Clostridium difficile causes severe diarrheal disease that results in billions of dollars per year in increased health care costs and more than 20,000 deaths annually in the United States. In the past decade, an epidemic strain has emerged (NAP1/B1/ribotype 027, toxinotype III) that is associated with a significant increase in morbidity and mortality. The incidence of C. difficile """"""""027"""""""" epidemic infections has increased at an alarming rate in the past 10 years and these infections have spread globally. Infections caused by this strain have lower cure rates and higher rates of relapsing disease than infections caused by other C. difficile isolates. Despite the predominance of 027 epidemic isolates, we do not know what properties of this lineage have enabled the rapid ascent of this strain. The long-term goal of this project is to determine how epidemic isolates of C. difficile proliferate in the host so that new approaches for preventing and treating infections can be identified. Based on our data, we hypothesize that epidemic C. difficile are more pervasive because they more successfully survive the effects of antimicrobial peptides (AMPs), allowing them to colonize and replicate better in the intestine. The specific objective of this application is to identify the genetic mechanisms in 027 epidemic C. difficile that confer increased AMP resistance in the host. Capitalizing on our previous experience with C. difficile antimicrobial peptide resistance, we will meet this objective through the experiments detailed in two specific aims. First, we will reveal the genetic mechanisms of AMP resistance in epidemic C. difficile strains through genetic analysis of mutants defective in AMP resistance. Next, we will determine the contribution of AMP resistance mechanisms to colonization and infection by epidemic isolates. The expected contribution of the proposed research is the identification of genetic mechanisms in 027 epidemic strains of C. difficile that confer increased antimicrobial peptide resistance compared to non-epidemic strains. This contribution is significant because it is the first step in understanding how the increased antimicrobial peptide resistance of 027 epidemic strains influences the spread of this important pathogen.

Public Health Relevance

The experiments in this proposal are designed to uncover the mechanisms used by epidemic strains of Clostridium difficile to resist antimicrobial peptides in the host. The project is relevant to the NIH's mission of understanding and preventing bacterial infections and digestive diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Small Research Grants (R03)
Project #
1R03DK101870-01
Application #
8684103
Study Section
Digestive Diseases and Nutrition C Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2014-02-01
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Emory University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Woods, Emily C; McBride, Shonna M (2017) Regulation of antimicrobial resistance by extracytoplasmic function (ECF) sigma factors. Microbes Infect 19:238-248
Ghose, Chandrabali; Eugenis, Ioannis; Sun, Xingmin et al. (2016) Immunogenicity and protective efficacy of recombinant Clostridium difficile flagellar protein FliC. Emerg Microbes Infect 5:e8
Edwards, Adrianne N; Tamayo, Rita; McBride, Shonna M (2016) A novel regulator controls Clostridium difficile sporulation, motility and toxin production. Mol Microbiol 100:954-71
Edwards, Adrianne N; Karim, Samiha T; Pascual, Ricardo A et al. (2016) Chemical and Stress Resistances of Clostridium difficile Spores and Vegetative Cells. Front Microbiol 7:1698
Nawrocki, Kathryn L; Edwards, Adrianne N; Daou, Nadine et al. (2016) CodY-Dependent Regulation of Sporulation in Clostridium difficile. J Bacteriol 198:2113-30
Childress, Kevin O; Edwards, Adrianne N; Nawrocki, Kathryn L et al. (2016) The Phosphotransfer Protein CD1492 Represses Sporulation Initiation in Clostridium difficile. Infect Immun 84:3434-3444
Ghose, Chandrabali; Eugenis, Ioannis; Edwards, Adrianne N et al. (2016) Immunogenicity and protective efficacy of Clostridium difficile spore proteins. Anaerobe 37:85-95
Woods, Emily C; Nawrocki, Kathryn L; Suárez, Jose M et al. (2016) The Clostridium difficile Dlt Pathway Is Controlled by the Extracytoplasmic Function Sigma Factor ?V in Response to Lysozyme. Infect Immun 84:1902-16
Edwards, Adrianne N; Pascual, Ricardo A; Childress, Kevin O et al. (2015) An alkaline phosphatase reporter for use in Clostridium difficile. Anaerobe 32:98-104
Bouillaut, Laurent; McBride, Shonna; Sorg, Joseph A et al. (2015) Effects of surotomycin on Clostridium difficile viability and toxin production in vitro. Antimicrob Agents Chemother 59:4199-205

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