authors.lastname: De la Barrera
authors.affiliation: Departamento de Química Biológica, e IQUIBICEN-CONICET, FCEyN, UBA, Intendente Güiraldes 2160, C1428EGA, Buenos Aires, Argentina. Electronic address: marti.marcelo@gmail.com.
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Marti
authors.affiliation: Plataforma de Bioinformática Argentina, Instituto de Cálculo, FCEyN, UBA, Intendente Güiraldes 2160, C1428EGA, Buenos Aires, Argentina. Electronic address: ezequieljsosa@gmail.com.
authors.forename: Ezequiel Jorge
authors.initials: EJ
authors.lastname: Sosa
authors.affiliation: Plataforma de Bioinformática Argentina, Instituto de Cálculo, FCEyN, UBA, Intendente Güiraldes 2160, C1428EGA, Buenos Aires, Argentina. Electronic address: dariofd@gmail.com.
authors.forename: Darío Augusto
authors.initials: DA
authors.lastname: Fernández Do Porto
authors.affiliation: Instituto Nacional de Enfermedades Infecciosas-ANLIS Carlos Malbrán, Av. Vélez Sarsfield 563, C1282AFF, Buenos Aires, Argentina. Electronic address: vivianaritacco@gmail.com.
authors.forename: Viviana
authors.initials: V
authors.lastname: Ritacco
authors.affiliation: Instituto de Biotecnología, Instituto Nacional de Tecnología Agropecuaria (INTA), N. Repetto and De los Reseros, Hurlingham, 1686, Buenos Aires, Argentina. Electronic address: bigi.fabiana@inta.gob.ar.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Bigi
authors.affiliation: Universidad de Buenos Aires, Facultad de Agronomía, Cátedra de Microbiología Agrícola.INBA-CONICET, Av. San Martín 4453, C1417DSE, Buenos Aires, Argentina. Electronic address: soria@agro.uba.ar.
authors.forename: Marcelo Abel
authors.initials: MA
authors.lastname: Soria
mesh_terms: D000995:Antitubercular Agents / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000235:genetics*; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics*; D015964:Gene Expression Regulation, Bacterial; D016680:Genome, Bacterial; D005838:Genotype; D054884:Host-Pathogen Interactions; D006801:Humans; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics* / Q000276:immunology / Q000472:pathogenicity; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D018088:Tuberculosis, Multidrug-Resistant / Q000175:diagnosis / Q000188:drug therapy / Q000276:immunology / Q000382:microbiology*
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins
keywords: Genome sequencing; Haarlem; MDR; Mycobacterium tuberculosis; Polymorphisms