Combined administration of synthetic RNA and a conventional vaccine improves immune responses and protection against foot-and-mouth disease virus in swine

Borrego, Belén; Blanco, Esther; Pulido, Miguel Rodríguez; Mateos, Francisco; Lorenzo, Gema; Cardillo, Sabrina Beatriz; Smitsaart, Eliana; Sánchez‐Madrid, Francisco; Sáiz, Margarita

doi:10.1016/j.antiviral.2017.03.009

Cited by 21 publications

(26 citation statements)

References 30 publications

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“…To our knowledge, this is the first report of an LGP2 cleavage event involving a virally encoded protein, with implications in the resulting type-I IFN response of the host against viral infection. FMDV is highly sensitive to IFN, and IFN-based strategies have proved to be efficient biotherapeutic approaches against the virus [ 43 – 45 ]. Cleavage of LGP2 by the Leader protease unveils a new antagonistic mechanism evolved by FMDV, and likely other aphthoviruses, directed to suppress the host IFN response.…”

Section: Discussionmentioning

confidence: 99%

Innate immune sensor LGP2 is cleaved by the Leader protease of foot-and-mouth disease virus

et al. 2018

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The RNA helicase LGP2 (Laboratory of Genetics and Physiology 2) is a non-signaling member of the retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), whose pivotal role on innate immune responses against RNA viruses is being increasingly uncovered. LGP2 is known to work in synergy with melanoma differentiation-associated gene 5 (MDA5) to promote the antiviral response induced by picornavirus infection. Here, we describe the activity of the foot-and-mouth disease virus (FMDV) Leader protease (Lpro) targeting LGP2 for cleavage. When LGP2 and Lpro were co-expressed, cleavage products were observed in an Lpro dose-dependent manner while co-expression with a catalytically inactive Lpro mutant had no effect on LGP2 levels or pattern. We further show that Lpro localizes and immunoprecipitates with LGP2 in transfected cells supporting their interaction within the cytoplasm. Evidence of LGP2 proteolysis was also detected during FMDV infection. Moreover, the inhibitory effect of LGP2 overexpression on FMDV growth observed was reverted when Lpro was co-expressed, concomitant with lower levels of IFN-β mRNA and antiviral activity in those cells. The Lpro target site in LGP2 was identified as an RGRAR sequence in a conserved helicase motif whose replacement to EGEAE abrogated LGP2 cleavage by Lpro. Taken together, these data suggest that LGP2 cleavage by the Leader protease of aphthoviruses may represent a novel antagonistic mechanism for immune evasion.

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Section: Discussionmentioning

confidence: 99%

Innate immune sensor LGP2 is cleaved by the Leader protease of foot-and-mouth disease virus

et al. 2018

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“…However, viruses are capable of selecting various strategies to evade the host immune system and thus contributing to viral pathogenicity ( Schulz and Mossman, 2004 ; Jackson et al, 2017 ; Sumner et al, 2017 ). For FMDV infection, type I IFNs also play important roles in counteracting viral infection represent a potent biotherapeutic method against FMDV ( Rodríguezpulido et al, 2011 ; Borrego et al, 2017 ). This minireview summarizes the current knowledge on how type I IFN is resistant to FMDV infection and how FMDV counteracts type I IFN induction and signaling transduction to evade the type I IFN system of host.…”

Section: Introductionmentioning

confidence: 99%

Type I Interferon Induced and Antagonized by Foot-and-Mouth Disease Virus

Chang

et al. 2018

Front. Microbiol.

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Viral infections trigger the innate immune system, serving as the first line of defense, and are characterized by the production of type I interferon (IFN). Type I IFN is expressed in a broad spectrum of cells and tissues in the host and includes various subtypes (IFN-α, IFN-β, IFN-δ, IFN-ε, IFN-κ, IFN-τ, IFN-ω, IFN-ν, and IFN-ζ). Since the discovery of type I IFN, our knowledge of the biology of type I IFN has accumulated immensely, and we now have a substantial amount of information on the molecular mechanisms of the response and induction of type I IFN, as well as the strategies utilized by viruses to evade the type I IFN response. Foot-and-mouth disease virus (FMDV) can selectively alter cellular pathways to promote viral replication and evade antiviral immune activation of type I IFN. RNA molecules generated by FMDV are sensed by the cellular receptor for pathogen-associated molecular patterns (PAMPs). FMDV preferentially activates different sensor molecules and various signal transduction pathways. Based on knowledge of the virus or RNA pathogen specificity as well as the function-structure relationship of RNA sensing, it is necessary to summarize numerous signaling adaptors that are reported to participate in the regulation of IFN gene activation.

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“…Evasion of the host immune response may contribute to viral pathogenicity and viruses often display redundant strategies to counteract it (Zinzula and Tramontano, 2013; Fensterl et al, 2015). IFN-based strategies have proved to be an efficient biotherapeutic approach against FMDV (Rodriguez-Pulido et al, 2011; Robinson et al, 2016b; Borrego et al, 2017), and the study of viral mechanisms interfering with immune functions has been a very active area of research over the last few years. This minireview summarizes our current knowledge on how FMDV antagonizes the IFN-α/β induction and signaling pathways to circumvent the host antiviral response.…”

Section: Introductionmentioning

confidence: 99%

Molecular Mechanisms of Foot-and-Mouth Disease Virus Targeting the Host Antiviral Response

Pulido

Sáiz

2017

Front. Cell. Infect. Microbiol.

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Foot-and-mouth disease virus (FMDV) is the causative agent of an acute vesicular disease affecting pigs, cattle and other domestic, and wild animals worldwide. The aim of the host interferon (IFN) response is to limit viral replication and spread. Detection of the viral genome and products by specialized cellular sensors initiates a signaling cascade that leads to a rapid antiviral response involving the secretion of type I- and type III-IFNs and other antiviral cytokines with antiproliferative and immunomodulatory functions. During co-evolution with their hosts, viruses have acquired strategies to actively counteract host antiviral responses and the balance between innate response and viral antagonism may determine the outcome of disease and pathogenesis. FMDV proteases Lpro and 3C have been found to antagonize the host IFN response by a repertoire of mechanisms. Moreover, the putative role of other viral proteins in IFN antagonism is being recently unveiled, uncovering sophisticated immune evasion strategies different to those reported to date for other members of the Picornaviridae family. Here, we review the interplay between antiviral responses induced by FMDV infection and viral countermeasures to block them. Research on strategies used by viruses to modulate immunity will provide insights into the function of host pathways involved in defense against pathogens and will also lead to development of new therapeutic strategies to fight virus infections.

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Combined administration of synthetic RNA and a conventional vaccine improves immune responses and protection against foot-and-mouth disease virus in swine

Cited by 21 publications

References 30 publications

Innate immune sensor LGP2 is cleaved by the Leader protease of foot-and-mouth disease virus

Innate immune sensor LGP2 is cleaved by the Leader protease of foot-and-mouth disease virus

Type I Interferon Induced and Antagonized by Foot-and-Mouth Disease Virus

Molecular Mechanisms of Foot-and-Mouth Disease Virus Targeting the Host Antiviral Response

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