Foot-and-Mouth Disease Virus Capsid Protein VP1 Antagonizes TPL2-Mediated Activation of the IRF3/IFN-β Signaling Pathway to Facilitate the Virus Replication

Abstract

Foot-and-mouth disease (FMD) is a severe, highly contagious viral disease of cloven-hoofed animals. In order to establish an infection, the FMD virus (FMDV) needs to counteract host antiviral responses. Tumor progression locus 2 (TPL2), a mitogen-activated protein kinase, can regulate innate and adaptive immunity; however, its exact mechanisms underlying TPL2-mediated regulation of the pathogenesis of FMDV infection remain unknown. In this study, we confirmed that TPL2 could inhibit FMDV replication in vitro and in vivo. The virus replication increased in Tpl2-deficient suckling mice in association with reduced expression of interferon-stimulated genes interferon-α (IFN-α) and myxovirus resistance (MX2) and significantly reduced expression of C-X-C motif chemokine ligand 10 (CXCL10), interferon regulatory factor 3 (IRF3), and IRF7, while the phosphorylation of IRF3 was not detected. Moreover, the interactions between TPL2 and VP1 were also confirmed. The overexpression of TPL2 promoted IRF3-mediated dose-dependent activation of the IFN-β signaling pathway in association with interactions between IRF3 and TPL2. VP1 also inhibited phosphorylation of TPL2 at Thr290, while Thr290 resulted as the key functional site associated with the TPL2-mediated antiviral response. Taken together, this study indicated that FMDV capsid protein VP1 antagonizes TPL2-mediated activation of the IRF3/IFN-β signaling pathway for immune escape and facilitated virus replication.

Foot-and-mouth disease virus VP1 promotes viral replication by regulating the expression of chemokines and GBP1

“…Our results showed that VP1 could trigger part of innate immune pathways such as NF-κB pathway, toll-like receptor pathway, RIG-Ilike receptor pathway, and so on. The results were consistent with recent studies which found that VP1 proteins could inhibit the production of IFN-I in cells by binding to sorcin protein and TPL2 protein (19)(20)(21). In addition, VP1 protein also competitively binds to MAVS with TARF3 to inhibit the innate immune response (22).…”

“…Studies have found that VP1 protein promotes host cells apoptosis by inhibiting the activation of the AKT pathway (18). It inhibits the production of IFN-I in cells by binding to sorcin protein and TPL2 protein (19)(20)(21). Besides, VP1 protein also competitively binds to MAVS with TARF3 to suppress the innate immune response, but the VP1 (E83K) mutation appears losing of this competitive inhibitory ability during the culture process (22).…”

A Pan-cancer Analysis of the Role of the Transmembrane Protein 91(TMEM91) in Human Tumors

“…At the same time, by conducting enrichment analysis, we explained the molecules potentially interacting with TMEM91 are mainly involved in response to interferon − beta/regulation of viral entry into host cell/modulation by symbiont of entry into host /regulation of viral genome replication/negative regulation of viral process/type I interferon signaling pathway. These processes also indicated the signi cant involvement of TMEM91 in the progression of tumors [25][26][27][28][29] , by reading the literature. Then, we identi ed the relationship between TMEM91 expression and medication response.…”

Viral Diseases in Water Buffalo (Bubalus bubalis): New Insights and Perspectives

“…In countries that “live” with the disease, immunization methods have been studied through inoculation twice a year, with a cocktail vaccine containing the specific serotypes circulating locally. The VP1 capsid protein has been proposed by molecular studies as a significant immunogenic site and tested for vaccines with encouraging results [ 25 ]. Recently, the first report on the genetic and antigenic variation of FMD virus during virus persistence in cattle and domestic Asian buffalo was published.…”