Gain-of-function mutations in the viral dsRNA sensor melanoma differentiation-associated protein 5 (MDA5) lead to autoimmune IFNopathies, including Singleton-Merten syndrome (SMS) and Aicardi-Goutières syndrome. However, much remains unclear regarding the mechanism of disease progression and how external factors such as infection or immune stimulation with vaccination can affect the immune response. With this aim, we generated mice with human MDA5 bearing the SMS-associated mutation R822Q (hM-R822Q). hM-R822Q transgenic (Tg) mice developed SMS-like heart fibrosis, aortic valve enlargement, and aortic calcification with a systemic IFN-stimulated gene signature resulting in the activation of the adaptive immune response. Although administration of the viral dsRNA mimic polyinosinic-polycytidylic acid [poly(I:C)] did not have remarkable effects on the cardiac phenotype, dramatic inflammation was observed in the intestines where IFN production was most elevated. Poly(I:C)-injected hM-R822Q Tg mice also developed lethal hypercytokinemia marked by massive IL-6 levels in the serum. Interrupting the IFN signaling through mitochondrial antiviral signaling protein or IFN-α/β receptor alleviated hM-R822Q-induced inflammation. Furthermore, inhibition of JAK signaling with tofacitinib reduced cytokine production and ameliorated mucosal damage, enabling the survival of poly(I:C)-injected hM-R822Q Tg mice. These findings demonstrate that the MDA5 R822Q mutant introduces a critical risk factor for uncontrollable inflammation on viral infection or vaccination.

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.2200367DOI Listing

Publication Analysis

Top Keywords

viral dsrna
8
immune response
8
mice developed
8
polyic-injected hm-r822q
8
hm-r822q mice
8
double-stranded rna
4
rna induces
4
induces mortality
4
mortality mda5-mediated
4
mda5-mediated type
4

Similar Publications

Emerging Roles of TRIM56 in Antiviral Innate Immunity.

Viruses

January 2025

Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38163, USA.

The tripartite-motif protein 56 (TRIM56) is a RING-type E3 ubiquitin ligase whose functions were recently beginning to be unveiled. While the physiological role(s) of TRIM56 remains unclear, emerging evidence suggests this protein participates in host innate defense mechanisms that guard against viral infections. Interestingly, TRIM56 has been shown to pose a barrier to viruses of distinct families by utilizing its different domains.

View Article and Find Full Text PDF

The increasing challenges posed by plant viral diseases demand innovative and sustainable management strategies to minimize agricultural losses. Exogenous double-stranded RNA (dsRNA)-mediated RNA interference (RNAi) represents a transformative approach to combat plant viral pathogens without the need for genetic transformation. This review explores the mechanisms underlying dsRNA-induced RNAi, highlighting its ability to silence specific viral genes through small interfering RNAs (siRNAs).

View Article and Find Full Text PDF

The immune system and neuroinflammation are now well established in the aetiology of neurodegeneration. Previous studies of transcriptomic and gene association studies have highlighted the potential of the 2'-5' oligoadenylate synthetase 1 (OAS1) to play a role in Alzheimer's disease. OAS1 is a viral response gene, interferon-induced, dsRNA activated enzyme, which binds RNase L to degrade dsRNA, and has been associated with COVID-19 response.

View Article and Find Full Text PDF

Killer yeasts, such as the K1 killer strain of S. Cerevisiae, express a secreted anti-competitive toxin whose production and propagation require the presence of two vertically-transmitted dsRNA viruses. In sensitive cells lacking killer virus infection, toxin binding to the cell wall results in ion pore formation, disruption of osmotic homeostasis, and cell death.

View Article and Find Full Text PDF

Limited impact of hepatitis A virus 3C protease-mediated cleavage on the functions of NEMO in human hepatocytes.

J Virol

January 2025

Department of Infectious Diseases, Molecular Virology, Section Virus-Host Interactions, Heidelberg University, Medical Faculty Heidelberg, Heidelberg, Germany.

NF-κB essential modulator (NEMO) is critically involved in the induction of interferons (IFNs) and pro-inflammatory cytokines. Hepatitis A virus (HAV) 3C protease was recently identified to cleave NEMO in non-hepatic cells. This study aimed at understanding efficiency and function of HAV 3C-mediated NEMO cleavage in hepatocytes.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!