Abstract
The Gram-positive, spore-forming pathogen Clostridium difficile is the leading definable cause of healthcare-associated diarrhea worldwide. C. difficile infections are difficult to treat because of their frequent recurrence, which can cause life-threatening complications such as pseudomembranous colitis. The spores of C. difficile are responsible for these high rates of recurrence, since they are the major transmissive form of the organism and resistant to antibiotics and many disinfectants. Despite the importance of spores to the pathogenesis of C. difficile, little is known about their composition or formation. Based on studies in Bacillus subtilis and other Clostridium spp., the sigma factors σF, σE, σG, and σK are predicted to control the transcription of genes required for sporulation, although their specific functions vary depending on the organism. In order to determine the roles of σF, σE, σG, and σK in regulating C. difficile sporulation, we generated loss-of-function mutations in genes encoding these sporulation sigma factors and performed RNA-Sequencing to identify specific sigma factor-dependent genes. This analysis identified 224 genes whose expression was collectively activated by sporulation sigma factors: 183 were σF-dependent, 169 were σE-dependent, 34 were σG-dependent, and 31 were σK-dependent. In contrast with B. subtilis, C. difficile σE was dispensable for σG activation, σG was dispensable for σK activation, and σF was required for post-translationally activating σG. Collectively, these results provide the first genome-wide transcriptional analysis of genes induced by specific sporulation sigma factors in the Clostridia and highlight that diverse mechanisms regulate sporulation sigma factor activity in the Firmicutes.
Highlights
Clostridium difficile is a Gram-positive, spore-forming, obligate anaerobe that causes gastrointestinal diseases including diarrhea, pseudomembranous colitis, and toxic megacolon [1,2,3]
While C. difficile is best known for causing hospitalacquired antibiotic-associated infections, recent epidemiologic studies indicate that community-acquired C. difficile infections are increasingly more common and associated with significant morbidity [6,7]
Since spores are resistant to most disinfectants and antibiotics, C. difficile infections frequently recur and are spread
Summary
Clostridium difficile is a Gram-positive, spore-forming, obligate anaerobe that causes gastrointestinal diseases including diarrhea, pseudomembranous colitis, and toxic megacolon [1,2,3]. C. difficile infections and C. difficile-related deaths have risen dramatically in the past decade, increasing the financial burden on health care systems [4,5,6,7]. While C. difficile is best known for causing hospitalacquired antibiotic-associated infections, recent epidemiologic studies indicate that community-acquired C. difficile infections are increasingly more common and associated with significant morbidity [6,7]. Spores are resistant to most disinfectants and antibiotics, making them difficult to eliminate both from infected humans and the environment [1,2,8]. C. difficile spores disseminate readily from person to person and cause high rates of recurrent infections, which can lead to serious illness or even death [1,2,3,9]
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