An ancestral mycobacterial effector promotes dissemination of infection

The human pathogen Mycobacterium tuberculosis typically causes lung disease but can also disseminate to other tissues. We identified a M. tuberculosis (Mtb) outbreak presenting with unusually high rates of extrap-ulmonary dissemination and bone disease. We found that the causal strain carried an ancestral full-length version of the type VII-secreted effector EsxM rather than the truncated version present in other modern Mtb lineages. The ancestral EsxM variant exacerbated dissemination through enhancement of macrophage motility, increased egress of macrophages from established granulomas, and alterations in macrophage actin dynamics. Reconstitution of the ancestral version of EsxM in an attenuated modern strain of Mtb altered the migratory mode of infected macrophages, enhancing their motility. In a zebrafish model, full-length EsxM promoted bone disease. The presence of a derived nonsense variant in EsxM throughout the major Mtb lin-eages 2, 3, and 4 is consistent with a role for EsxM in regulating the extent of dissemination.

Automated summary

The human pathogen Mycobacterium tuberculosis can cause lung disease and disseminate to other tissues. This study identified an outbreak of M. tuberculosis with high rates of extrapulmonary dissemination and bone disease. The causal strain carried a full-length ancestral version of the effector protein EsxM, which exacerbated dissemination through enhancement of macrophage motility and egress from granulomas, as well as alterations in macrophage actin dynamics. Reconstitution of ancestral EsxM in a modern attenuated strain altered the migratory mode of infected macrophages and promoted bone disease in a zebrafish model. The presence of a derived nonsense variant in EsxM in major M. tuberculosis lineages suggests a role for EsxM in regulating dissemination.