Mutation in Spike Protein Cleavage Site and Pathogenesis of Feline Coronavirus

Beth N Licitra,Gary R Whittaker,Jean K Millet,Andrew D Regan,Gerald E Duhamel,Vera D Rinaldi,Brian S Hamilton

doi:10.3201/eid1907.121094

Abstract

Feline coronaviruses (FCoV) exist as 2 biotypes: feline enteric coronavirus (FECV) and feline infectious peritonitis virus (FIPV). FECV causes subclinical infections; FIPV causes feline infectious peritonitis (FIP), a systemic and fatal disease. It is thought that mutations in FECV enable infection of macrophages, causing FIP. However, the molecular basis for this biotype switch is unknown. We examined a furin cleavage site in the region between receptor-binding (S1) and fusion (S2) domains of the spike of serotype 1 FCoV. FECV sequences were compared with FIPV sequences. All FECVs had a conserved furin cleavage motif. For FIPV, there was a correlation with the disease and >1 substitution in the S1/S2 motif. Fluorogenic peptide assays confirmed that the substitutions modulate furin cleavage. We document a functionally relevant S1/S2 mutation that arises when FIP develops in a cat. These insights into FIP pathogenesis may be useful in development of diagnostic, prevention, and treatment measures against coronaviruses.

Highlights

Feline coronaviruses (FCoV) exist as 2 biotypes: feline enteric coronavirus (FECV) and feline infectious peritonitis virus (FIPV)
Acquisition of macrophage tropism for a serotype 2 FCoV has previously been mapped to the spike gene [16], further suggesting that key mutations within spike protein may be important for the biotype switch
To perform comparative analysis of the S1/S2 cleavage site between FECVs and FIPVs, we identified cases of FIP that were confirmed postmortem by using immunohistochemistry, the standard for FIP diagnosis; archival immunohistochemistry-positive formalin-fixed tissues were used as the source of FIPV RNA

Summary

Introduction

Feline coronaviruses (FCoV) exist as 2 biotypes: feline enteric coronavirus (FECV) and feline infectious peritonitis virus (FIPV). FECV causes subclinical infections; FIPV causes feline infectious peritonitis (FIP), a systemic and fatal disease. It is thought that mutations in FECV enable infection of macrophages, causing FIP. A long-standing hypothesis is that FIP viruses arise from internal mutation of endemic FECVs [12], which is believed to occur in approximately 1%–5% of enteric infections, resulting in the ability of the virus to infect blood monocytes and tissue macrophages. Acquisition of macrophage tropism for a serotype 2 FCoV has previously been mapped to the spike gene [16], further suggesting that key mutations within spike protein may be important for the biotype switch

Methods

Results

Conclusion