The C. difficile clnRAB operon initiates adaptations to the host environment in response to LL-37

• Type of Material: Article
• Authors: Emily C. Woods, Emory University; Adrianne Edwards, Emory University; Kevin O. Childress, Vanderbilt University; Joshua B. Jones, Emory University; Shonna McBride, Emory University
• Language: English
• Date: 2018-08-01
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2018 Woods et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.ppat.1007153
• Title of Journal or Parent Work: PLoS Pathogens
• ISSN: 1553-7366
• Volume: 14
• Issue: 8
• Start Page: e1007153
• End Page: e1007153
• Grant/Funding Information: The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; This work was funded by grants DK087763 (National Institutes of Health Diabetes and Digestive and Kidney Diseases; https://www.niddk.nih.gov) to SMM, DK101870 (National Institutes of Health Diabetes and Digestive and Kidney Diseases; https://www.niddk.nih.gov) to SMM, AI109526 (National Institutes of Health Allergy and Infectious Diseases; https://www.niaid.nih.gov) to SMM, AI121684 (National Institutes of Health Allergy and Infectious Diseases; https://www.niaid.nih.gov) to SMM, and GM008169 (National Institutes of Health General Medical Sciences; https://www.nigms.nih.gov) to ECW.
• Keywords: DEPENDENT REGULATION; ESCHERICHIA-COLI; SIGMA FACTORS; Parasitology; RESISTANCE; TOXIN GENE-EXPRESSION; IMMUNE-RESPONSE; METABOLISM; Science & Technology; CLOSTRIDIUM-DIFFICILE; Life Sciences & Biomedicine; ANTIMICROBIAL PEPTIDE LL-37; Microbiology; Virology; PSEUDOMEMBRANOUS COLITIS
• Research Categories: Biology, Microbiology; Biology, Virology

Abstract

To cause disease, Clostridioides (Clostridium) difficile must resist killing by innate immune effectors in the intestine, including the host antimicrobial peptide, cathelicidin (LL-37). The mechanisms that enable C. difficile to adapt to the intestine in the presence of antimicrobial peptides are unknown. Expression analyses revealed an operon, CD630_16170-CD630_16190 (clnRAB), which is highly induced by LL-37 and is not expressed in response to other cell-surface active antimicrobials. This operon encodes a predicted transcriptional regulator (ClnR) and an ABC transporter system (ClnAB), all of which are required for function. Analyses of a clnR mutant indicate that ClnR is a pleiotropic regulator that directly binds to LL-37 and controls expression of numerous genes, including many involved in metabolism, cellular transport, signaling, gene regulation, and pathogenesis. The data suggest that ClnRAB is a novel regulatory mechanism that senses LL-37 as a host signal and regulates gene expression to adapt to the host intestinal environment during infection.