Clostridium difficile infection (CDI) is a significant cause of morbidity and mortality. Disease related to CDI ranges from asymptomatic colonization to mild diarrheal disease to severe pseudomembranous colifis. Despite the extensive characterizafion of the histologic lesions associated with C. difficile infection, virtually nothing is known mechanistically about the contribution of host factors in disease. It is likely that some of the clinical differences encountered in infected individuals are due to variafion in host response to colonization with C. difficile. We hypothesize that variation in the host innate and adaptive responses for C. difficile are in part responsible for the different clinical phenotypes that are seen in the setting of CDI. Furthermore, we speculate that these variable responses reflect underiying genetic and possibly epigenetic differences in the host. To address these hypotheses we propose the following specific aims: In the first aim we will characterize the innate and adaptive immune response to C. difficile colonization and determine the role of this response in determining the disease manifestations. In the second aim we will identify serum fecal biomarkers and epigenetic changes that correlate distinct clinical outcomes.
This aim will examine samples obtained from the Project area #1 for this purpose.
The third aim will examine the interaction between host genetics/immune response and C. difficile genotype in the pathogenesis of disease. Mice with defined differences in host response will be challenged with C. difficile strains generated and characterized from the human studies in Project area #1. This will provide an examinafion ofthe relative contribution of host and pathogen factors in disease. These experiments will increase our understanding ofthe host and microbial mechanisms of C. d/Wc/Ve-induced colonic inflammation vs. asymptomatic colonization and identify biomarkers that can be used to improve clinical treatments and outcomes.
Clostridium difficile infection is associated with the development of severe inflammation ofthe large intestine, resulting in signiflcant morbidity and mortality. Our objective is to understand the mechanisms of this inflammation and identify biomarkers that can be used to improve clinical treatments and outcomes.
|Ulrich, Robert J; Santhosh, Kavitha; Mogle, Jill A et al. (2017) Is Clostridium difficile infection a risk factor for subsequent bloodstream infection? Anaerobe 48:27-33|
|Dahl, Jan-Ulrik; Gray, Michael J; Bazopoulou, Daphne et al. (2017) The anti-inflammatory drug mesalamine targets bacterial polyphosphate accumulation. Nat Microbiol 2:16267|
|Chen, Liang; Wilson, Justin E; Koenigsknecht, Mark J et al. (2017) NLRP12 attenuates colon inflammation by maintaining colonic microbial diversity and promoting protective commensal bacterial growth. Nat Immunol 18:541-551|
|McDermott, Andrew J; Falkowski, Nicole R; McDonald, Roderick A et al. (2017) Role of interferon-? and inflammatory monocytes in driving colonic inflammation during acute Clostridium difficile infection in mice. Immunology 150:468-477|
|Rogers, M A M; Aronoff, D M (2016) The influence of non-steroidal anti-inflammatory drugs on the gut microbiome. Clin Microbiol Infect 22:178.e1-178.e9|
|Seekatz, Anna Maria; Rao, Anna Maria; Santhosh, Kavitha et al. (2016) Dynamics of the fecal microbiome in patients with recurrent and nonrecurrent Clostridium difficile infection. Genome Med 8:47|
|Leslie, Jhansi L; Young, Vincent B (2016) A whole new ball game: Stem cell-derived epithelia in the study of host-microbe interactions. Anaerobe 37:25-8|
|Theriot, Casey M; Bowman, Alison A; Young, Vincent B (2016) Antibiotic-Induced Alterations of the Gut Microbiota Alter Secondary Bile Acid Production and Allow for Clostridium difficile Spore Germination and Outgrowth in the Large Intestine. mSphere 1:|
|Young, V B (2016) Therapeutic manipulation of the microbiota: past, present, and considerations for the future. Clin Microbiol Infect 22:905-909|
|Rao, Krishna; Santhosh, Kavitha; Mogle, Jill A et al. (2016) Elevated fecal calprotectin associates with adverse outcomes from Clostridium difficile infection in older adults. Infect Dis (Lond) 48:663-9|
Showing the most recent 10 out of 84 publications