Activating FcγRI inhibits RIG-I-mediated host antiviral innate immunity by FGR during PRRSV-ADE infection

Area of Science:

• Veterinary Immunology
• Virology
• Innate Immunity

Background:

• Antibody-dependent enhancement (ADE) is a significant challenge in developing effective vaccines against porcine reproductive and respiratory syndrome virus (PRRSV).
• Understanding the molecular mechanisms of PRRSV-ADE is crucial for overcoming persistent infections and improving vaccine strategies.

Purpose of the Study:

• To investigate the role of Fc gamma receptor I (FcγRI), Fc epsilon receptor gamma chain (FCER1G), and FGR in the host's antiviral innate immune response during PRRSV-ADE infection.
• To elucidate the molecular pathways by which PRRSV-ADE impacts innate immunity in porcine alveolar macrophages (PAMs).

Main Methods:

• In vitro assessment of PRRSV-ADE infection in PAMs.
• Analysis of key innate immune response gene and protein expression (RIG-I, TBK-1, IRF-3, STAT-1, STAT-2, IFN-α, ISG15, etc.).
• Gene knockdown studies targeting FcγRI, FCER1G, and FGR.

Main Results:

• PRRSV-ADE significantly inhibited the expression of RIG-I, TBK-1, IRF-3, STAT-1, and STAT-2 in PAMs.
• Production of crucial antiviral factors like IFN-α and various interferon-stimulated genes (ISGs) was dramatically decreased under PRRSV-ADE conditions.
• PRRSV-ADE upregulates FGR expression via FcγRI activation, and knockdown of FcγRI, FCER1G, or FGR alleviated immune suppression.

Conclusions:

• FcγRI activation suppresses the RIG-I-mediated antiviral innate immune response through FGR during PRRSV-ADE infection.
• This immune suppression facilitates PRRSV replication, highlighting a key mechanism of intrinsic ADE (iADE).
• Findings provide critical insights for designing novel, more effective PRRSV vaccines by targeting these pathways.