Type 2 immunity in Clostridioides difficile infection

The role of type 2 immunity in protection against C. difficile infection (CDI) has recently become better appreciated, prompting further exploration into mechanistic underpinnings of host response to infection. Though it is known that abundance of type 2 effector cells negatively correlates with CDI severity in mice and humans and that experimental treatment with those effectors or type 2-promoting cytokines protects against severe disease, the underlying signaling pathways and downstream functions of effector cells remain unclear. Group 2 innate lymphoid cells (ILC2s), eosinophils, and alternatively activated macrophages (AAMs) have been identified as mediators of type 2 protection in CDI. ILC2s have been the most well-characterized thus far, as their stimulation by type 2 alarmins induces downstream effects on immune and epithelial cell processes. Eosinophils may contribute to enhanced tissue repair, immunomodulation, or antimicrobial effects during CDI, but their functional roles have not yet been defined. Alternatively activated macrophages may also contribute to tissue repair, though more mechanistic work must be performed to determine this. In this mini-review, we summarize existing knowledge of type 2-mediated protection in CDI and identify open areas of research and potential cells and signaling molecules of interest for future functional and mechanistic interrogation. Given the demonstrated importance of type 2 immunity in human and experimental CDI, these studies will be essential in the development of immunotherapeutic interventions for acute and recurrent CDI.