Feline infectious peritonitis (FIP) is a lethal systemic infection in cats, caused by a feline coronavirus (FCoV). Infection by FCoV normally causes mild and often inapparent enteritis, in which case the virus is referred to as feline enteric coronavirus (FECV). In the “internal mutation” model of FIP, it is believed that a process of mutation within an individual cat confers the ability of FECV to infect macrophages, and so become feline infectious peritonitis virus (FIPV) – the virus that causes FIP. However, there has been little experimental support to date for the internal mutation theory of FIPV. This researcher has previously shown that the FCoV spike protein is differentially processed by host cell proteases, which leads to acquisition of a hyper-fusogenic spike protein and confers the ability of the virus to infect macrophages – and so initiate the process of FIP. This project will extend these studies to examine how differential cleavage impacts the entry process of the virus in various cell types (epithelial cells, monocytes, macrophages and dendritic cells), and how this connects to usage of the different FCoV receptors (fAPN, Fc, DC-SIGN). The overall goal is to determine the molecular changes that account for the acquisition of an FIP phenotype by feline coronaviruses.