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Neuropathogenesis of viral infections
Published in Avindra Nath, Joseph R. Berger, Clinical Neurovirology, 2020
Avindra Nath, Joseph R. Berger
Once a cell binds IFN-α or IFN-β, which use a common receptor, a cascade of cellular signaling occurs resulting in the transcription of several proteins that aid in conferring a hostile environment to viral infection. There are three key antiviral proteins that have been identified as a result of this transcriptional activation: 2′–5′ oligoadenylate synthetase, protein kinase PKR and Mx protein [31]. The 2′–5′ oligoadenylate synthetase polymerizes adenosine triphosphate into a series of 2′–5′ linked oligomers, which differs from normal nucleotides that are joined 3′–5′. These oligomers in turn activate RNase L, a constitutive endoribonuclease. This enzyme degrades viral RNA. Protein kinase PKR is activated by the presence of double-stranded RNA. Upon activation, PKR phosphorylates the cellular translation initiation factor eIF-2. The result of this is an inhibition of translation and protein synthesis, contributing to the inhibition of viral replication. The Mx protein is a protein that acts in the nucleus of an infected cell to confer resistance to influenza virus. The Mx protein acts in the nucleus of the cell infected with influenza and inhibits the synthesis of the influenza virus mRNA [32].
Soluble Mediators of Cellular Cooperation: The Cytokines
Published in Constantin A. Bona, Francisco A. Bonilla, Textbook of Immunology, 2019
Constantin A. Bona, Francisco A. Bonilla
Biological activities. Type 1 IFNs activate several non-specific antiviral mechanisms. IFNs induce the production of two enzymes (and others, less well-characterized) which may affect synthesis of viral proteins during infection. These are a protein kinase, and a 2’–5’ oligoadenylate synthetase. Double-stranded RNA (dsRNA) appears to be required for activity of these proteins. While dsRNA does not normally occur in eukaryotic cells, it is found as an intermediate in replication of many viruses. The protein kinase inactivates eukaryotic initiation factor-2a (eIF-2a), thereby inhibiting protein synthesis. The 2’-5’ oligo-A synthetase forms 2’-5’ oligoadenylic acid, a cofactor needed for activity of an endogenous ribonuclease, RNAse L. RNAse L degrades messenger and ribosomal RNAs.
Viral-Specific and Immune-Based Nonspecific Antiviral Therapies for CFS
Published in Roberto Patarca-Montero, Treatment of Chronic Fatigue Syndrome in the Antiviral Revolution Era, 2014
Based on the premise that the clinical symptoms of CFS could be explained by a persistent viral infection, some researchers have reasoned that alterations in the 2′,5′-oligoadenylate (2–5) synthetase/RNase L antiviral pathways may underlie CFS.180, 181 This double-stranded RNA (dsRNA)-dependent, interferon-inducible pathway is part of the antiviral defense mechanism of mammalian cells which also regulates cell growth and differentiation.182–185 When activated by dsRNA, 2–5A synthetase converts ATP to 2′,5′-linked oligoadenylates. These biologically active 2–5A molecules bind to and activate a latent endoribonuclease (RNase L) to hydrolyze single-stranded viral and cellular RNA, thus inhibiting protein synthesis.
Fatigue in ANCA-associated vasculitis (AAV) and systemic sclerosis (SSc): similarities with Myalgic encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). A critical review of the literature
Published in Expert Review of Clinical Immunology, 2022
Charmaine van Eeden, Mohammed S. Osman, Jan Willem Cohen Tervaert
Other important impaired immunoregulatory cells in ME/CFS, AAV, and SSc include natural killer (NK) cells. In particular, NK cell cytotoxicity is significantly reduced in ME/CFS patients [40–44] – suggested the NK cells may be activated but are incapable of eliminating the target [41]. Like other leukocytes, NK cell functions are regulated by the balance of activating and inhibitor receptors [45]. Hence, increases in KIR3DL1, an NK cell inhibitory receptor which has been observed in ME/CFS [43], may promote NK cell functional attenuation. Further to this, a reduction in NK cell cytotoxicity has been observed in both SSc and AAV [46], with a reduction in the expression of various activating receptors including, NKG2D suggested to be associated with SSc [47,48]. Antiviral defense mechanisms may also attenuate NK cell functions [49,50]. Hence, increased ribonuclease L/2-5A synthetase (RNase L) activity and RNase L proteolysis may further promote this as suggested in patients with ME/CFS [49,50].