The Impact and Regulation of IL-6 in Clostridioides difficile Infection

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Project Summary Clostridioides difficile is a Gram-positive bacterium responsible for more hospital-acquired infections than any other pathogen. C. difficile infection (CDI) manifests in a range of severity from diarrheal illness to death, especially in advanced aged patients. Current therapy for CDI largely relies on antibiotics and, while effective short term, greatly increases the risk for recurrent infection. To address this issue, we look to identify immunomodulatory approaches that spare the protective gut microbial communities. In this proposal I will interrogate the role of IL-6 in CDI disease progression. In preliminary experiments, we found that neutralizing IL-6 worsened disease symptoms in our CDI murine model, suggesting a protective role for IL-6 in CDI. Further, we found that transcription of a neurotransmitter receptor and positive regulator of IL-6, the alpha 2 adrenergic receptor(a2ar), is decreased in severe CDI as compared to mild CDI. Norepinephrine and epinephrine can bind a2ar in immune cells to increase their production of IL-6. Released IL-6 can act through two signaling pathways: trans-signaling and classical signaling. IL-6 trans-signaling typically causes pro-inflammatory effects while classical signaling tends to have anti-inflammatory, regenerative effects. We hypothesize that IL-6 acts through classical signaling to induce epithelial regeneration and, in turn, decrease disease severity in CDI. To test this hypothesis, I will use a murine model of CDI. In Aim 1 I will investigate the role of IL-6 and determine if classical or trans-signaling pathways dictate the effect of IL-6 by monitoring disease severity and inflammatory profile in models deficient in IL-6 activity or stimulated or deficient in trans-signaling. In Aim 2, I will identify the primary cellular source of IL-6 during CDI and determine whether IL-6 production is regulated by catecholamines norepinephrine and epinephrine in this context. Together, these data will allow us to consider the signaling axes and cellular determinants that are potentially targetable in CDI. This work not only has implications for CDI therapy but more broadly, it will allow us to understand the contributing factors to the pleiotropic role of IL-6 in the gut.