The host immune response affects pathogen virulence in
Clostridium difficile infection (CDI). Thus,
cytokine responses to CDI likely are associated with disease initiation and progression. Understanding the molecular drivers of
inflammation and
biochemical markers of disease severity is important for developing novel
therapies and predicting disease prognosis. In this study, we investigated
cytokine production in patients with CDI and evaluated the potential of
cytokines to serve as
biomarkers for CDI and predictors of disease severity. The systemic
cytokine profiles of 36 CDI patients (20 with severe disease) and 8 healthy donors and the toxin-induced
cytokine profiles of peripheral blood mononuclear cells (PBMC) were determined. Further, we evaluated
glucosyltransferase (GT) activity in regulation of toxin-induced
cytokine expression. We found upregulation of the majority of measured
cytokines (11/20, 55%) in CDI patients. Interleukin-1β (IL-1β),
IL-6,
IL-8,
IL-17A, and
IL-16 were the most upregulated. High serum levels of
IL-2 and
IL-15 were associated with a poor prognosis in CDI patients, whereas high levels of
IL-5 and
gamma interferon (IFN-γ) were associated with less severe disease. Both TcdA and
TcdB were potent inducers of
cytokine responses, as demonstrated by stimulation of a greater number and amount of
cytokines. In addition to confirming prior reports on the role of
IL-8, IL-1β, and
IL-6 in CDI, our data suggest that
IL-16 and
IL-17A, as well as the IL-1β/Th17 axis, play a key role in driving inflammatory responses in CDI. A functional GT domain of C. difficile toxins was required for the induction of a majority of
cytokines investigated.