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Clostridioides difficile  flagellin FliC is associated with toxin gene expression, bacterial colonization, and virulence, and is also involved in pleiotropic gene regulation during  in vivo  infection. However, how  fliC  expression is regulated in  C. difficile  remains unclear. In  Bacillus subtilis , flagellin homeostasis and motility are coregulated by flagellar assembly factor (FliW), flagellin Hag (FliC homolog), and Carbon storage regulator A (CsrA), which is referred to as partner-switching mechanism “FliW-CsrA-Hag.” In this study, we characterized FliW and CsrA functions by deleting or overexpressing  fliW ,  csrA , and  fliW - csrA  in  C. difficile  R20291. We showed that  fliW  deletion,  csrA  overexpression in R20291, and  csrA  complementation in R20291ΔWA ( fliW - csrA  codeletion mutant) dramatically decreased FliC production, but not  fliC  gene transcription. Suppression of  fliC  translation by  csrA  overexpression can be relieved mostly when  fliW  was coexpressed, and no significant difference in FliC production was detected when only  fliW  was complemented in R20291ΔWA. Further, loss of  fliW  led to increased biofilm formation, cell adhesion, toxin production, and pathogenicity in a mouse model of  C. difficile  infection (CDI), while  fliW - csrA  codeletion decreased toxin production and mortality  in vivo . Our data suggest that CsrA negatively modulates  fliC  expression and FliW indirectly affects  fliC  expression through inhibition of CsrA post-transcriptional regulation. In light of “FliW-CsrA-Hag” switch coregulation mechanism reported in  B. subtilis , our data also suggest that “FliW-CsrA- fliC /FliC” can regulate many facets of  C. difficile  R20291 pathogenicity. These findings further aid us in understanding the virulence regulation in  C. difficile .

FliW and CsrA Govern Flagellin (FliC) Synthesis and Play Pleiotropic Roles in Virulence and Physiology of Clostridioides difficile R20291