@article{6b931db44bf14d68970210613d3f79d8,
title = "An ancestral mycobacterial effector promotes dissemination of infection",
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.",
keywords = "dissemination, ESX-5, EsxM, evolution, macrophage, Mycobacterium marinum, Mycobacterium tuberculosis, tuberculosis, type VII secretion",
author = "Saelens, {Joseph W.} and Sweeney, {Mollie I.} and Gopinath Viswanathan and Xet-Mull, {Ana Mar{\'i}a} and {Jurcic Smith}, {Kristen L.} and Sisk, {Dana M.} and Hu, {Daniel D.} and Cronin, {Rachel M.} and Hughes, {Erika J.} and Brewer, {W. Jared} and J{\"o}rn Coers and Champion, {Matthew M.} and Champion, {Patricia A.} and Lowe, {Craig B.} and Smith, {Clare M.} and Sunhee Lee and Stout, {Jason E.} and Tobin, {David M.}",
note = "Funding Information: We thank R. Asrican, R. Beerman, M. Braunstein, L. Cameron, L. Dolat, Y. Gao, S. Harris, E. Hunt, R. Meade, S. Miller, K. Murphy, C. Pyle, R. Vancini, and C. Xander for experimental advice and assistance; E. Hunt, I. Padmanaban, and A. Yu for zebrafish care; T. Graf for BLaER1 cells; M. Bagnat, J. Bear, T. Ioerger, D. Pickup, M. Welch, and members of the Tobin laboratory for helpful discussions; and M. Cronan and L. Dolat for comments on the manuscript. Graphical abstract created in part with BioRender. This work was funded by National Institutes of Health grants AI125517 (D.M.T. J.E.S. and S.L.), AI130236, AI127115 (D.M.T), AI142127, AI149147, AI106872 (P.A.C.), Whitehead Scholar Awards (C.B.L. and C.M.S), an NIH Director's New Innovator Award 1DP2-GM146458-01 (C.M.S.), and a Vallee Scholar Award (D.M.T.). Biocontainment work performed in the Duke Regional Biocontainment Laboratory received partial support for construction from NIAID (UC6-AI058607). J.W.S. S.L. J.E.S. and D.M.T. conceived and designed the project; J.W.S. M.I.S. and G.V. performed and analyzed all zebrafish experiments; M.I.S. A.M.X.-M. E.J.H. and C.M.S. performed mouse experiments; G.V. performed bacterial expression analysis; J.W.S. W.J.B. D.M.T. and C.B.L. analyzed publicly available sequence data; W.J.B. and M.I.S. analyzed RNA-seq data; D.M.S. and K.L.J.S. isolated and grew the outbreak strain; A.M.X.-M. performed infection experiments and migration assays; D.D.H, R.M.C. M.M.C. and P.A.C performed and analyzed proteomic experiments; J.C. supervised BLaER1 cell assays; C.M.S. designed and supervised mouse infection experiments; J.W.S. M.I.S. and D.M.T. wrote the manuscript with substantial contributions by G.V. and additional input from all authors. The authors declare no competing interests. Funding Information: We thank R. Asrican, R. Beerman, M. Braunstein, L. Cameron, L. Dolat, Y. Gao, S. Harris, E. Hunt, R. Meade, S. Miller, K. Murphy, C. Pyle, R. Vancini, and C. Xander for experimental advice and assistance; E. Hunt, I. Padmanaban, and A. Yu for zebrafish care; T. Graf for BLaER1 cells; M. Bagnat, J. Bear, T. Ioerger, D. Pickup, M. Welch, and members of the Tobin laboratory for helpful discussions; and M. Cronan and L. Dolat for comments on the manuscript. Graphical abstract created in part with BioRender. This work was funded by National Institutes of Health grants AI125517 (D.M.T., J.E.S., and S.L.), AI130236 , AI127115 (D.M.T), AI142127 , AI149147 , AI106872 (P.A.C.), Whitehead Scholar Awards (C.B.L. and C.M.S), an NIH Director{\textquoteright}s New Innovator Award 1DP2-GM146458-01 (C.M.S.), and a Vallee Scholar Award (D.M.T.). Biocontainment work performed in the Duke Regional Biocontainment Laboratory received partial support for construction from NIAID ( UC6-AI058607 ). Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = nov,
day = "23",
doi = "10.1016/j.cell.2022.10.019",
language = "English (US)",
volume = "185",
pages = "4507--4525.e18",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "24",
}