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Inflammatory Myopathy
Published in Maher Kurdi, Neuromuscular Pathology Made Easy, 2021
Anti-MDA5 antibody (melanoma differentiation-associated protein 5) was first identified as CADM-140 antigen. It is a cytoplasmic RNA-specific helicase that belongs to a family of retinoic acid-inducible gene (RIG) I-like receptors. It is associated with amyopathic DM or DM/PM spectrum (non-ARS). These patients are clinically asymptomatic with minimal skin features. There is no perifascicular pathology, but MHC class-I may show either widespread or perifascicular expression. The majority of these cases have high prevalence of rapid progressive interstitial lung disease leading to early death.
Neurological manifestations of West Nile virus
Published in Avindra Nath, Joseph R. Berger, Clinical Neurovirology, 2020
Daniel E. Smith, J. David Beckham, Daniel M. Pastula, Kenneth L. Tyler
A specific example of the role of innate immunity comes from recent work looking at the pattern recognition receptors RIG-I-like receptor (RLR) and melanoma differentiation antigen 5 (MDA5). Both of these PRRs are important in recognition of flavivirus single-stranded RNA molecules and induction of host type 1 IFN responses (alpha- and beta-interferon). In mice that lack both receptors (double-knockouts), there is complete absence of innate immune gene induction in cells infected with WNV [17]. MDA5 also has effects on the host adaptive immune response. MDA5 activity modulates CD8+ T cell activation to support clearance of WNV from the central nervous system (CNS). Knockout mice for this gene have reduced survival after WNV infection as well as elevated viral loads in the CNS [18].
Recognition of microbe-associated molecular patterns by pattern recognition receptors
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
RNA sensing occurs through the activity of retinoic acid gene-I (RIG-I)-like receptors (RLR). These classically serve to sense the presence of RNA species generated during viral infection and can detect both single (ss) and double-stranded (ds) RNA. Three RLRs have been described: RIG-I, melanoma differentiation associated gene 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2). RIG-I and MDA5 consist of two amino-terminal caspase-associated recruitment domains (CARDs), which signal the presence of RNA species that bind a DEAD box (N-terminal) helicase/ATPase domain that is normally repressed by a carboxy-terminal regulatory domain (CTD). RIG-I detects short dsRNA species that possess 5′ end di- and tri-phosphorylated sequences generated by oligoadenylate synthetase (OAS) and RNaseL processing of RNA viruses or Pol III generated dsRNA species from dsDNA viruses. Upon RNA binding and ubiquitination by Riplet and TRIM25, RIG-I binds mitochondrial antiviral-signaling protein (MAVS) to activate two pathways, which together converge on the production of myeloid interferons: TANK-binding kinase-1 (TBK1) and IκB kinase epsilon (IKKe) phosphorylation and activation of IRF3 and IRF7 or induction of NF-κB on repression of IκB. The interferons induced are secreted and activate IFN receptor signaling and the induction of interferon-stimulated genes through the activation of STAT1, STAT2, and IRF9. MDA-5 senses long dsRNA species in a ubiquitin-independent pathway. The third member of the RLR family is less well understood; it binds RNA species but lacks a CARD domain.
Cytokine release syndrome in COVID-19: a major mechanism of morbidity and mortality
Published in International Reviews of Immunology, 2022
Yifan Que, Chao Hu, Kun Wan, Peng Hu, Runsheng Wang, Jiang Luo, Tianzhi Li, Rongyu Ping, Qinyong Hu, Yu Sun, Xudong Wu, Lei Tu, Yingzhen Du, Christopher Chang, Guogang Xu
A delayed type 1 IFN response has been proposed as a mechanism for the development of CRS. This is believed to be similar to the case of SARS and MERS [32–34] (Figure 2). RIG-I-like receptors (RLRs) or toll-like receptors (TLRs) recognize viral RNA and the caspase activation recruitment domains of RLRs combined with adapter mitochondrial antiviral signaling protein (MAVS), which recruits TANK-binding kinase 1 (TBK1) and inducible IκB kinase (IKKi). Interferon regulatory factor 3/7(IRF3/7) is phosphorylated by TBK1 and IKKi and further activates the expression of IFN-α/β, which induces the production of IFN-stimulated genes (ISGs) via the JAK-STAT pathway to counter the virus [35]. Coronavirus has been reported to antagonize IFN production and signaling by evading recognition by PRRs, inhibiting RIG-1 or TLRs signaling or blocking IRF3 activation. A recent study showed that expression of open reading frame 6 (ORF6) inhibited RLRs, MAVS and IRF3 through its C-terminus to limit IFN activation and the subsequent interferon-stimulated response element, ISG56 and STAT signal to delay IFN response in the early stages [35]. Low levels of IFN and high levels of proinflammatory cytokines and chemokines are significant characteristics of a delayed IFN response. Monocyte-derived macrophages and DCs respond to viral infection early and release inflammatory cytokines, while the production of IFN-by plasmacytoid dendritic cells is delayed [34].
