Host-Specific Interplay between Foot-and-Mouth Disease Virus 3D Polymerase and the Type-I Interferon Pathway

Area of Science:

• Virology
• Immunology
• Molecular Biology

Background:

• Foot-and-mouth disease (FMD) is a highly contagious viral illness impacting cloven-hoofed animals.
• The persistence of the foot-and-mouth disease virus (FMDV) is a significant challenge, potentially linked to viral protein interactions with the host's interferon (IFN) response pathway.
• Understanding these interactions is crucial for developing strategies against FMDV persistence.

Purpose of the Study:

• To investigate protein-protein interactions (PPI) between FMDV proteins and key type-I IFN pathway proteins across cattle, sheep, goats, and swine.
• To identify novel PPI and determine their species-specificity, focusing on the FMDV 3D^pol protein.
• To elucidate the role of FMDV 3D^pol in evading the host's innate immune response.

Main Methods:

• Nanoluciferase-2-hybrid complementation assay was employed to screen PPI between FMDV proteins and sixteen type-I IFN pathway proteins.
• GST pull-down assays were used to confirm identified PPI.
• Luciferase reporter assays were conducted to assess the impact of 3D^pol on IFN pathway induction.

Main Results:

• Multiple PPI were identified between FMDV 3D^pol and seven IFN pathway proteins (IKKα, IKKε, IRF3, IRF7, NEMO, MDA5, MAVS).
• These interactions were largely conserved across cattle, sheep, and goats.
• A notable exception was the interaction between 3D^pol and MAVS, which was specific to swine.
• FMDV 3D^pol was shown to inhibit the induction phase of the IFN pathway.

Conclusions:

• The FMDV 3D^pol protein interacts with multiple host IFN pathway components.
• These interactions are predominantly conserved across susceptible species but show species-specific differences, particularly with MAVS in swine.
• The findings provide the first evidence for a potential role of 3D^pol in FMDV's evasion of the innate immune system, contributing to viral persistence.