An ancestral mycobacterial effector promotes dissemination of infection

Joseph W. Saelens, Mollie I. Sweeney, Gopinath Viswanathan, Ana María Xet-Mull, Kristen L. Jurcic Smith, Dana M. Sisk, Daniel D. Hu, Rachel M. Cronin, Erika J. Hughes, W. Jared Brewer, Jörn Coers, Matthew M. Champion, Patricia A. Champion, Craig B. Lowe, Clare M. Smith, Sunhee Lee, Jason E. Stout, David M. Tobin

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

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 extrapulmonary 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 lineages 2, 3, and 4 is consistent with a role for EsxM in regulating the extent of dissemination.

Original languageEnglish (US)
Pages (from-to)4507-4525.e18
JournalCell
Volume185
Issue number24
DOIs
StatePublished - Nov 23 2022
Externally publishedYes

Keywords

  • ESX-5
  • EsxM
  • Mycobacterium marinum
  • Mycobacterium tuberculosis
  • dissemination
  • evolution
  • macrophage
  • tuberculosis
  • type VII secretion

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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