Pleiotropic roles of <i>Clostridium difficile sin</i> locus

Published on 2018-03-12T17:51:59Z (GMT) by
<div><p><i>Clostridium difficile</i> is the primary cause of nosocomial diarrhea and pseudomembranous colitis. It produces dormant spores, which serve as an infectious vehicle responsible for transmission of the disease and persistence of the organism in the environment. In <i>Bacillus subtilis</i>, the <i>sin</i> locus coding SinR (113 aa) and SinI (57 aa) is responsible for sporulation inhibition. In <i>B</i>. <i>subtilis</i>, SinR mainly acts as a repressor of its target genes to control sporulation, biofilm formation, and autolysis. SinI is an inhibitor of SinR, so their interaction determines whether SinR can inhibit its target gene expression. The <i>C</i>. <i>difficile</i> genome carries two <i>sinR</i> homologs in the operon that we named <i>sinR</i> and <i>sinR’</i>, coding for SinR (112 aa) and SinR’ (105 aa), respectively. In this study, we constructed and characterized <i>sin</i> locus mutants in two different <i>C</i>. <i>difficile</i> strains R20291 and JIR8094, to decipher the locus’s role in <i>C</i>. <i>difficile</i> physiology. Transcriptome analysis of the <i>sinRR’</i> mutants revealed their pleiotropic roles in controlling several pathways including sporulation, toxin production, and motility in <i>C</i>. <i>difficile</i>. Through various genetic and biochemical experiments, we have shown that SinR can regulate transcription of key regulators in these pathways, which includes <i>sigD</i>, <i>spo0A</i>, and <i>codY</i>. We have found that SinR’ acts as an antagonist to SinR by blocking its repressor activity. Using a hamster model, we have also demonstrated that the <i>sin</i> locus is needed for successful <i>C</i>. <i>difficile</i> infection. This study reveals the <i>sin</i> locus as a central link that connects the gene regulatory networks of sporulation, toxin production, and motility; three key pathways that are important for <i>C</i>. <i>difficile</i> pathogenesis.</p></div>

Cite this collection

Girinathan, Brintha Parasumanna; Ou, Junjun; Dupuy, Bruno; Govind, Revathi (2018): Pleiotropic roles of Clostridium difficile sin locus. PLOS Pathogens.