PUBLICATION
An ancestral mycobacterial effector promotes dissemination of infection
- Authors
- Saelens, J.W., Sweeney, M.I., Viswanathan, G., Xet-Mull, A.M., Jurcic Smith, K.L., Sisk, D.M., Hu, D.D., Cronin, R.M., Hughes, E.J., Brewer, W.J., Coers, J., Champion, M.M., Champion, P.A., Lowe, C.B., Smith, C.M., Lee, S., Stout, J.E., Tobin, D.M.
- ID
- ZDB-PUB-221115-14
- Date
- 2022
- Source
- Cell 185(24): 4507-4525.e18 (Journal)
- Registered Authors
- Tobin, David
- Keywords
- ESX-5, EsxM, Mycobacterium marinum, Mycobacterium tuberculosis, dissemination, evolution, macrophage, tuberculosis, type VII secretion
- MeSH Terms
-
- Animals
- Bacterial Proteins/genetics
- Bone Diseases*
- Humans
- Macrophages/microbiology
- Mycobacterium marinum*
- Mycobacterium tuberculosis*
- Tuberculosis*/microbiology
- Zebrafish
- PubMed
- 36356582 Full text @ Cell
Citation
Saelens, J.W., Sweeney, M.I., Viswanathan, G., Xet-Mull, A.M., Jurcic Smith, K.L., Sisk, D.M., Hu, D.D., Cronin, R.M., Hughes, E.J., Brewer, W.J., Coers, J., Champion, M.M., Champion, P.A., Lowe, C.B., Smith, C.M., Lee, S., Stout, J.E., Tobin, D.M. (2022) An ancestral mycobacterial effector promotes dissemination of infection. Cell. 185(24):4507-4525.e18.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping