Immune Cell Signaling in Feline Infectious Peritonitis Virus Infection and Implications for Vaccine Design.

Feline infectious peritonitis virus (FIPV) remains one of the most challenging viral diseases in veterinary medicine, largely owing to the absence of a consistently effective and safe vaccine. Despite widespread feline coronavirus infection, only a subset of infected cats progresses to feline infectious peritonitis, indicating that host immune responses are key determinants of disease outcomes. Accumulating evidence indicates that disease severity is driven not only by viral replication but also by macrophage- and monocyte-centered immune signaling, leading to excessive inflammation and systemic immunopathology in the host. Previous vaccine approaches against FIPV have failed to provide consistent protection and, in some cases, have been associated with enhanced disease. These outcomes suggest that vaccine-induced immune responses that recapitulate pathogenic signaling patterns may exacerbate disease rather than confer protection. In this review, we discuss the current knowledge of immune cell signaling pathways implicated in FIPV infection, including innate sensing through Toll-like receptors, downstream mitogen-activated protein kinases and NF-κB signaling, cytokine production profiles, Fc receptor-associated processes, and intracellular pathways such as autophagy, and how these mechanisms shape vaccine-induced immunity. By integrating insights from immune signaling kinetics, antibody functionality, adjuvant-driven pathway engagement, and platform-specific immune signatures, this review emphasizes the need to reframe FIPV vaccine development strategies that actively shape host immune responses. Rather than maximizing immunogenicity, successful vaccine design is likely to depend on limiting sustained macrophage activation and pro-inflammatory cytokine amplification while supporting antiviral immune functions, thereby reducing the risk of antibody-dependent enhancement and immunopathology. Beyond feline diseases, these considerations provide broader lessons for vaccine design in settings where immune-mediated pathology contributes to disease severity.