Harnessing the Immune System to Treat C diff Infection
Clostridium difficile (C diff) is a bacterial pathogen that was first identified as the cause of antibiotic-associated diarrhea in the late 1970s.1 Today, C diff causes an estimated 500,000 infections per year and has become the most common hospital-acquired infection in the United States.2 Although community-acquired cases are increasingly common, hospitals and long term care facilities are particularly vulnerable to the spread of C diff, which forms hardy chemical- and oxygen-resistant spores. Patients typically become infected with C diff following antibiotic treatment, which disrupts the healthy bacteria found in the gut that are responsible for out-competing the pathogen and promoting beneficial immune responses. Additional risk factors include age, inflammatory bowel disease, immunosuppression, and use of proton-pump inhibitors.3
C diff spores are transmitted via the fecal-oral route and germinate into actively dividing bacteria upon reaching the intestine. This pathogen produces toxins that are primarily responsible for the symptoms of infection, as nontoxigenic strains are not associated with disease. Symptoms of C diff infection (CDI) range from mild diarrhea to life-threatening pseudomembranous colitis and toxic megacolon. Treatment involves stopping the offending antibiotic that preceded infection and administration of metronidazole or vancomycin, both of which kill C diff. Currently, trials are under way to test fecal microbiota transplantation as a treatment for CDI. Preliminary evidence suggests this approach to restore healthy gut microbiota is effective; however, it is not without risks, as our current understanding of the role of the microbiota in diverse health conditions is limited.4
One of the major challenges to successful CDI management is frequent disease recurrence, as 10% to 35% of infected patients become reinfected following treatment. This is likely complicated by the fact that the very antibiotics used to treat disease may also perpetuate the disruption of healthy gut bacteria. Reinfection frequently involves a second strain of C diff, suggesting that the original treatment effectively eradicates the pathogen but patients remain susceptible to new infection.5 Successful resolution of CDI involves generation of a protective immune response against the bacterium and its toxins, and recurrence has been associated with significantly lower levels of antitoxin antibodies.6 Indeed, the type and intensity of inflammation generated in response to C diff appear to be a crucial determinant of outcome, as recent studies show high levels of the inflammatory cytokines interleukin-8 and chemokine ligand 5 were better predictors of severe disease than C diff burden.7,8
"Hypervirulent" C diff
Ribotype 027 strains demonstrate increased antibiotic resistance, most notably to the fluoroquinolone class of antibiotics, and multiple studies have demonstrated an association between infection with ribotype 027 strains and highly transmissible severe disease with increased rates of recurrence.9-11 However, other studies have failed to find associations between ribotype 027 strains and more severe disease, prompting debate within the field over the classification of the strains as hypervirulent. In fact, the conflicting findings may implicate differences between individual ribotype 027 strains, the environment in which the infection occurs, or other unidentified patient characteristics.
The Binary Toxin C diff Transferase
CDT-positive strains have become increasingly common over the last 15 years, stimulating investigation into the role of this toxin during disease. Evidence exists to show that CDT could enhance adherence of C diff to human cells, suggesting that it may promote the ability of C diff to infect patients.13 However, it was unclear whether or how this toxin could impact the immune response of infected individuals. Because the generation of a healthy immune response to C diff is critical to infection outcome, determining how CDT influences the course of disease and the immune response to infection is critical to understanding its role in disease.
Eosinophils and a Protective Immune Response to CDI
These results agree with previous findings demonstrating the protective capacity of eosinophils during CDI. Indeed, eosinophils appear to be controlled at least in part by the microbiota-regulated signaling molecule interleukin-25, which is able to boost eosinophil responses and protect mice from death due to infection.15 Although it is unclear what beneficial function these cells perform, their capacity to promote tissue healing and antibody production is well known in other contexts and seems to be a promising target.16
New Perspective on Inflammation
This view of infection gives hope to the idea of directing the immune system to treat acute CDI or to prevent disease recurrence in a more targeted fashion, and suggests that including CDT as a target for future vaccines or antibody-based therapies is essential. Although more work is required to demonstrate the feasibility of these approaches, particularly in human studies, these results open promising areas for the development of new treatments for CDI.
— Carrie A. Cowardin, PhD, who completed her doctoral work on the immune response to C diff in the laboratory of William A. Petri, Jr, MD, PhD, at the University of Virginia, is a postdoctoral research associate at Washington University in St. Louis, focused on the communication between gut microbes and the host immune and skeletal systems.
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