The genes encoding accessory proteins 3a, 3b, 3c, 7a and 7b, the S2 domain of the spike (S) protein gene and the membrane (M) protein gene of feline infectious peritonitis virus (FIPV) and feline enteric coronavirus (FECV) samples were amplified, cloned and sequenced. For this faeces and/or ascites samples from 19 cats suffering from feline infectious peritonitis (FIP) as well as from 20 FECV-infected healthy cats were used. Sequence comparisons revealed that 3c genes of animals with FIP were heavily affected by nucleotide deletions and point mutations compared to animals infected with FECV; these alterations resulted either in early termination or destruction of the translation initiation codon. Two ascites-derived samples of cats with FIP which displayed no alterations of ORF3c harboured mutations in the S2 domain of the S protein gene which resulted in amino acid exchanges or deletions. Moreover, changes in 3c were often accompanied by mutations in S2. In contrast, in samples obtained from faeces of healthy cats, the ORF3c was never affected by such mutations. Similarly ORF3c from faecal samples of the cats with FIP was mostly intact and showed only in a few cases the same mutations found in the respective ascites samples. The genes encoding 3a, 3b, 7a and 7b displayed no mutations linked to the feline coronavirus (FCoV) biotype. The M protein gene was found to be conserved between FECV and FIPV samples. Our findings suggest that mutations of 3c and spike protein genes correlate with the occurrence of FIP.

Persistent infection of domestic cats with feline coronaviruses (FCoVs) can lead to a highly lethal, immunopathological disease termed feline infectious peritonitis (FIP).Coronaviruses are enveloped positive-stranded RNA viruses that infect a wide range of vertebrate species including livestock, companion animals, and humans. Coronaviruses are associated mainly with respiratory and enteric infections that can cause, in conjunction with systemic and/or persistent infection, severe diseases in animals and humans (17,18,32). Many coronaviruses have adopted a pronounced tropism for monocytic cells such as conventional dendritic cells (cDCs) and macrophages that can be attributed to particular receptor specificities of coronavirus surface (S) glycoproteins (1,18,22,28,33). On the cellular level, infection of macrophages results in a host cell transcriptional response that virtually lacks type I interferon (IFN) expression but is characterized mainly by a markedly increased level of expression of inflammatory cytokines (6,18,20,25,28). These inflammatory stimuli initiate and contribute to the pathogenesis of coronavirus-induced severe diseases. For example, overshooting inflammatory cytokine responses are associated with (i) mouse hepatitis virus-

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Feline infectious peritonitis (FIP) is a lethal immunopathological disease caused by feline coronaviruses (FCoVs). Here, we describe a reverse genetics approach to study FIP by assessing the pathogenicity of recombinant type I and type II and chimeric type I/type II FCoVs. All recombinant FCoVs established productive infection in cats, and recombinant type II FCoV (strain 79-1146) induced FIP. Virus sequence analyses from FIP-diseased cats revealed that the 3c gene stop codon of strain 79-1146 has changed to restore a full-length open reading frame (ORF).

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