title: Virulence, immunopathology and transmissibility of selected strains of Mycobacterium tuberculosis in a murine model.
abstract: After encounter with Mycobacterium tuberculosis, a series of non-uniform immune responses are triggered that define the course of the infection. Eight M. tuberculosis strains were selected from a prospective population-based study of pulmonary tuberculosis patients (1995-2003) based on relevant clinical/epidemiological patterns and tested in a well-characterized BALB/c mouse model of progressive pulmonary tuberculosis. In addition, a new mouse model of transmissibility consisting of prolonged cohousing (up to 60 days) of infected and naïve animals was tested. Four phenotypes were defined based on strain virulence (mouse survival, lung bacillary load and tissue damage), immunology response (cytokine expression determined by real-time polymerase chain reaction) and transmissibility (lung bacillary loads and cutaneous delayed-type hypersensitivity in naïve animals).We identified four clearly defined strain phenotypes: (1) hypervirulent strain with non-protective immune response and highly transmissible; (2) virulent strain, associated with high expression of proinflammatory cytokines (tumour necrosis factor and interferon) and very low anti-inflammatory cytokine expression (interleukins 4 and 10), which induced accelerated death by immunopathology; (3) strain inducing efficient protective immunity with lower virulence, and (4) strain demonstrating strong and early macrophage activation (innate immunity) with delayed participation of acquired immunity (interferon expression). We were able to correlate virulent and transmissible phenotypes in the mouse model and markers of community transmission such as tuberculin reactivity among contacts, rapid progression to disease and cluster status. However, we were not able to find correlation with the other two phenotypes. Our new transmission model supported the hypothesis that among these strains increased virulence was linked to increased transmission.
authors.affiliation: Sección de Patología Experimental, Departamento de Patología, Instituto Nacional de Ciencias Medicas y Nutrición, Salvador Zubiran, Mexico.
authors.forename: Brenda
authors.initials: B
authors.lastname: Marquina-Castillo
authors.forename: Lourdes
authors.initials: L
authors.lastname: García-García
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ponce-de-León
authors.forename: Maria-Eugenia
authors.initials: ME
authors.lastname: Jimenez-Corona
authors.forename: Miriam
authors.initials: M
authors.lastname: Bobadilla-Del Valle
authors.forename: Bulmaro
authors.initials: B
authors.lastname: Cano-Arellano
authors.forename: Sergio
authors.initials: S
authors.lastname: Canizales-Quintero
authors.forename: Areli
authors.initials: A
authors.lastname: Martinez-Gamboa
authors.forename: Midori
authors.initials: M
authors.lastname: Kato-Maeda
authors.forename: Brian
authors.initials: B
authors.lastname: Robertson
authors.forename: Douglas
authors.initials: D
authors.lastname: Young
authors.forename: Peter
authors.initials: P
authors.lastname: Small
authors.forename: Gary
authors.initials: G
authors.lastname: Schoolnik
authors.forename: Jose
authors.initials: J
authors.lastname: Sifuentes-Osornio
authors.forename: Rogelio
authors.initials: R
authors.lastname: Hernandez-Pando
mesh_terms: D000328:Adult; D000818:Animals; D015169:Colony Count, Microbial; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D006801:Humans; D008168:Lung / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000145:classification / Q000254:growth & development / Q000276:immunology / Q000472:pathogenicity*; D010641:Phenotype; D016133:Polymerase Chain Reaction / Q000379:methods; D016019:Survival Analysis; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000382:microbiology / Q000635:transmission; D014774:Virulence
chemical_list: D016207:Cytokines