tcdA

TcdA, also known as toxin A, is a major virulence factor produced by Clostridioides difficile. Along with toxin B (TcdB), it is responsible for many manifestations of Clostridioides difficile infection (CDI), including watery diarrhea and colitis. The genes encoding TcdA and TcdB are located in the pathogenicity locus PaLoc, together with regulatory genes such as tcdC and tcdR.

TcdA is a large single-chain protein of about 300 kilodaltons. It belongs to the family of large clostridial toxins and contains an N-terminal glucosyltransferase domain that modifies and inactivates Rho family GTPases by transferring a glucose moiety from UDP-glucose. A nearby cysteine protease domain enables autoproteolytic release of the enzymatic GTD into the cytosol upon activation by inositol hexakisphosphate. The toxin also possesses a translocation domain and a receptor-binding domain that mediates cell entry.

Mechanistically, TcdA binds to host cells, is endocytosed, and undergoes pH-triggered membrane insertion to translocate the GTD into the cytoplasm. The CPD then cleaves to release GTD, which glucosylates Rho, Rac, and Cdc42 GTPases, disrupting the actin cytoskeleton. This leads to cell rounding, loss of tight junctions and cytotoxicity, and triggers inflammatory pathways that contribute to mucosal damage and diarrhea.

In disease, TcdA contributes to the symptoms of CDI, though the relative importance of TcdA versus TcdB can vary among strains; some strains produce both toxins. Diagnosis often relies on toxin detection or cytotoxicity assays, while treatment involves antibiotics such as vancomycin or fidaxomicin and, in some cases, toxin-targeted therapies.