An ancestral mycobacterial effector promotes dissemination of infection.

Autor:	Saelens JW; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA., Sweeney MI; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA., Viswanathan G; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA., Xet-Mull AM; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA., Jurcic Smith KL; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA., Sisk DM; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA., Hu DD; Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA., Cronin RM; Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA., Hughes EJ; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA., Brewer WJ; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA., Coers J; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA; Department of Immunology, Duke University School of Medicine, Durham, NC 27710, USA., Champion MM; Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA; Eck Institute for Global Health, University of Notre Dame, Notre Dame, IN 46556, USA., Champion PA; Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA; Eck Institute for Global Health, University of Notre Dame, Notre Dame, IN 46556, USA., Lowe CB; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA., Smith CM; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA., Lee S; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA; Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA. Electronic address: sunhlee@utmb.edu., Stout JE; Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA; Division of Infectious Diseases and International Health, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: jason.stout@duke.edu., Tobin DM; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA; Department of Immunology, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: david.tobin@duke.edu.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2022 Nov 23; Vol. 185 (24), pp. 4507-4525.e18. Date of Electronic Publication: 2022 Nov 09.
DOI:	10.1016/j.cell.2022.10.019
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu