Feline Infectious Peritonitis Virus Nsp5 Inhibits Type I Interferon Production by Cleaving NEMO at Multiple Sites

Area of Science:

• Virology
• Immunology
• Molecular Biology

Background:

• Feline infectious peritonitis (FIP) is a deadly disease in cats caused by a virulent feline coronavirus.
• Type I interferon (IFN) responses are crucial for controlling viral infections.
• Coronaviruses often possess mechanisms to evade host IFN responses, but FIPV's strategy was unknown.

Purpose of the Study:

• To investigate whether feline infectious peritonitis virus (FIPV) antagonizes type I interferon (IFN) signaling in cats.
• To elucidate the molecular mechanisms by which FIPV might interfere with the host's innate immune response.

Main Methods:

• Infection of cells with FIPV strain DF2.
• Assessing the production of interferon-β (IFN-β) and interferon-stimulated genes (ISGs).
• Investigating the role of FIPV non-structural protein nsp5 in cleaving nuclear factor κB (NF-κB) essential modulator (NEMO).
• Analyzing the impact of NEMO cleavage on IFN-β promoter activity and downstream signaling pathways involving TANK and IRF3.

Main Results:

• FIPV strain DF2 infection failed to induce IFN-β and ISG production.
• FIPV inhibited IFN-β production induced by Sendai virus (SEV) or polyinosinic-polycytidylic acid (poly(I:C)).
• FIPV nsp5 protein cleaved NEMO at specific sites (Q132, Q205, Q231) in a protease-dependent manner.
• Cleavage of NEMO by nsp5 disrupted TANK recruitment, reduced IRF3 phosphorylation, and ultimately inhibited type I IFN production.

Conclusions:

• Feline infectious peritonitis virus (FIPV) actively antagonizes the host's type I interferon signaling pathway.
• The viral protein nsp5 plays a key role in this antagonism by cleaving NEMO, a critical component of the IFN signaling cascade.
• This mechanism allows FIPV to evade innate immune responses, contributing to the pathogenesis of FIP.