  Feline infectious peritonitis (FIP) is associated with mutations in the
feline coronavirus (FCoV) genome that are thought to convert the subclinical
feline enteric coronavirus (FECV) into the lethal feline infectious peritonitis
virus (FIPV). A key feature of FIPV, not shared with FECV, is the productive
infection of macrophages. Therefore mutations in proteins that govern cell
tropism, such as the spike glycoprotein, may play an important role in FIP
progression. In a prior study, involving a limited number of samples, we have
shown an association of FIP with mutations in the protease cleavage-activation
site located between the receptor-binding and fusion domains of the FCoV spike
(S1/S2). Here, we extend these studies to investigate a larger sample set and
to obtain a more refined analysis of the mutations at this S1/S2 site. Our
larger data set more clearly shows that the mutations acquired by FIPV at S1/S2
are also accompanied by additional mutations at a second protease
cleavage-activation site located in the fusion domain (S2'), adjacent to the
viral fusion peptide. Overall, our data indicate a pattern of mutations across
the two protease recognition sites that results in substitutions, and/or
altered recognition, of critical basic/polar amino acid residues needed for
virus activation in the enteric tract. Typically, FIPVs have substitutions of
non-polar, aliphatic or aromatic residues in the protease recognition sites.
These changes likely modulate the proteolytic activation of the virus and its
ability to productively infect macrophages in vivo.
