FMDV Leader Protein Interacts with the NACHT and LRR Domains of NLRP3 to Promote IL-1β Production

Sk Mohiuddin Choudhury,Xusheng Ma,Zixiang Zhu,Yonghua Ma,Xiaofeng Nian,Weijun Cao,Zhikuan Luo,Yuanyuan Li,Fan Yang,Haixue Zheng

doi:10.3390/v14010022

Abstract

Foot-and-mouth disease virus (FMDV) infection causes inflammatory clinical symptoms, such as high fever and vesicular lesions, even death of animals. Interleukin-1β (IL-1β) is an inflammatory cytokine that plays an essential role in inflammatory responses against viral infection. The viruses have developed multiple strategies to induce the inflammatory responses, including regulation of IL-1β production. However, the molecular mechanism underlying the induction of IL-1β by FMDV remains not fully understood. Here, we found that FMDV robustly induced IL-1β production in macrophages and pigs. Infection of Casp-1 inhibitor-treated cells and NOD-, LRR- and pyrin domain-containing 3 (NLRP3)-knockdown cells indicated that NLRP3 is essential for FMDV-induced IL-1β secretion. More importantly, we found that FMDV Lpro associates with the NACHT and LRR domains of NLRP3 to promote NLRP3 inflammasome assembly and IL-1β secretion. Moreover, FMDV Lpro induces calcium influx and potassium efflux, which trigger NLRP3 activation. Our data revealed the mechanism underlying the activation of the NLRP3 inflammasome after FMDV Lpro expression, thus providing insights for the control of FMDV infection-induced inflammation.

Highlights

Foot-and-mouth disease (FMD) is a highly contagious acute and economically devastating viral disease of cloven-hoofed animals caused by the foot-and-mouth disease virus (FMDV)
Our study reveals that FMDV infection promotes IL-1β production by interacting with NLRP3 inflammasome via the ion channels and nucleus factor-κB (NF-κB) mediated pathway, providing a theoretical basis for the control of FMDV-induced inflammation
To address the effect of FMDV on NLRP3 inflammasome-mediated IL-1β production, we found that IL-1β secretion and protein maturation were impaired in PK-15 cells expressing shNLRP3 after FMDV infection compared with control cells (Figure 2C,D)

Summary

Introduction

Foot-and-mouth disease (FMD) is a highly contagious acute and economically devastating viral disease of cloven-hoofed animals caused by the foot-and-mouth disease virus (FMDV). FMDV infection can damage host tissues and induce an inflammatory response, such as fever, blisters and ulcers in the mouth, hoof, nose, or breast, ulcers in the throat, trachea, bronchus and gastric mucosa, and hemorrhagic inflammation in the small intestine and large intestine mucosa [1,2]. FMDV or FMDV proteins have been described to induce innate immune response. FMDV infection causes inflammatory response in cloven-hoofed animals, such as pigs, cattle, and sheep [6]; cytokine mRNAs are significantly increased in FMDV-infected cattle [7]. FMDV VP3 protein interacts with TLR4 (Toll-like receptor 4, TLR4) to promote TLR4-mediated inflammatory response [6]. Previous reports have demonstrated that proinflammatory cytokines are essential components of host innate immunity, which have a strong effect in virus defense [9,10]

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Results

Conclusion