Promising drug repurposing approach targeted for cytokine storm implicated in SARS-CoV-2 complications
Published in Immunopharmacology and Immunotoxicology, 2021
May Ahmed Shawki, Noha Salah Elsayed, Eman M. Mantawy, Riham S. Said
The inflammatory pathways involve the secretion of cytokines by both innate and adaptive immune cells. At the entry of the virus inside the body, the innate immune system response starts by detecting pathogen- associated molecular patterns (PAMP). In the case of the positive-strand RNA virus, the dsRNA and 5-triphosphate-bearing RNA molecules, replication intermediates of the virus, are all PAMPs. They are sensed by the cytoplasmic RNA sensors like the retinoic acid-inducible gene I (RIG-I)-like receptors composing of RIG-I, MDA5, and LGP2 [26]. Moreover, toll like receptors (TLR3 and TLR4) play a key role in the recognition of PAMPs [27]. All of these cytoplasmic sensors activate the transcription factors interferon (IFN)-regulatory factor 3 and 7 (IRF3, IRF7) and nuclear factor Kappa B (NF-kB) which lead to excretion of Type-I IFN and pro-inflammatory cytokines (Figure 3(A,B)). Subsequently, the Janus kinase/signal transducers and activators of transcription (JAK-STAT) signaling pathway will be activated followed by stimulation of the expression of antiviral interferon-stimulated genes (ISGs), (Figure 3(C)). These ISGs target the viral cycle steps to block viral replication [30]. Following these events, the leukocytes and plasma proteins are recruited to the site of infection.
cGAS-STING effectively restricts murine norovirus infection but antagonizes the antiviral action of N-terminus of RIG-I in mouse macrophages
Published in Gut Microbes, 2021
Peifa Yu, Zhijiang Miao, Yang Li, Ruchi Bansal, Maikel P. Peppelenbosch, Qiuwei Pan
Innate immune response plays a key role in the early recognition and restriction of viral infection. In the cytoplasm, viral RNA is mainly sensed by retinoic acid inducible gene-I (RIG-I)-like receptors (RLRs) including RIG-I and melanoma differentiation associated gene 5 (MDA5), and Toll-like receptors (TLRs).4,5 Upon recognition, the RNA-stimulated signaling proceeds through adaptor mitochondrial antiviral signaling (MAVS; also called IPS-1, VISA, and Cardif) protein that activates transcription factors such as nuclear factor-ĸB (NF-ĸB) and interferon (IFN)-regulatory factors 3 (IRF3), which then translocate into the nucleus to drive secretion of various cytokines including IFNs, the potent inhibitors of viral replication.6–9 Cytosolic DNA derived from pathogens is recognized by a DNA binding protein, cyclic GMP-AMP (cGAMP) synthase (cGAS).8,10 Upon viral DNA recognition, cGAS produces 2ʹ3ʹ-cGAMP, which engages an endoplasmic reticulum (ER)-localized protein stimulator of interferon genes (STING; also called MITA, TMEM173, MPYS, and ERIS).8,11 Binding of 2ʹ3ʹ-cGAMP to STING induces a conformational change and activates the following transcription factor IRF3, leading to expression of IFNs.8,12 The released IFNs can bind to their receptors and activate Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway, initiating transcription of hundreds of IFN-stimulated genes (ISGs). A subset of ISGs are considered as the ultimate antiviral effectors limiting viral replication, including norovirus.9,13–15