Grant: Project Grant

Clostridium difficile infection (CDI) is the leading cause of hospital-acquired diarrhea in developed countries and a major source of morbidity, mortality, and health care costs. CDI classically develops following ingestion of spores spread from other patients (usually in the health care setting) plus antibiotic treatment, which depletes normal bacteria in the gut, although community-acquired cases and cases without preceding antibiotics are becoming more common. Illness due to C. difficile is caused by two toxins, TcdA and TcdB, with the latter likely more pathogenic in patients. Even though CDI can be successfully treated with specific antibiotics as many as 30% of people develop spontaneous relapses, where the symptoms return after treatment. Each relapse raises the risk of subsequent relapses, and sometimes patients can only be cured by fecal microbial therapy (FMT or "stool transplant"). It remains impossible to accurately predict relapsing CDI, and as a result newer, expensive treatments that can reduce relapse risk are seldom utilized. The immune system probably plays an important role in helping people recover from CDI. Naturally occurring antibodies against TcdA and TcdB are predicted to protect against infection and relapse, but studies examining this effect have been inconsistent. Moreover, CD4+ T cells, also known as helper T cells, are required for robust antibody generation, but have never been studied in CDI. In preliminary studies, we have developed a new test that can measure and characterize CD4+ T cells that specifically recognize TcdA and TcdB. Using this test, we have found high levels of TcdB-specific T cells in patients with recurrent CDI. Our goal is to better characterize these cells and compare their function in patients with recurrent versus new-onset CDI, to be able to better predict clinical outcomes in CDI, and help guide the development of new treatments and vaccines for this important illness.