Integration of metabolism and virulence in Clostridium difficile

Bouillaut, Laurent; Dubois, Thomas; Sonenshein, Abraham L.; Dupuy, Bruno

doi:10.1016/j.resmic.2014.10.002

Cited by 105 publications

(131 citation statements)

References 87 publications

(140 reference statements)

Supporting

Mentioning

128

Contrasting

Unclassified

Order By: Relevance

“…Toxin expression in C. difficile is affected by multiple regulatory factors that integrate complex cellular nutritional signals to control nutrient acquisition and motility (37). TcdA and TcdB are directly transcribed by the toxin-specific sigma factor TcdR, which in turn is transcribed by the motility sigma factor SigD (FliA) (38)(39)(40).…”

Section: Deletion Of Cd1492 Results In Decreased Virulence In An Animmentioning

confidence: 99%

The Phosphotransfer Protein CD1492 Represses Sporulation Initiation in Clostridium difficile

et al. 2016

View full text Add to dashboard Cite

The formation of spores is critical for the survival of Clostridium difficile outside the host gastrointestinal tract. Persistence of C. difficile spores greatly contributes to the spread of C. difficile infection (CDI), and the resistance of spores to antimicrobials facilitates the relapse of infection. Despite the importance of sporulation to C. difficile pathogenesis, the molecular mechanisms controlling spore formation are not well understood. The initiation of sporulation is known to be regulated through activation of the conserved transcription factor Spo0A. Multiple regulators influence Spo0A activation in other species; however, many of these factors are not conserved in C. difficile and few novel factors have been identified. Here, we investigated the function of a protein, CD1492, that is annotated as a kinase and was originally proposed to promote sporulation by directly phosphorylating Spo0A. We found that deletion of CD1492 resulted in increased sporulation, indicating that CD1492 is a negative regulator of sporulation. Accordingly, we observed increased transcription of Spo0A-dependent genes in the CD1492 mutant. Deletion of CD1492 also resulted in decreased toxin production in vitro and in decreased virulence in the hamster model of CDI. Further, the CD1492 mutant demonstrated effects on gene expression that are not associated with Spo0A activation, including lower sigD and rstA transcription, suggesting that this protein interacts with factors other than Spo0A. Altogether, the data indicate that CD1492 negatively affects sporulation and positively influences motility and virulence. These results provide further evidence that C. difficile sporulation is regulated differently from that of other endospore-forming species.

show abstract

Section: Deletion Of Cd1492 Results In Decreased Virulence In An Animmentioning

confidence: 99%

The Phosphotransfer Protein CD1492 Represses Sporulation Initiation in Clostridium difficile

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Our in vivo experiments suggest a link between toxin expression and sporulation in C. difficile VPI 10463. Since there is a strong relationship between C. difficile metabolism and virulence, defining differences between the microbial and metabolic environment in the ileum and cecum may be important for elucidating virulence signals (27).…”

Section: Discussionmentioning

confidence: 99%

Dynamics and Establishment of Clostridium difficile Infection in the Murine Gastrointestinal Tract

