Abstract
Clostridium difficile spores must germinate in vivo to become actively growing bacteria in order to produce the toxins that are necessary for disease. C. difficile spores germinate in vitro in response to certain bile acids and glycine. In other sporulating bacteria, proteins embedded within the inner membrane of the spore sense the presence of germinants and trigger the release of Ca++-dipicolinic acid (Ca++-DPA) from the spore core and subsequent hydrolysis of the spore cortex, a specialized peptidoglycan. Based upon homology searches of known germinant receptors from other spore-forming bacteria, C. difficile likely uses unique mechanisms to recognize germinants. Here, we identify the germination-specific protease, CspC, as the C. difficile bile acid germinant receptor and show that bile acid-mediated germination is important for establishing C. difficile disease in the hamster model of infection. These results highlight the importance of bile acids in triggering in vivo germination and provide the first description of a C. difficile spore germinant receptor. Blocking the interaction of bile acids with the C. difficile spore may represent an attractive target for novel therapeutics.
Highlights
Clostridium difficile infections (CDI) are steadily increasing in the United States and other countries [1,2]
To initiate infection, C. difficile spores must germinate in vivo to actively growing bacteria
We find that mutations in cspC alter the specificity of germinant recognition or abrogate the ability of C. difficile spore to germinate in response to bile acids
Summary
Clostridium difficile infections (CDI) are steadily increasing in the United States and other countries [1,2]. C. difficile spores must germinate to form the actively growing, anaerobic bacteria that produce the two toxins that are necessary for disease (TcdA and TcdB) [4,5,6] These two toxins are secreted by the bacterium where they enter host epithelial cells by receptor-mediated endocytosis and, upon escape into the cytosol, glucosylate members of the Rhofamily of GTPases [7]. The action of these toxins lead to symptoms normally associated with CDI (e.g. diarrhea) and release of C. difficile spores into the environment [8]. In Bacillus subtilis, L-alanine or a mixture of L-asparagine, glucose, fructose and potassium ions triggers germination, while spores of certain strains of Clostridium perfringens initiate germination in response to inorganic phosphate and sodium ions [11]
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