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There is broad variation in susceptibility to Mycobacterium tuberculosis (MTB), and mouse models play a key role in elucidating the underlying mechanisms. The authors tested the hypothesis that caseation within pulmonary lesions is a specific effect of the sst1 (supersusceptibility to tuberculosis 1) locus on chromosome 1.
Typical mouse lesions described in the literature lack central caseation. However, the C3HeB/FeJ strain of mouse develops large necrotising granulomas after exposure to MTB. The authors compared the course of infection in an MTB-resistant mouse strain (B6) with an sst1-susceptible congenic strain (B6.C3H-sst1) which was genetically identical except for the interval containing the sst1 locus.
They found that, although initial dissemination was similar, bacterial loads, clinical disease, lung necrosis and mortality were considerably worse in the strain containing the sst1-susceptible allele. In addition, relapse after 3 months of isoniazid was faster and more rampant in this group. After demonstrating significantly slower disease progression and milder histopathology in the B6.C3H-sst1 strain compared with the C3HeB/FeJ strain, the authors concluded that the effect of the sst1 locus is modified by the genetic background of the host. Enhanced pro-inflammatory cytokine production by macrophages was observed in the susceptible strains; however, this appears to be controlled by loci other than sst1.
Further characterisation of sst1-encoded molecular mechanisms may not only shed light on a key aspect of the pathogenesis of tuberculosis, but may also suggest therapeutic interventions to reduce lung pathology and transmission of the pathogen.
▸ Pichugin AV, Yan B, Sloutsky A, et al. Dominant role of the sst1 locus in pathogenesis of necrotizing lung granulomas during chronic tuberculosis infection and reactivation in genetically resistant hosts. Am J Pathol 2009;174:2190–201
Provenance and Peer review Commissioned; not externally peer reviewed.
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