Historically, the majority of feline infectious peritonitis (FIP) cases have been caused by feline coronavirus type 1 (FCoV-1) as opposed to feline coronavirus type II (FCoV-2). FCoV-2’s can be thought of as rare in nature, as an individual strain arises from a recombination event between a canine coronavirus type 2 (CCoV-2) and an FCoV- 1. FCoV-2 remains poorly characterized in terms of its medical outcomes and pathogenesis, yet it was the causative agent of a severe outbreak of feline infectious peritonitis (FIP) in Cyprus in 2023. During this epizootic, cats were developing FIP at an alarming rate, with abnormally fast rates of disease progression, cats were developing FIP just days or weeks after infection. Thousands of infected cats were dying, despite antiviral treatment being administered. This outbreak, caused by a novel FCoV-2 variant designated as “FCoV-23”, resulted in the deaths of thousands of cats and represented a unique large-scale event of aggressive fatal FIP cases. Genomic analysis revealed that the spike (S) protein of FCoV-23 exists in two distinct forms: a full-length “long S” and a truncated “short S” form in which all or part of the zero domain is deleted. The zero-domain deletion has been associated with markedly increased fusogenicity in multiple feline cell lines and shortened incubation times, suggesting an enhanced capacity for viral spread. The Whittaker Lab has identified additional FCoV-2 isolates containing this zero-domain deletion, though no functional or in vitro host-range studies have yet been conducted. I hypothesize that FCoV-1 and FCoV-2 differ in their pathogenesis of FIP, with the presence or deletion of the zero domain contributing to these differences. Specifically, I predict that FCoV-2 will display distinct tissue tropism and infection dynamics compared to FCoV-1. To test these hypotheses, I will generate pseudo-particles bearing the naturally occurring long and short forms of the S protein and perform in vitro cell-based assays to measure fusogenicity and infection kinetics. Additionally, I will assess tissue tropism through immunohistochemistry of tissues harvested from naturally infected cats to identify the distribution and cellular targets of FCoV-2 variants.