et al. 2015

View full text Add to dashboard Cite

Clostridium difficile infection (CDI) following antibiotic therapy is a major public health threat. While antibiotic disruption of the indigenous microbiota underlies the majority of cases of CDI, the early dynamics of infection in the disturbed intestinal ecosystem are poorly characterized. This study defines the dynamics of infection with C. difficile strain VPI 10463 throughout the gastrointestinal (GI) tract using a murine model of infection. After inducing susceptibility to C. difficile colonization via antibiotic administration, we followed the dynamics of spore germination, colonization, sporulation, toxin activity, and disease progression throughout the GI tract. C. difficile spores were able to germinate within 6 h postchallenge, resulting in the establishment of vegetative bacteria in the distal GI tract. Spores and cytotoxin activity were detected by 24 h postchallenge, and histopathologic colitis developed by 30 h. Within 36 h, all infected mice succumbed to infection. We correlated the establishment of infection with changes in the microbiota and bile acid profile of the small and large intestines. Antibiotic administration resulted in significant changes to the microbiota in the small and large intestines, as well as a significant shift in the abundance of primary and secondary bile acids. Ex vivo analysis suggested the small intestine as the site of spore germination. This study provides an integrated understanding of the timing and location of the events surrounding C. difficile colonization and identifies potential targets for the development of new therapeutic strategies.C lostridium difficile infection (CDI) is the most common cause of health care-associated infectious diarrhea and colitis. CDI results in upwards of 14,000 deaths annually and $4.8 billion in excess health care costs in the United States (1). C. difficile is a Gram-positive, anaerobic, spore-forming bacterium that produces toxins that inactivate Rho family GTPases, resulting in a loss of epithelial barrier function, mucosal inflammation, and intestinal damage (2). Individuals infected with C. difficile exhibit clinical manifestations that can range from mild diarrhea to toxic megacolon and death (2).CDI is initiated by transmission of the environmentally stable spore form of the pathogen. To establish infection, the spore must germinate following interactions with small molecule germinants, which are primarily bile acids (3). After germination, a productive infection will result in vegetative growth of the pathogen, which then produces toxin, resulting in colitis. Thus, CDI results when C. difficile spores encounter an intestinal environment that supports all of the aspects of C. difficile physiology. The use of antibiotics is a primary risk factor for developing CDI due to loss of the protective effects of the gut microbiota, deemed colonization resistance (4-6).The loss of colonization resistance against CDI results in an environment that allows for C. difficile germination and growth. How the gut microbiota mediates coloniza...

show abstract

“…C. difficile can oxidatively deaminate and decarboxylate amino acids in Stickland metabolism to generate ATP and NADH (52). In this manner, NADH accumulates and must be reduced to NAD ϩ .…”

Section: Growth-promoting Germinantsmentioning

confidence: 99%

Germinants and Their Receptors in Clostridia

2016

View full text Add to dashboard Cite

Many anaerobic spore-forming clostridial species are pathogenic, and some are industrially useful. Although many are strict anaerobes, the bacteria persist under aerobic and growth-limiting conditions as multilayered metabolically dormant spores. For many pathogens, the spore form is what most commonly transmits the organism between hosts. After the spores are introduced into the host, certain proteins (germinant receptors) recognize specific signals (germinants), inducing spores to germinate and subsequently grow into metabolically active cells. Upon germination of the spore into the metabolically active vegetative form, the resulting bacteria can colonize the host and cause disease due to the secretion of toxins from the cell. Spores are resistant to many environmental stressors, which make them challenging to remove from clinical environments. Identifying the conditions and the mechanisms of germination in toxin-producing species could help develop affordable remedies for some infections by inhibiting germination of the spore form. Unrelated to infectious disease, spore formation in species used in the industrial production of chemicals hinders the optimum production of the chemicals due to the depletion of the vegetative cells from the population. Understanding spore germination in acetone-butanol-ethanol-producing species can help boost the production of chemicals, leading to cheaper ethanol-based fuels. Until recently, clostridial spore germination is assumed to be similar to that of Bacillus subtilis. However, recent studies in Clostridium difficile shed light on a mechanism of spore germination that has not been observed in any endospore-forming organisms to date. In this review, we focus on the germinants and the receptors recognizing these germinants in various clostridial species.

show abstract

Integration of metabolism and virulence in Clostridium difficile

Cited by 105 publications

References 87 publications

The Phosphotransfer Protein CD1492 Represses Sporulation Initiation in Clostridium difficile

The Phosphotransfer Protein CD1492 Represses Sporulation Initiation in Clostridium difficile

Dynamics and Establishment of Clostridium difficile Infection in the Murine Gastrointestinal Tract

Germinants and Their Receptors in Clostridia

Contact Info

Product

Resources

About