Beyond macrophages: FIPV tropism includes T and B lymphocytes

If untreated, feline infectious peritonitis (FIP) is a fatal disease that is caused by feline infectious peritonitis virus (FIPV), a virulent biotype of feline coronavirus (FCoV) that disseminates broadly and triggers severe systemic inflammation. While the prevailing model holds that FIPV selectively infects monocytes/macrophages, the full range of susceptible cell types and the mechanisms of immune cell invasion remain poorly defined. Here, we applied single-cell RNA sequencing, multiplex immunofluorescence, and in situ hybridization to mesenteric lymph node aspirates and formalin fixed and paraffin embedded lymph node tissues from cats with naturally occurring effusive FIP. We identified FIPV RNA and nucleocapsid protein in T and B lymphocytes and myeloid cells, and subgenomic viral RNA in T cells, demonstrating cell entry and viral genomic replication across multiple immune compartments. Rare FIPV RNA–positive lymphocytes persisted after antiviral treatment cessation and resolution of clinical signs. These findings revise current models of FIPV pathogenesis and reveal new insights into coronavirus-driven immune dysregulation, viral persistence, and relapse. Our study highlights the utility of FIP as a naturally occurring animal model for exploring adaptive immune cell infection in coronavirus diseases, providing a translational platform for understanding virus–host interactions that drive chronic or relapsing immunopathology. • Current models of FIP pathogenesis posit that FIPV is restricted to monocytes and macrophages; we confirm this tropism and provide additional evidence of viral entry into lymphocytes. • Single-cell RNA sequencing and confocal immunofluorescence methods identified FIPV RNA and nucleocapsid protein in T and B lymphocytes from cats with effusive FIP. • Subgenomic FIPV RNA, indicative of active viral RNA synthesis, was detected in CD3⁺ T cells via BaseScope in situ hybridization. • FIPV RNA–positive lymphocytes exhibited heightened interferon-stimulated gene expression signatures, supporting a biologically active antiviral response. • Rare lymphocytes harboring FIPV RNA persisted in lymph nodes after antiviral treatment, suggesting possible immune cell–associated viral persistence despite clinical resolution.