Abstract
Feline infectious peritonitis (FIP), caused by virulent feline coronavirus, is the leading infectious cause of death in cats. The type I interferon (type I IFN)-mediated immune responses provide host protection from infectious diseases. Several coronaviruses have been reported to evolve diverse strategies to evade host IFN response. However, whether feline infectious peritonitis virus (FIPV) antagonizes the type I IFN signaling remains unclear. In this study, we demonstrated that FIPV strain DF2 infection not only failed to induce interferon-β (IFN-β) and interferon-stimulated gene (ISG) production, but also inhibited Sendai virus (SEV) or polyinosinic-polycytidylic acid (poly(I:C))-induced IFN-β production. Subsequently, we found that one of the non-structural proteins encoded by the FIPV genome, nsp5, interrupted type I IFN signaling in a protease-dependent manner by cleaving the nuclear factor κB (NF-κB) essential modulator (NEMO) at three sites—glutamine132 (Q132), Q205, and Q231. Further investigation revealed that the cleavage products of NEMO lost the ability to activate the IFN-β promoter. Mechanistically, the nsp5-mediated NEMO cleavage disrupted the recruitment of the TRAF family member-associated NF-κB activator (TANK) to NEMO, which reduced the phosphorylation of interferon regulatory factor 3 (IRF3), leading to the inhibition of type I IFN production. Our research provides new insights into the mechanism for FIPV to counteract host innate immune response.
Highlights
Feline coronaviruses (FCoVs) are important pathogens of domestic cats and wild felids, includingAfrican and mountain lions [1,2]
We found that feline infectious peritonitis virus (FIPV)-DF2 infection barely induced Viperin (Figure 1B), ISG15 (Figure 1C), and IFITMI (Figure 1D) mRNA levels, the relative interferon-stimulated gene (ISG) production were enhanced in IFN-α-pretreated cells
We further investigated whether cellular caspase activity or proteasome or lysosome signaling are required for FIPV nsp5-mediated NF-κB essential modulator (NEMO) cleavage
Summary
Feline coronaviruses (FCoVs) are important pathogens of domestic cats and wild felids, includingAfrican and mountain lions [1,2]. FCoVs are classified into two pathotypes, the avirulent feline enteric coronavirus (FECV), and the virulent feline infectious peritonitis virus (FIPV). Both FECV and FIPV have two serotypes, type I and type II FCoVs, based on differences in the amino acid sequence of the S protein [3,4]. Infection with FECV is widespread among cats, especially in high-density environments, causing inapparent or mild enteritis with little clinical consequence. A small portion of cats develop FIP during the course of FECV infection and succumb to the disease [5].
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