Differential induction of PD-L1 expression in cells infected with feline infectious peritonitis virus and feline enteric coronavirus.

Abstract

Feline infectious peritonitis (FIP) is a fatal systemic disease of cats, which is caused by FIP virus (FIPV), a virulent biotype of feline coronavirus (FCoV). In a small number of cats infected with feline enteric coronavirus (FECV), virus mutation may emerge that enable infection of monocytes and macrophages, leading to the development of FIP. This cell tropism shift, along with impaired T cell response, plays a critical role in FIP development. Programmed cell death protein (PD-1) and its ligands (PD-L1 and PD-L2) play crucial roles in immune responses as an immune checkpoint system. The PD-1 axis downregulates T cell response and is reported to be involved in immune evading mechanisms of various viruses. In this study, we used two virus strains FIPV-1146 and FECV-1683 corresponding to FIPV and FECV biotypes, respectively, to study the role of PD-L1 expression as a potential mechanism for FIP development. While both viruses demonstrated robust viral replication at comparable levels, FIPV-1146, but not FECV-1683, significantly upregulated PD-L1 expression in CRFK and and Fcwf-4 cells. Infection of Fcwf-4 cells with FIPV-Black strain also increased PD-L1 levels. Co-culture studies using Jurkat cells and Fcwf-4 cells infected with FIPV-1146 or FECV-1683 showed that PD-L1 induction by FIPV-1146 attenuated T cell activation. The cell signaling profiling assays showed that FIPV-1146, but not FECV-1683, induced the type I IFN synthesis, which is a well-known regulator for PD-L1 expression. The elevated PD-L1 levels by FIPV may lead to dampened T cell response, allowing persistent infection in macrophages and development of the FIP clinical disease.