Sunday, December 22, 2024
12/22/2024
PROJECT SUMMARY The overall goal of this application is to better understand and harness group 3 innate lymphocyte (ILC3) biology to enhance mucosal immune responses to Clostridioides difficile infection (CDI). We lack fully effective treatments for this pathogen and there is critical need to better understand how C. difficile interacts with our immune system. ILC3s are rare immune cells localized within mucosal tissues that help protect against bacterial infections, including C. difficile. Upon activation, ILC3s secrete high levels of the cytokine interleukin-22 (IL-22) which is a critical regulator of tissue responses during inflammation. Our recent published study shows that a major virulence factor of C. difficile, toxin B (TcdB), directly activates ILC3s. Furthermore, work from others has shown that administration of recombinant IL-22 provides protection in a mouse CDI model suggesting that boosting the cytokine over its naturally produced levels during infection could aid CDI patients. Therefore, we are investigating the molecular pathways in ILC3s important for activation to identify novel pathways to enhance function. One family of pathways of great interest is cellular metabolism. Our preliminary data show that polyamines positively regulate TcdB-mediated activation of ILC3s. Polyamine levels are increased in activated ILC3s and when the key biosynthesis enzyme is inhibited, ILC3s produce less IL-22. Polyamines are important in transcription and translation, have important roles in activation of other immune cells and have yet to be fully investigated in ILC3s. The central hypothesis is that polyamine biology is important for ILC3 activation, and polyamines can be leveraged for improving outcomes to C. difficile infection and/or recurrence. In this proposal we will examine how a metabolic pathway controls ILC3 activation, which has translatable implications on these immune cells in C. difficile infection. The central hypothesis will be tested by pursuing two specific aims: 1) Determine the mechanism(s) of polyamine function in C. difficile-activated ILC3s and 2) Determine how to leverage polyamine biology in primary and recurrent CDI. Under the first aim, we will undertake targeted and untargeted approaches to determine the cellular pathway(s) that polyamines target in C. difficile-mediated ILC3 activation. The second aim will test how polyamines can be targeted in vivo to boost the innate immune response and thereby prevent or reduce CDI severity in primary or recurrent disease. Upon completion of these aims, the expected outcomes are two-fold as we will (1) gain an understanding of fundamental immunology of how polyamines regulate ILC3 activation and (2) determine the translatable potential of how polyamines can be leveraged during CDI to boost immunity. These results will have a positive impact on our understanding of immune responses to C. difficile as they will provide strong evidence-based rationale for further development of ILC3 and IL-22 biology targeted therapies for CDI patients.
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