title: Mycobacterium tuberculosis strains with the Beijing genotype demonstrate variability in virulence associated with transmission.
abstract: Phylogenetic analysis has shown that Beijing genotype strains can be grouped into at least 7 different sublineages. We aimed to test the hypothesis that the virulence of Beijing genotype strains differed among members of the different sublineages and that the level of virulence correlated with their ability to spread and cause disease. BALB/c mice were infected with Beijing strains representative of the different lineages and of different epidemiological characteristics (transmitted vs. non-transmitted). Survival times, lung pathology, bacterial load and immunology kinetics were evaluated at defined intervals post-infection. Transmissibility was determined by co-housing infected and uninfected mice in close contact for 1-2 months. The results show that mice infected with the highly transmitted Beijing strains began showing mortality 3 weeks post-infection and all had died by 5 weeks, suggesting high virulence phenotypes. In contrast, >80% of mice infected with the non-transmitted strains survived 4 months post-infection, suggesting low virulence phenotypes. Our co-housing transmission model confirmed these virulence phenotypes. Extensive tissue damage and the induction of lower levels of IFNγ and iNOS expression, as well as high but ephemeral TNFα expression were associated with the high virulence phenotype. In contrast, minimal tissue damage and progressive expression of IFNγ and TNFα were associated with the low virulence phenotype. Both virulence phenotypes induced similar levels of IL-4 expression during the early stages of infection after which the high virulence strain induced significantly higher levels of IL-4 expression. In conclusion, this study demonstrates that Beijing genotype strains display a spectrum of virulence phenotypes in mice which mimic their epidemiological characteristics. Both transmissible and non-transmissible strains may exist in the same sublineage.
authors.affiliation: Experimental Pathology Section, Dept. of Pathology, National Institute of Medical Sciences and Nutrition Salvador Zubiràn, Vasco de Quiroga 15, Tlalpan, Mexico City CP-14000, Mexico.
authors.forename: D
authors.initials: D
authors.lastname: Aguilar
authors.forename: M
authors.initials: M
authors.lastname: Hanekom
authors.forename: D
authors.initials: D
authors.lastname: Mata
authors.forename: N C
authors.initials: NC
authors.lastname: Gey van Pittius
authors.forename: P D
authors.initials: PD
authors.lastname: van Helden
authors.forename: R M
authors.initials: RM
authors.lastname: Warren
authors.forename: R
authors.initials: R
authors.lastname: Hernandez-Pando
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005838:Genotype; D007194:India / Q000453:epidemiology; D008168:Lung / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D017720:Molecular Epidemiology; D009169:Mycobacterium tuberculosis / Q000145:classification / Q000235:genetics / Q000302:isolation & purification* / Q000472:pathogenicity*; D010802:Phylogeny; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014397:Tuberculosis, Pulmonary / Q000235:genetics / Q000276:immunology / Q000635:transmission*; D014774:Virulence