Clostridium difficile is a toxin-producing bacterium that is a frequent cause of hospital-acquired and antibiotic-associated diarrhea. The incidence and severity of C. difficile infection (CDI) are increasing, in parallel with increases in community-acquired infections, making CDI a major public health problem. Following inoculation, patients may clear C. difficile from their intestinal tract, become asymptomatically colonized, or develop CDI, ranging in severity from mild diarrhea to fulminant colitis and/or death. Older adults are disproportionately affected by CDI, experiencing greater morbidity and mortality. Antibiotics treat CDI, but refractory disease and relapses occur. Major gaps exist in our understanding ofthe host and microbial factors that determine the outcome of human contact with C. difficile. The broad objective of this ERIN CRC is to develop innovative approaches to the diagnosis, prevention, and treatment of CDI based on understanding the molecular mechanisms of disease. The goals of this Proiect are to use genomic information obtained from clinical C. difficile strains, to identify microbial determinants of infection and develop a rapid, high-throughput assay to predict the clinical behavior of individual C. difficile strains. We hypothesize that there is a genomic basis for the different clinical presentations of C. difficile (colonization, mild or severe infection, and relapse) in susceptible hosts.
The Specific Aims of this proposal seek to: (1) Establish a collection of isolates that spans the genetic diversity of C. difficile associated with both asymptomatically colonized adults and those with initial and recurrent infection;(2) Perform a comparative phylogenomic analysis of representative C. difficile isolates obtained from Aim 1;and (3) Develop a high-throughput single nucleotide polymorphism (SNP) typing system for the rapid discrimination and risk-assessment ofC. difficile infection. This project will collect clinicoepidemiological data, biological specimens and C. difficile strains, which will be used in all three major projects of this ERIN.
Clostridium difficile is a common cause of antibiotic-associated and hospital-associated diarrhea. It is an emerging pathogen that is highly transmissible and opportunistic, imposing a significant burden on global health and healthcare resources. The best method to control the spread of CDI is to better understand its pathogenesis. These studies will provide an important foundation for developing more accurate diagnostic, preventive, and therapeutic regimens against this important problem.
|Kopliku, Fatos A; Schubert, Alyxandria M; Mogle, Jill et al. (2015) Low prevalence of Clostridium septicum fecal carriage in an adult population. Anaerobe 32:34-6|
|Leslie, Jhansi L; Young, Vincent B (2015) The rest of the story: the microbiome and gastrointestinal infections. Curr Opin Microbiol 23:121-5|
|Seekatz, Anna M; Young, Vincent B (2014) Clostridium difficile and the microbiota. J Clin Invest 124:4182-9|
|Islam, J; Taylor, A L; Rao, K et al. (2014) The role of the humoral immune response to Clostridium difficile toxins A and B in susceptibility to C. difficile infection: a case-control study. Anaerobe 27:82-6|
|Rao, Krishna; Young, Vincent B; Aronoff, David M (2014) Fecal microbiota therapy: ready for prime time? Infect Control Hosp Epidemiol 35:28-30|
|Theriot, Casey M; Koenigsknecht, Mark J; Carlson Jr, Paul E et al. (2014) Antibiotic-induced shifts in the mouse gut microbiome and metabolome increase susceptibility to Clostridium difficile infection. Nat Commun 5:3114|
|El-Zaatari, Mohamad; Chang, Yu-Ming; Zhang, Min et al. (2014) Tryptophan catabolism restricts IFN-?-expressing neutrophils and Clostridium difficile immunopathology. J Immunol 193:807-16|
|Huang, A M; Marini, B L; Frame, D et al. (2014) Risk factors for recurrent Clostridium difficile infection in hematopoietic stem cell transplant recipients. Transpl Infect Dis 16:744-50|
|Schloss, Patrick D; Iverson, Kathryn D; Petrosino, Joseph F et al. (2014) The dynamics of a family's gut microbiota reveal variations on a theme. Microbiome 2:25|
|Marino, Simeone; Baxter, Nielson T; Huffnagle, Gary B et al. (2014) Mathematical modeling of primary succession of murine intestinal microbiota. Proc Natl Acad Sci U S A 111:439-44|
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