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Clostridium Difficile Toxin B Induces Senescence in Enteric Glial Cells: A Potential New Mechanism of Clostridium Difficile Pathogenesis

Clostridium Difficile Toxin B Induces Senescence in Enteric Glial Cells: A Potential New Mechanism of Clostridium Difficile Pathogenesis

Katia Fettucciari, Lara Macchioni, Magdalena Davidescu, Paolo Scarpelli, Camilla Palumbo, Lanfranco Corazzi, Andrea Marchegiani, Matteo Cerquetella, Andrea Spaterna, Pierfrancesco Marconi, Gabrio Bassotti

Biochim Biophys Acta Mol Cell Res. 2018 Dec;1865(12):1945-1958.

PMID: 30296499

Abstract:

Clostridium difficile infection (CDI) causes nosocomial/antibiotic-associated diarrhea and pseudomembranous colitis, with dramatic incidence/mortality worldwide. C. difficile virulence factors are toxin A and toxin B (TcdB) which cause cytopathic/cytotoxic effects and inflammation. Until now studies were focused on molecular effects of C. difficile toxins (Tcds) on different cells while unexplored aspect is the status/fate of cells that survived their cytotoxicity. Recently we demonstrated that enteric glial cells (EGCs) are susceptible to TcdB cytotoxicity, but several EGCs survived and were irreversibly cell-cycle arrested and metabolically active, suggesting that EGCs could became senescent. This is important because allowed us to evaluate the not explored status/fate of cells surviving Tcds cytotoxicity, and particularly if TcdB induces senescence in EGCs. Rat-transformed EGCs were treated with 10 ng/ml TcdB for 6 h-48 h, or for 48 h, followed by incubation for additional 4 or 11 days in absence of TcdB (6 or 13 total days). Senescence markers/effectors were examined by specific assays. TcdB induces senescence in EGCs, as demonstrated by the senescence markers: irreversible cell-cycle arrest, senescence-associated-β‑galactosidase positivity, flat morphology, early and persistent DNA damage (ATM and H2AX phosphorylation), p27 overexpression, pRB hypophosphorylation, c‑Myc, cyclin B1, cdc2 and phosphorylated-cdc2 downregulation, Sirtuin‑2 and Sirtuin‑3 overexpression. TcdB-induced EGC senescence is dependent by JNK and AKT activation but independent by ROS, p16 and p53/p21 pathways. In conclusion, TcdB induces senescence in EGCs. The extrapolation of these results to CDI leads to hypothesize that EGCs that survived TcdB, once they have acquired a senescence state, could cause irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and tumors due to persistent inflammation, transfer of senescence status and stimulation of pre-neoplastic cells.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4242912	Clostridium difficile Toxin B			Price

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