Feline Infectious Peritonitis: Role of the Feline Coronavirus 3c gene and the Characterization of Cellular Immune Responses in Experimental Infection

Feline infectious peritonitis (FIP), a fatal infectious disease of cats is one of the most serious threats faced by multiple cat environments. Several theories have emerged on the origin of feline infectious peritonitis virus (FIPV), which is a feline coronavirus (FCoV) and the etiologic agent for FIP. However, strong evidence links FIPV emergence to an 'internal mutation' of the relatively nonpathogenic feline enteric coronavirus (FECV). This mutation was presumed to originate from mutations in the feline coronavirus 3c gene. Our findings revealed an intact 3c gene for isolates of fecal origin of healthy cats, while the 3c gene sequence from FIP-diseased tissues revealed either an intact or a mutated 3c. Regardless of 3c gene sequence, coronaviruses from diseased tissues were capable of inducing FIP whereas fecal isolates from healthy cats were infectious but did not cause FIP thus confirming their FECV status. Also of note, an intact 3c gene is essential for intestinal replication by both biotypes and truncated 3c is not always responsible for the conversion of FECV to FIPV. A previous general assumption on FECV and FIPV cell/tissue tropism was also shown to be relative rather than absolute due to findings showing that FECV is able to infect macrophages but with much less efficiency. Since FIPV and FECV are constantly evolving within and between host cats, care must be taken on the interpretation of FCoV genetic comparisons particularly in the studies involving shelter cats, which usually are infected with many FCoV isolates of different origins.;Specific pathogenic events that arise from conversion of FECV to FIPV in an individual feline host as well as a relationship between these events to host antiviral immune responses, remain to be elucidated. Experimental studies involving cats at either primary or rechallenge infections allow a thorough investigation of immune correlates responsible for FIP disease resistance. Analysis of virus-specific immune responses to either whole-killed virus or FIPV spike peptides did not reveal definitive antiviral T cell response correlates for resistance to the development of FIP during primary FIPVi3c2 infection of naive cats. Nevertheless, some trends including an earlier appearance of both CD4 and CD8 T cell responses, were noted in the cats showing either slow progression of disease (slow progressors) and or no evidence of FIP (survivors). In addition, antiviral T cell responses were evident at the later stage of primary infection in cats within these two outcome groups when compared to the absence of responses observed for cats showing rapid progression to FIP. Interestingly, a robust antiviral T cell response was observed in mesenteric lymph nodes harvested from slow progressors, but was absent in mesenteric nodes sampled from rapid progressors. Notably, a significantly higher antiviral T cell response was observed in survivor cats within three weeks after rechallenge with FIPVi3c2 when compared to responses observed during primary infection at the same time point.;Consistent with findings in other reports, a reduction of lymphocyte and CD3 T cell numbers with comparable loss of CD4 and CD8 T cells were observed during primary FIPVi3c2 infection regardless of disease outcome or development of FIP. An expansion of the Treg subset was noted in the cats during rechallenge infection, particularly for survivor cats more recently exposed to FIPVi3c2. Along with these findings are preservation of functional T cell proliferative responses and the capability of T cells to secrete interleukin-2. An increased T cell production of TNF-alpha in response to mitogen stimulation was also observed for cats in both primary and rechallenge FIPVi3c2 infections suggesting a FIPV-induced pro-inflammatory state. Collectively, these findings implicate an importance for both immunoregulatory elements and preservation of T cell functions for resistance to FIP development, but do not provide strong evidence for a role of virus-specific T cell responses in FIP resistance during primary infection. Further investigation for additional host mechanisms that may also be critical for limiting the susceptibility of cats to this devastating disease is warranted and will be critical in the design of an efficacious FIPV vaccine strategies.