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dc.contributor.authorOrmsby, Michael Jen_UK
dc.contributor.authorVaz, Filipaen_UK
dc.contributor.authorKirk, Joseph Aen_UK
dc.contributor.authorBarwinska-Sendra, Annaen_UK
dc.contributor.authorHallam, Jennifer Cen_UK
dc.contributor.authorLanzoni-Mangutchi, Paolaen_UK
dc.contributor.authorCole, Johnen_UK
dc.contributor.authorChaudhuri, Roy Ren_UK
dc.contributor.authorSalgado, Paula Sen_UK
dc.contributor.authorFagan, Robert Pen_UK
dc.contributor.authorDouce, Gillian Ren_UK
dc.contributor.editorMcClane, Bruce A.en_UK
dc.description.abstractClostridioides difficile is responsible for substantial morbidity and mortality in antibiotically-treated, hospitalised, elderly patients, in which toxin production correlates with diarrhoeal disease. While the function of these toxins has been studied in detail, the contribution of other factors, including the paracrystalline surface layer (S-layer), to disease is less well understood. Here, we highlight the essentiality of the S-layer in vivo by reporting the recovery of S-layer variants, following infection with the S-layer-null strain, FM2.5. These variants carry either correction of the original point mutation, or sequence modifications which restored the reading frame, and translation of slpA. Selection of these variant clones was rapid in vivo, and independent of toxin production, with up to 90% of the recovered C. difficile population encoding modified slpA sequence within 24 h post infection. Two variants, subsequently named FM2.5varA and FM2.5varB, were selected for study in greater detail. Structural determination of SlpA from FM2.5varB indicated an alteration in the orientation of protein domains, resulting in a reorganisation of the lattice assembly, and changes in interacting interfaces, which might alter function. Interestingly, variant FM2.5varB displayed an attenuated, FM2.5-like phenotype in vivo compared to FM2.5varA, which caused disease severity more comparable to that of R20291. Comparative RNA sequencing (RNA-Seq) analysis of in vitro grown isolates revealed large changes in gene expression between R20291 and FM2.5. Downregulation of tcdA/tcdB and several genes associated with sporulation and cell wall integrity may account for the reported attenuated phenotype of FM2.5 in vivo. RNA-seq data correlated well with disease severity with the more virulent variant, FM2.5varA, showing s similar profile of gene expression to R20291 in vitro, while the attenuated FM2.5varB showed downregulation of many of the same virulence associated traits as FM2.5. Cumulatively, these data add to a growing body of evidence that the S-layer contributes to C. difficile pathogenesis and disease severity.en_UK
dc.publisherPublic Library of Science (PLoS)en_UK
dc.relationOrmsby MJ, Vaz F, Kirk JA, Barwinska-Sendra A, Hallam JC, Lanzoni-Mangutchi P, Cole J, Chaudhuri RR, Salgado PS, Fagan RP & Douce GR (2023) An intact S-layer is advantageous to Clostridioides difficile within the host. McClane BA (Editor) <i>PLOS Pathogens</i>, 19 (6), Art. No.: e1011015.
dc.rightsCopyright: © 2023 Ormsby et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_UK
dc.subjectMolecular Biologyen_UK
dc.titleAn intact S-layer is advantageous to Clostridioides difficile within the hosten_UK
dc.typeJournal Articleen_UK
dc.citation.jtitlePLoS Pathogensen_UK
dc.type.statusVoR - Version of Recorden_UK
dc.contributor.funderUniversity of Glasgowen_UK
dc.contributor.affiliationBiological and Environmental Sciencesen_UK
dc.contributor.affiliationUniversity of Osloen_UK
dc.contributor.affiliationUniversity of Sheffielden_UK
dc.contributor.affiliationNewcastle Universityen_UK
dc.contributor.affiliationUniversity of Glasgowen_UK
dc.contributor.affiliationUniversité Grenoble Alpes (UGA)en_UK
dc.contributor.affiliationUniversity of Glasgowen_UK
dc.contributor.affiliationUniversity of Sheffielden_UK
dc.contributor.affiliationNewcastle Universityen_UK
dc.contributor.affiliationUniversity of Sheffielden_UK
dc.contributor.affiliationUniversity of Glasgowen_UK
rioxxterms.apcnot requireden_UK
rioxxterms.typeJournal Article/Reviewen_UK
local.rioxx.authorOrmsby, Michael J|0000-0002-3991-2336en_UK
local.rioxx.authorVaz, Filipa|en_UK
local.rioxx.authorKirk, Joseph A|en_UK
local.rioxx.authorBarwinska-Sendra, Anna|en_UK
local.rioxx.authorHallam, Jennifer C|en_UK
local.rioxx.authorLanzoni-Mangutchi, Paola|en_UK
local.rioxx.authorCole, John|en_UK
local.rioxx.authorChaudhuri, Roy R|en_UK
local.rioxx.authorSalgado, Paula S|en_UK
local.rioxx.authorFagan, Robert P|0000-0002-8704-4828en_UK
local.rioxx.authorDouce, Gillian R|0000-0002-6654-7346en_UK
local.rioxx.projectProject ID unknown|University of Glasgow|
local.rioxx.contributorMcClane, Bruce A.|en_UK
Appears in Collections:Biological and Environmental Sciences Journal Articles

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