Foot-and-mouth disease virus VP1 target the MAVS to inhibit type-I interferon signaling and VP1 E83K mutation results in virus attenuation.

Pathum Ekanayaka,Thilina U B Herath,Hyuncheol Lee,W A Gayan Chathuranga,Jong-Hyeon Park,Seo-Yong Lee,Kiramage Chathuranga,Tae-Hwan Kim,Jong-Soo Lee,Jae-Hoon Kim

doi:10.1371/journal.ppat.1009057

Abstract

VP1, a pivotal capsid protein encoded by the foot-and-mouth disease virus (FMDV), plays an important role in receptor-mediated attachment and humoral immune responses. Previous studies show that amino acid changes in the VP1 protein of cell culture-adapted strains of FMDV alter the properties of the virus. In addition, FMDV VP1 modulates host IFN signal transduction. Here, we examined the ability of cell culture-adapted FMDV VP1(83K) and wild-type FMDV VP1(83E) to evade host immunity by blocking mitochondrial antiviral signaling protein (MAVS)/TNF Receptor Associated Factor 3 (TRAF3) mediated cellular innate responses. Wild-type FMDV VP1(83E) interacted specifically with C-terminal TRAF3-binding site within MAVS and this interaction inhibited binding of TRAF3 to MAVS, thereby suppressing interferon-mediated responses. This was not observed for cell culture-adapted FMDV VP1(83K). Finally, chimeric FMDV harboring VP1(83K) showed very low pathogenicity in pigs. Collectively, these data highlight a critical role of VP1 with respect to suppression of type-I IFN pathway and attenuation of FMDV by the E83K mutation in VP1.

Highlights

Foot-and-mouth disease (FMD) virus is the causative agent of a highly infectious disease with a huge economic impact; the virus infects cloven-hoofed mammals, including cattle, swine, and more than 70 species of wild animal [1,2]
Adaptation of field-isolated foot-and-mouth disease virus (FMDV) is accompanied by changes in viral properties, including amino acid mutations
A VP1 E83K mutation in cell culture-adapted FMDV was identified previously; here, we examined the impact of VP1 E83K on virus

Summary

Introduction

Foot-and-mouth disease (FMD) virus is the causative agent of a highly infectious disease with a huge economic impact; the virus infects cloven-hoofed mammals, including cattle, swine, and more than 70 species of wild animal [1,2]. FMDV attaches to host cells via an arginine-glycine-aspartic acid (RGD) sequence in the G-H loop of VP1 [13,16,17,18]; this sequence binds to any of four integrins (αυβ, αυβ, αυβ, and αυβ8) that act as receptors [19,20,21,22,23,24,25] on the surface of susceptible cells. FMDV can enter cells through non-integrin-mediated pathways; for example, cell culture-adapted FMD viruses attach to host cells via heparan sulfate (HS), which is a cell surface glycosaminoglycan [26,27]. Serial passage of viruses in cultured cells leads to evolution of cell culture-adapted mutated viruses [32]; some of these mutations can either attenuate or increase virulence [27,33]

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Conclusion