Topic
MDA5
About: MDA5 is a research topic. Over the lifetime, 740 publications have been published within this topic receiving 80681 citations. The topic is also known as: DEAD/H (Asp-Glu-Ala-Asp/His) box polypeptide & MDA-5.
Papers published on a yearly basis
Papers
TL;DR: This study provides the first global profile of a robust virus-induced innate immune response in bats and indicates that henipavirus IFN antagonist mechanisms are likely active in bat cells.
Abstract: Bats are important reservoirs for several viruses, many of which cause lethal infections in humans but have reduced pathogenicity in bats. As the innate immune response is critical for controlling viruses, the nature of this response in bats and how it may differ from that in other mammals are of great interest. Using next-generation transcriptome sequencing (mRNA-seq), we profiled the transcriptional response of Pteropus vampyrus bat kidney (PVK) cells to Newcastle disease virus (NDV), an avian paramyxovirus known to elicit a strong innate immune response in mammalian cells. The Pteropus genus is a known reservoir of Nipah virus (NiV) and Hendra virus (HeV). Analysis of the 200 to 300 regulated genes showed that genes for interferon (IFN) and antiviral pathways are highly upregulated in NDV-infected PVK cells, including genes for beta IFN, RIG-I, MDA5, ISG15, and IRF1. NDV-infected cells also upregulated several genes not previously characterized to be antiviral, such as RND1, SERTAD1, CHAC1, and MORC3. In fact, we show that MORC3 is induced by both IFN and NDV infection in PVK cells but is not induced by either stimulus in human A549 cells. In contrast to NDV infection, HeV and NiV infection of PVK cells failed to induce these innate immune response genes. Likewise, an attenuated response was observed in PVK cells infected with recombinant NDVs expressing the NiV IFN antagonist proteins V and W. This study provides the first global profile of a robust virus-induced innate immune response in bats and indicates that henipavirus IFN antagonist mechanisms are likely active in bat cells. IMPORTANCE Bats are the reservoir host for many highly pathogenic human viruses, including henipaviruses, lyssaviruses, severe acute respiratory syndrome coronavirus, and filoviruses, and many other viruses have also been isolated from bats. Viral infections are reportedly asymptomatic or heavily attenuated in bat populations. Despite their ecological importance to viral maintenance, research into their immune system and mechanisms for viral control has only recently begun. Nipah virus and Hendra virus are two paramyxoviruses associated with high mortality rates in humans and whose reservoir is the Pteropus genus of bats. Greater knowledge of the innate immune response of P. vampyrus bats to viral infection may elucidate how bats serve as a reservoir for so many viruses.
76 citations
TL;DR: This work has identified RIO kinase 3 (RIOK3) as a protein kinase that phosphorylates the MDA5 C-terminal region and revealed a regulatory mechanism underlying the activation of the cytoplasmic viral RNA sensor MDA 5 in both uninfected and virus-infected cells.
75 citations
TL;DR: Evidence is provided of a novel antiviral pathway that is dependent on dsRNA length, but independent of the type 1 IFN system, and of an innate antiviral response in fibroblasts in the absence of both IRF3 and type 1IFN induction.
Abstract: Virus infection elicits a robust innate antiviral response dominated by the production of type 1 IFN. In nonprofessional innate immune cells such as fibroblasts, type 1 IFN is rapidly produced following the recognition of viral dsRNA and the subsequent activation of the constitutively expressed transcription factor IFN regulatory factor 3 (IRF3). Although origin, localization, and length are factors in mediating dsRNA recognition and binding by cellular dsRNA-binding proteins, the biological significance of differential dsRNA binding is unclear, since the subsequent signaling pathways converge on IRF3. In this study, we show a dsRNA length-dependent activation of IRFs, IFNs, and IFN-stimulated genes in mouse fibroblasts. The length dependence was exacerbated in fibroblasts deficient in the mitochondria-associated adaptor IFN-β promoter stimulator 1 and IRF3, suggesting that antiviral gene induction mediated by short and long dsRNA molecules is predominantly IFN-β promoter stimulator 1 and IRF3 dependent and independent, respectively. Furthermore, we provide evidence of an innate antiviral response in fibroblasts in the absence of both IRF3 and type 1 IFN induction. Even with these key modulators missing, a 60–90% inhibition of virus replication was observed following 24-h treatment with short or long dsRNA molecules, respectively. These data provide evidence of a novel antiviral pathway that is dependent on dsRNA length, but independent of the type 1 IFN system.
