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Synergistic innate immune recognition of Coxsackievirus B5 by RIG-I and MDA5

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posted on 2023-06-08, 11:42 authored by Edward John Albert Richer
Coxsackievirus B5 (CBV5) is a positive sense, single-stranded RNA virus belonging to the Enterovirus genus of the Picornaviridae family. It can cause many serious diseases, including viral myocarditis (which can lead on to dilated cardiomyopathy), aseptic meningitis, and pancreatitis. The structure and cell cycle of CBV5 is typical of a picornavirus. Viral RNA is detected by Toll-like receptors (TLRs) and retinoic acid inducible gene-I (RIG-I)-like receptors (RLRs). The RLR family, consisting of RIG-I, MDA5 (melanoma differentiation-associated gene 5), and LGP2, are pattern recognition receptors that detect a range of different viruses. RIG-I and MDA5 are homologous cytoplasmic proteins containing an N-terminal region with two caspase activation and recruitment domains (CARDs), a central SF2 type DExD/H-box RNA helicase domain, and a C-terminal repressor domain (RD). Once a viral ligand has been detected and bound by RIG-I and MDA5, both signal downstream through their CARDs to activate IRF3/7 and NF-?B indirectly, via the protein intermediate IPS-1 (IFN-ß promoter stimulator 1), and initiate an immune response. RIG-I and MDA5 contribute to antiviral signalling in different ways depending on the virus involved. MDA5 has been shown to be critical for Picornaviridae detection, whilst RIG-I can detect a wide variety of different viruses and pathogen associated molecular patterns. Results presented here show the expression levels of both are upregulated in response to CBV5 infection in human cardiac cells, with MDA5 expression levels being slightly greater than RIG-I. However, in Huh cells, RIG-I expression levels are greater than those of MDA5, indicating that it plays a role in CBV5 sensing. The presence of both phospho-I?B (corresponding to NF-?B activation) and IRF3 is detected in both cardiac cells and Huh cells in response to CBV5, and IFN-ß production is also greatly upregulated. RIG-I and MDA5 colocalise with the adaptor protein IPS-1 in response to CBV5 infection, again indicating the synergistic response by the two RLRs, and both RLRs form homodimers in the cytoplasm. Overall, this suggest that both MDA5 and RIG-I act synergistically to detect CBV5 and initiate a downstream immune response, although MDA5 appears to be the marginally stronger sensor.


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