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

Clostridium difficile is a major nosocomial pathogen that causes severe diarrheal disease. Though C. difficile is known to inhabit the human gastrointestinal tract, the mechanisms that allow this pathogen to adapt to the intestine and survive host defenses are not known. In this work, we investigated the response of C. difficile to the host defense peptide, LL-37, to determine the mechanisms underlying host adaptation and survival. Expression analyses revealed a previously unknown locus, which we named clnRAB, that is highly induced by LL-37 and acts as a global regulator of gene expression in C. difficile. Mutant analyses indicate that ClnRAB is a novel regulatory system that senses LL-37 as a host signal to regulate adaptation to the intestinal environment. Strain 630∆erm without LL-37 served as the control strain. Expression in 630∆erm with LL-37 and expression in the clnR mutant without LL-37 were compared to this control strain. Expression in the clnR mutant with LL-37 was compared to 630∆erm with LL-37. Two independent replicates are included.