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Abstract
Clostridioides difficile toxin B (TcdB) is a key virulence factor that causes C. difficile associated diseases (CDAD) including diarrhea and pseudomembranous colitis. TcdB can be divided into multiple subtypes/variants based on their sequence variations, of which four (TcdB1-4) are dominant types found in major epidemic isolates. Here, we find that these variants are highly diverse in their receptor preference: TcdB1 uses two known receptors CSPG4 and Frizzled (FZD) proteins, TcdB2 selectively uses CSPG4, TcdB3 prefers to use FZDs, whereas TcdB4 uses neither CSPG4 nor FZDs. By creating chimeric toxins and systematically switching residues between TcdB1 and TcdB3, we determine that regions in the N-terminal cysteine protease domain (CPD) are involved in CSPG4-recognition. We further evaluate the pathological effects induced by TcdB1-4 with a mouse intrarectal installation model. TcdB1 leads to the most severe overall symptoms, followed by TcdB2 and TcdB3. When comparing the TcdB2 and TcdB3, TcdB2 causes stronger oedema while TcdB3 induces severer inflammatory cell infiltration. These findings together demonstrate divergence in the receptor preference and further lead to colonic pathology for predominant TcdB subtypes.
Highlights
Clostridioides difficile is a spore-forming anaerobic bacterium that is a major cause of nosocomial and community-acquired gastrointestinal infections
The bacterium produces three exotoxins including TcdA, TcdB, and C. difficile binary toxin (CDT), of which TcdB is known as a key virulence factor causing the diseases
HeLa cells express a high level of chondroitin sulfate proteoglycan 4 (CSPG4), low levels of FZDs, and probably no poliovirus receptor-like 3 (PVRL3) [30,37]; they are suitable to investigate the preference of TcdB variants on CSPG4 and FZDs
Summary
Clostridioides difficile (formerly known as Clostridium difficile) is a spore-forming anaerobic bacterium that is a major cause of nosocomial and community-acquired gastrointestinal infections. Once the normal gut flora is disrupted by antibiotic treatment, C. difficile can colonize the colon and induce diarrhea and pseudomembranous colitis [1,2]. Due to the emergence of hypervirulence and antibiotic-resistant strains, the global burden of C. difficile infection (CDI) is exacerbated [3,4,5]. TcdA (308 kDa) and TcdB (270 kDa), are the major virulence factors produced by C. difficile that disrupt the colonic epithelium and induce tissue damage. TcdB is considered as the primary disease-causing toxin because TcdB alone can induce a full spectrum of disease in both animals and humans [6,7,8], and many TcdA–TcdB+ strains have been clinically isolated [9,10]. Some C. difficile strains express a third toxin called C. difficile binary toxin (CDT), which has been reported to suppress the host eosinophilic response [11]
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