Virulence, immunopathology and transmissibility of selected strains ofMycobacterium tuberculosisin a murine model

Abstract

Summary 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.

Genomic Signatures of the Haarlem Lineage of Mycobacterium tuberculosis : Implications of Strain Genetic Variation in Drug and Vaccine Development

“…Animal models that take advantage of an identical genetic background, and therefore a uniform host immune response, have given insight regarding the contribution of strain genetic diversity to the outcome of the infectious process (7,20). It is currently accepted that genetically different M. tuberculosis strains produce markedly different immunopathological events in isogenic mice (4,18).…”

Mycobacterium tuberculosis strains from ancient and modern lineages induce distinct patterns of immune responses

“…Several studies have reported heterogeneity in the cytokine response induced by various genotypes of MTB [5,20]. Strains of modern lineages (lineage 2, 3 and 4) were shown to induce lower levels of proinflamatory cytokines when compared with ancient lineages (lineage 1) [10].…”

“…It was traditionally assumed that MTB was genetically homogenous because early studies revealed very low levels of DNA sequence variation. However, after the discovery of molecular typing methods, it is now well known that different types and subtypes of MTB do exist and that genotype might be associated with differences in virulence, antibiotic susceptibility, relapse and prevalence of disease [3][4][5][6]. Several recent studies, including ours, suggest that phylogenetic diversity of the strains is also associated with diversity in biological response of the host [7].…”

Immunotherapeutic effects of recombinant adenovirus encoding granulocyte–macrophage colony-stimulating factor in experimental pulmonary tuberculosis

“…Our transmissibility model is based on long co-housing between infected and healthy mice [23]. This model was used to determine whether or not AdGM-CSF treatment was able to prevent infection of healthy mice co-housed with animals infected with moderate (H37Rv) or highly virulent (Beijing 900-1000) strains.…”

“…The transmissibility experimental model has been described previously [23]. Five BALB/c mice infected (2·5 ¥ 10 5 bacilli) with Mtb H37Rv or highly virulent Beijing strain 9001000 were co-housed in the same micro-isolator from the first day of infection with five healthy non-infected BALB/c mice (contacts), which received AdGM-CSF (1 ¥ 10 8 pfu IT) by the i.t.…”