MDA5

Abstract: Mitochondrial antiviral signaling protein (MAVS), an innate immune signaling adapter coordinates the signals received from two independent cytosolic pathogen recognition receptors (RIG-1 and MDA5) to induce antiviral genes. In the present study the MAVS gene of Lates calcarifer (LcMAVS) was cloned and characterized. The complete cDNA sequence of LcMAVS was 3160 bp and encodes a poly peptide of 577 amino acids. Structural analysis of LcMAVS revealed an N-terminal CARD-like domain, central proline-rich domain and a C-terminal transmembrane domain. Phylogenetic analysis indicated that LcMAVS exhibited the closest relationship to P. olivaceous MAVS. LcMAVS was ubiquitously expressed in all tested tissues of healthy fish viz., brain, gill, heart, liver, spleen, kidney and intestine, with highest transcript level in spleen. The mRNA transcript level of LcMAVS in different developmental stages showed constitutive expression in all the stages tested suggesting the maternal transfer of the gene. Significant up regulation in MAVS expression was observed post nervous necrosis virus (NNV) challenge in vivo in all the selected tissues. Further, time course analysis showed that LcMAVS transcripts significantly increased in the brain and spleen tissues after NNV infection. These findings provide useful information for further elucidating the function of LcMAVS in antiviral innate immune response against NNV in Asian seabass.

Abstract: Hepatitis A virus (HAV) belongs to the family Picornaviridae. It is the pathogen of acute viral hepatitis caused by fecal-oral transmission. RNA viruses are sensed by pathogen-associated pattern recognition receptors (PRRs) such as Toll-like receptor 3 (TLR3), retinoic acid-inducible gene I (RIG-I), and melanoma differentiation-associated gene 5 (MDA5). PRR activation leads to production of type 1 interferon (IFN-α/β), serving as the first line of defense against viruses. However, HAV has developed various strategies to compromise the innate immune system and promote viral propagation within the host cells. The long coevolution of HAV in hosts has prompted the development of effective immune antagonism strategies that actively fight against host antiviral responses. Proteases encoded by HAV can cleave the mitochondrial antiviral signaling protein (MAVS, also known as IPS-1, VISA, or Cardif), TIR domain- containing adaptor inducing IFN-β (TRIF, also known as TICAM-1) and nuclear factor-κB (NF-κB) essential modulator (NEMO), which are key adaptor proteins in RIG-I-like receptor (RLR), TLR3 and NF-κB signaling, respectively. In this mini-review, we summarize all the recent progress on the interaction between HAV and the host, especially focusing on how HAV abrogates the antiviral effects of the innate immune system.

Abstract: The RIG-I-like receptors (RLRs), RIG-I (retinoic acid inducible gene 1), MDA5 (melanoma differentiation-associated gene 5) and LGP2 (laboratory of genetics and physiology 2) play an essential role in sensing viral infection and initiating interferon-mediated antiviral immune response. RLRs share similar domain architecture to support specific detection of viral RNA (ribonucleic acid). RIG-I has an auto-inhibitory conformation and upon binding of RNA ligand undergoes conformational changes to expose N-terminal CARDs (caspase activation and recruitment domains) for interaction with the adaptor protein MAVS (mitochondrial antiviral-signalling protein) for signalling. MDA5 adopts an open but inactive conformation and is able to oligomerise on long RNA duplexes to bring its CARDs into close proximity to MAVS. The downstream signalling cascade up-regulates the type I interferon expression. Post-translational modifications, alternative splicing and translational variants as well as several regulatory proteins play important roles in the regulation of RLRs signalling. Although robust activation of RLRs is essential for clearance of viral infection, uncontrolled activation of RLR signalling could potentially trigger or exacerbate pre-existing autoimmune conditions. Key Concepts RIG-I-like receptors (RLRs) are pattern recognition receptor (PRR) which specifically recognise viral RNAs RLRs undergo conformational changes leading to activation when bound to viral RNA RLRs relay signal to a common signalling adaptor MAVS (mitochondrial antiviral-signalling protein) leading to activation of transcription factors promoting the expression of interferons and pro-inflammatory cytokines which reduces initial viral replication and spread RLRs are tightly regulated by various proteins and post-translational modifications to prevent undesired auto-activation Keywords: interferon; innate immunity; RNA viruses; pattern recognition receptor