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: It is demonstrated that MDA5−/− dendritic cells(DC) have a defect in cytokine response to MNV-1, the first demonstration of an innate immune sensor for norovirus, and shows that Mda5 is required for the control of M NV-1 infection.
Abstract: Noroviruses are important human pathogens responsible for most cases of viral epidemic gastroenteritis worldwide. Murine norovirus-1 (MNV-1) is one of several murine noroviruses isolated from research mouse facilities and has been used as a model of human norovirus infection. MNV-1 infection has been shown to require components of innate and adaptive immunity for clearance; however, the initial host protein that recognizes MNV-1 infection is unknown. Because noroviruses are RNA viruses, we investigated whether MDA5 and TLR3, cellular sensors that recognize dsRNA, are important for the host response to MNV-1. We demonstrate that MDA5−/− dendritic cells(DC) have a defect in cytokine response to MNV-1. In addition, MNV-1 replicates to higher levels in MDA5−/− DCs as well as in MDA5−/− mice in vivo. Interestingly, TLR3−/− DCs do not have a defect in vitro, but TLR3−/− mice have a slight increase in viral titers. This is the first demonstration of an innate immune sensor for norovirus and shows that MDA5 is required for the control of MNV-1 infection. Knowledge of the host response to MNV-1 may provide keys for prevention and treatment of the human disease.
TL;DR: The results demonstrate that MHV is recognized by both RIG-I and MDA5 and induces IFN-α/β through the activation of the IRF-3 signaling pathway, and suggest thatactivation of the NF-κB pathway might not play a critical role in IFN/β induction by MHV infection in oligodendrocytes.
Abstract: The murine coronavirus mouse hepatitis virus (MHV) induced the expression of type I interferon (alpha/beta interferon [IFN-alpha/beta]) in mouse oligodendrocytic N20.1 cells. This induction is completely dependent on virus replication, since infection with UV light-inactivated virus could no longer induce IFN-alpha/beta. We show that MHV infection activated both transcription factors, the IFN regulatory factor 3 (IRF-3) and nuclear factor kappaB (NF-kappaB), as evidenced by phosphorylation and nuclear translocation of IRF-3 and an increased promoter binding activity for IRF-3 and NF-kappaB. Furthermore, the cytoplasmic pattern recognition receptor retinoic acid-inducible gene I (RIG-I) was induced by MHV infection. Knockdown of RIG-I by small interfering RNAs blocked the activation of IRF-3 and subsequent IFN-alpha/beta production induced by MHV infection. Knockdown of another cytoplasmic receptor, the melanoma-differentiation-associated gene 5 (MDA5), by small interfering RNAs also blocked IFN-beta induction. These results demonstrate that MHV is recognized by both RIG-I and MDA5 and induces IFN-alpha/beta through the activation of the IRF-3 signaling pathway. However, knockdown of RIG-I only partially blocked NF-kappaB activity induced by MHV infection and inhibition of NF-kappaB activity by a decoy peptide inhibitor had little effect on IFN-alpha/beta production. These data suggest that activation of the NF-kappaB pathway might not play a critical role in IFN-alpha/beta induction by MHV infection in oligodendrocytes.
TL;DR: A new role is established for the commonly inactivated tumor suppressor FBXW7 in viral sensing and sensitivity to immunotherapy in melanoma patients who displayed heterogeneous responses to anti-PD-1 therapy.
Abstract: The molecular mechanisms leading to resistance to PD-1 blockade are largely unknown. Here, we characterize tumor biopsies from a patient with melanoma who displayed heterogeneous responses to anti-PD-1 therapy. We observe that a resistant tumor exhibited a loss-of-function mutation in the tumor suppressor gene FBXW7, whereas a sensitive tumor from the same patient did not. Consistent with a functional role in immunotherapy response, inactivation of Fbxw7 in murine tumor cell lines caused resistance to anti-PD-1 in immunocompetent animals. Loss of Fbxw7 was associated with altered immune microenvironment, decreased tumor-intrinsic expression of the double-stranded RNA (dsRNA) sensors MDA5 and RIG1, and diminished induction of type I IFN and MHC-I expression. In contrast, restoration of dsRNA sensing in Fbxw7-deficient cells was sufficient to sensitize them to anti-PD-1. Our results thus establish a new role for the commonly inactivated tumor suppressor FBXW7 in viral sensing and sensitivity to immunotherapy. SIGNIFICANCE: Our findings establish a role of the commonly inactivated tumor suppressor FBXW7 as a genomic driver of response to anti-PD-1 therapy. Fbxw7 loss promotes resistance to anti-PD-1 through the downregulation of viral sensing pathways, suggesting that therapeutic reactivation of these pathways could improve clinical responses to checkpoint inhibitors in genomically defined cancer patient populations.This article is highlighted in the In This Issue feature, p. 1241.
TL;DR: The mRNA expression levels of 15 cytosolic pattern recognition molecules in 11 solid organs of human and mice suggest that the cell-type-, organ- and species-specific expression and regulation need to be considered in the design and interpretation of related studies.
Abstract: The cell-type-, organ- and species-specific expression of the surface and endosomally located Toll-like receptors are well described but little is known about the respective expression profiles of cytosolic pattern recognition molecules. We therefore determined the mRNA expression levels of 15 cytosolic pattern recognition molecules in 11 solid organs of human and mice. Human organs revealed lower mRNA levels of most molecules as in spleen but at least 2-fold higher were inflammasome-related NOD, leucine-rich repeat and pyrin domain-containing protein 1‐3 (NLRP1‐3) and -12 in brain, LGP2, retinoic acid-inducible gene I (RIG-I) and NLRP10 in liver, NLRP10 in small intestine, LGP2, RIG-I, NAIP, NLRP2 and -3 in testis and RIG-I, NLRP2 and -10 in muscle. In mice, most organs also expressed lower mRNA levels compared with spleen. Only NLRP6 in liver, NAIP and NLRP6 in small intestine, LGP2, nucleotide-binding oligomerization domain 1 (NOD1), NLRP1, -2, -6, -10 and -12 in colon and MDA5, RIG-I, NLRC4, NOD1, -2, NLRP1, -2, -6, -10 and -12 mRNA levels in kidney were higher. Resting human and mouse monocytes and T cells expressed most molecules and produced IL-1b and CCL5/RANTES upon activation. However, murine monocytes strongly up-regulated, whereas human monocytes down-regulated receptor expression upon activation. These data suggest that the cell-type-, organ- and species-specific expression and regulation need to be considered in the design and interpretation of related studies.
TL;DR: This work engineered the cMDA5 viral RNA sensing domain (C-terminal domain, CTD) such that it functions similarly to human RIG-I (hRig-I) and significantly enhanced interferon-mediated immune responses, making them invaluable strategies for production of IAV-resistant chickens.
Related Topics (5)
Performance Metrics
| Year | Papers |
|---|---|
| 2025 | 44 |
| 2024 | 75 |
| 2023 | 80 |
| 2022 | 127 |
| 2021 | 55 |
| 2020 | 53 |