Large Clostridial Toxins: Mechanisms and Roles in Disease

Orrell, Kathleen E.; Melnyk, Roman A.

doi:10.1128/mmbr.00064-21

Cited by 68 publications

(67 citation statements)

References 288 publications

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“…TcdA and TcdB bind to their respective receptors on human colonocytes which initiates a chain reaction that leads to a loss of epithelial barrier integrity through the disruption of the skeletal structure and tight junctions, and cell death (Farrow et al, 2013;Di Bella et al, 2016;Chandrasekaran and Lacy, 2017;Orrell and Melnyk, 2021). This results in translocation of intestinal bacteria and stress in colonic epithelial cells.…”

Section: Clostridioides Difficile Producing Toxin a And Toxin Bmentioning

confidence: 99%

Host Immune Responses to Clostridioides difficile: Toxins and Beyond

et al. 2021

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Clostridioides difficile is often resistant to the actions of antibiotics to treat other bacterial infections and the resulting C. difficile infection (CDI) is among the leading causes of nosocomial infectious diarrhea worldwide. The primary virulence mechanism contributing to CDI is the production of toxins. Treatment failures and recurrence of CDI have urged the medical community to search for novel treatment options. Strains that do not produce toxins, so called non-toxigenic C. difficile, have been known to colonize the colon and protect the host against CDI. In this review, a comprehensive description and comparison of the immune responses to toxigenic C. difficile and non-toxigenic adherence, and colonization factors, here called non-toxin proteins, is provided. This revealed a number of similarities between the host immune responses to toxigenic C. difficile and non-toxin proteins, such as the influx of granulocytes and the type of T-cell response. Differences may reflect genuine variation between the responses to toxigenic or non-toxigenic C. difficile or gaps in the current knowledge with respect to the immune response toward non-toxigenic C. difficile. Toxin-based and non-toxin-based immunization studies have been evaluated to further explore the role of B cells and reveal that plasma cells are important in protection against CDI. Since the success of toxin-based interventions in humans to date is limited, it is vital that future research will focus on the immune responses to non-toxin proteins and in particular non-toxigenic strains.

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Section: Clostridioides Difficile Producing Toxin a And Toxin Bmentioning

confidence: 99%

Host Immune Responses to Clostridioides difficile: Toxins and Beyond

et al. 2021

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“…TcdA (∼308 kD) and TcdB (∼270 kD) belong to the large clostridial glucosylating toxin (LCGT) family, which also include Paeniclostridium sordellii toxins TcsL and TcsH, Clostridium novyi toxin TcnA, and Clostridium perfringens toxin TpeL ( Aktories et al, 2017 ; Orrell & Melnyk, 2021 ). Most of these toxins are composed of four structural modules: an N-terminal glucosyltransferase domain (GTD), followed by a cysteine protease domain (CPD), a delivery and receptor-binding domain (DRBD), and a large C-terminal combined repetitive oligopeptides domain (CROPs) ( Aktories et al, 2017 ; Orrell & Melnyk, 2021 ) ( Fig 1A ). The cellular uptake of TcdA and TcdB are mediated by receptor-mediated endocytosis ( Papatheodorou et al, 2010 ; Tao et al, 2016 , 2019 ; Aktories et al, 2017 ; Chen et al, 2018 , 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Structure and conformational dynamics of Clostridioides difficile toxin A

et al. 2022

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Clostridioides difficile toxin A and B (TcdA and TcdB) are two major virulence factors responsible for diseases associated with C. difficile infection (CDI). Here, we report the 3.18-Å resolution crystal structure of a TcdA fragment (residues L843–T2481), which advances our understanding of the complete structure of TcdA holotoxin. Our structural analysis, together with complementary single molecule FRET and limited proteolysis studies, reveal that TcdA adopts a dynamic structure and its CROPs domain can sample a spectrum of open and closed conformations in a pH-dependent manner. Furthermore, a small globular subdomain (SGS) and the CROPs protect the pore-forming region of TcdA in the closed state at neutral pH, which could contribute to modulating the pH-dependent pore formation of TcdA. A rationally designed TcdA mutation that trapped the CROPs in the closed conformation showed drastically reduced cytotoxicity. Taken together, these studies shed new lights into the conformational dynamics of TcdA and its roles in TcdA intoxication.

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“…PMC is characterized by a loss of epithelial barrier function and massive colonic inflammation. TcdA and TcdB are large singlechain protein toxins with a multi-domain organization, allowing self-mediated entry of the N-terminal glucosyltransferase domain into mammalian target cells by receptor-mediated endocytosis (Aktories et al, 2017;Kordus et al, 2021;Orrell and Melnyk, 2021). Upon internalization into the cytosol, the glucosyltransferase domain catalyzes divalent metal ion-dependent mono-O-glucosylation and thereby inactivation of small GTPases of Rho and Ras families (Genth et al, 2014(Genth et al, , 2016(Genth et al, , 2018.…”

Section: Introductionmentioning

confidence: 99%

The Essential Role of Rac1 Glucosylation in Clostridioides difficile Toxin B-Induced Arrest of G1-S Transition

et al. 2022

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Clostridioides difficile infection (CDI) in humans causes pseudomembranous colitis (PMC), which is a severe pathology characterized by a loss of epithelial barrier function and massive colonic inflammation. PMC has been attributed to the action of two large protein toxins, Toxin A (TcdA) and Toxin B (TcdB). TcdA and TcdB mono-O-glucosylate and thereby inactivate a broad spectrum of Rho GTPases and (in the case of TcdA) also some Ras GTPases. Rho/Ras GTPases promote G1-S transition through the activation of components of the ERK, AKT, and WNT signaling pathways. With regard to CDI pathology, TcdB is regarded of being capable of inhibiting colonic stem cell proliferation and colonic regeneration, which is likely causative for PMC. In particular, it is still unclear, the glucosylation of which substrate Rho-GTPase is critical for TcdB-induced arrest of G1-S transition. Exploiting SV40-immortalized mouse embryonic fibroblasts (MEFs) with deleted Rho subtype GTPases, evidence is provided that Rac1 (not Cdc42) positively regulates Cyclin D1, an essential factor of G1-S transition. TcdB-catalyzed Rac1 glucosylation results in Cyclin D1 suppression and arrested G1-S transition in MEFs and in human colonic epithelial cells (HCEC), Remarkably, Rac1−/− MEFs are insensitive to TcdB-induced arrest of G1-S transition, suggesting that TcdB arrests G1-S transition in a Rac1 glucosylation-dependent manner. Human intestinal organoids (HIOs) specifically expressed Cyclin D1 (neither Cyclin D2 nor Cyclin D3), which expression was suppressed upon TcdB treatment. In sum, Cyclin D1 expression in colonic cells seems to be regulated by Rho GTPases (most likely Rac1) and in turn seems to be susceptible to TcdB-induced suppression. With regard to PMC, toxin-catalyzed Rac1 glucosylation and subsequent G1-S arrest of colonic stem cells seems to be causative for decreased repair capacity of the colonic epithelium and delayed epithelial renewal.

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Large Clostridial Toxins: Mechanisms and Roles in Disease

Cited by 68 publications

References 288 publications

Host Immune Responses to Clostridioides difficile: Toxins and Beyond

Host Immune Responses to Clostridioides difficile: Toxins and Beyond

Structure and conformational dynamics of Clostridioides difficile toxin A

The Essential Role of Rac1 Glucosylation in Clostridioides difficile Toxin B-Induced Arrest of G1-S Transition

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