75 citations
TL;DR: A wide spectrum ofTLR3 ligand structures beyond dsRNA and their delivery systems provide new insights into the physiological role of TLR3 in virus- or host-derived RNA-induced immune responses.
Abstract: The innate immune system recognizes pathogen- and damage-associated molecular patterns using pattern-recognition receptors that activate a wide range of signalling cascades to maintain host homoeostasis against infection and inflammation. Endosomal TLR3 (Toll-like receptor 3), a type I transmembrane protein, senses RNAs derived from cells with viral infection or sterile tissue damage, leading to the induction of type I interferon and cytokine production, as well as dendritic cell maturation. It has been accepted that TLR3 recognizes perfect dsRNA, but little has been addressed experimentally with regard to the structural features of virus- or host-derived RNAs that activate TLR3. Recently, a TLR3 agonist was identified, which was a virus-derived 'structured' RNA with incomplete stem structures. Both dsRNA and structured RNA are similarly internalized through clathrin- and raftlin-dependent endocytosis and delivered to endosomal TLR3. The dsRNA uptake machinery, in addition to TLR3, is critical for extracellular viral RNA-induced immune responses. A wide spectrum of TLR3 ligand structures beyond dsRNA and their delivery systems provide new insights into the physiological role of TLR3 in virus- or host-derived RNA-induced immune responses. In the present paper, we focus on the system for extracellular recognition of RNA and its delivery to TLR3.
74 citations
TL;DR: It is demonstrated that UAP56 is utilized by influenza A viruses to prevent the formation of dsRNA and, hence, the activation of the innate immune response.
Abstract: The cellular DEAD box RNA helicase UAP56 plays a pivotal role in the efficient transcription/replication of influenza A virus. UAP56 is recruited by the nucleoprotein (NP) of influenza A viruses, and recent data revealed that the RNA helicase is required for the nuclear export of a subset of spliced and unspliced viral mRNAs. The fact that influenza viruses do not produce detectable amounts of double-stranded RNA (dsRNA) intermediates during transcription/replication suggests the involvement of cellular RNA helicases. Hence, we examined whether the RNA-unwinding activity of UAP56 or its paralog URH49 plays a role in preventing the accumulation of dsRNA during infection. First, our data showed that not only UAP56 but also its paralog URH49 can interact with NPs of avian and human influenza A viruses. The small interfering RNA (siRNA)-mediated depletion of either RNA helicase reduced the transport of M1 and hemagglutinin (HA) mRNAs and, to a lesser extent, NP and NS1 mRNAs into the cytoplasm. Moreover, we found that virus infection of UAP56-depleted cells leads to the rapid accumulation of dsRNA in the perinuclear region. In parallel, we observed a robust virus-mediated activation of dsRNA-dependent protein kinase R (PKR), indicating that the cellular RNA helicase UAP56 may be recruited by influenza virus to prevent dsRNA formation. The accumulation of dsRNA was blocked when actinomycin D or cycloheximide was used to inhibit viral transcription/replication or translation, respectively. In summary, we demonstrate that UAP56 is utilized by influenza A viruses to prevent the formation of dsRNA and, hence, the activation of the innate immune response.
74 citations
Related Topics (5)
Performance Metrics
| Year | Papers |
|---|---|
| 2025 | 44 |
| 2024 | 75 |
| 2023 | 80 |
| 2022 | 127 |
| 2021 | 55 |
| 2020 | 53 |