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Rabies and other lyssaviruses
Published in Avindra Nath, Joseph R. Berger, Clinical Neurovirology, 2020
Thiravat Hemachudha, Jiraporn Laothamatas, Henry Wilde
Rabies virus is also able to escape adaptive immune responses in the CNS. In rabies, T-cells and monocytes can activate and enter into the CNS despite the intactness of the BBB. After infection with a virulent strain in mice, the brain was infiltrated with T-cells expressing markers of activation (CD69), as well as collapsing response mediator protein 2 (CRMP2), a marker of T-cell polarization and migration [103]. Invading T-cells and monocytes, however, undergo apoptosis shortly after their entry into the brain parenchyma. Immunohistochemical studies in postmortem rabid human brains revealed that leukocytes were the only cells undergoing death [104]. In postmortem human brains infected with vampire bat virus (genotype 1), only infiltrating adaptive immune T-cells (CD4+ and CD8+) were apoptotic, not NK cells, macrophages, astrocytes, or neurons [105]. Paradoxically, rabies virus exploits the innate immune response to induce apoptosis of infiltrating T-cells. This was demonstrated in a transgenic mouse model overexpressing LGP2 to impair RIG-I-mediated innate immune response; following RV infection, lower morbidity and more viral clearance in the brain were found in LGP2+ mice, with reduction of infiltrating CD4+ T cells but less disappearance of infiltrating CD8+ T cells [106] showing that host innate immune response favors the infiltration of T-cells but promotes CD8+ T cell elimination at the same time.
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.
Controlling Neuroinflammation
Published in Sunit K. Singh, Daniel Růžek, Neuroviral Infections, 2013
Cells sense the presence of pathogens or damaged cells (danger signals) through a plethora of receptors, including toll-like receptors (TLRs); retinoic acid-inducible gene (RIG)-like receptors (RLRs); nucleotide binding oligomerization domain (NOD)-like receptors (NLRs) (Brodsky and Monack 2009); inflammasome-related NOD, leucine-rich repeat and pyrin-domain-containing proteins (NLRPs); scavenger receptors, class A, MARCO, and CD36 (Yamada et al. 1998); purinergic receptors of the P2 such as P2X7; complement receptors (CR3, CR4); new cytoplasmic receptors such as IFIT1 (Pichlmair et al. 2011); and the unidentified sensors of membrane disruption (cellular stress) (Noyce et al. 2011). The TLRs are a family of 13 members. The RLR family, mainly involved in virus detection, consists of three proteins: RIG-I, melanoma differentiation-associated gene 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2) proteins. Most of these receptors are at the surface of the cells, detecting the presence of danger signals present in the extracellular milieu. Such were the case for purinergic receptors, scavenger receptors, and TLRs such as TLR2 or TLR4. Other receptors are expressed in the cytoplasma (RLRs and NLRs) or in endosomal vesicles (TLR3 and TLR7—TLR9), allowing the detection of danger signals produced in the early steps of the entry or replication of intracellular pathogens or after phagocytosis of cell debris.
Novel approach to identify putative Epstein–Barr–virus microRNAs regulating host cell genes with relevance in tumor biology and immunology
Published in OncoImmunology, 2022
Simon Jasinski-Bergner, Juliane Blümke, Marcus Bauer, Saskia Luise Skiebe, Ofer Mandelboim, Claudia Wickenhauser, Barbara Seliger
First, the expression of genes relevant for the functionality of the innate immune system known to exert anti-viral activities were compared. These include involving anti-viral cytokines/chemokines, their receptors, downstream signaling molecules and pattern recognition receptors with anti-viral functions like the toll-like receptors (TLR)3, TLR7, TLR8, and TLR9 and the intracellular pattern recognition factors RIG-1 (DDX58), MDA5 (IFIH1) and LGP2 (DHX58)39–42 (Figure 3A–B). A statistically significant enhanced expression was detected for the anti-viral chemokine CXCL10 (p = 2.1E-05), an almost statistically significant gene expression was detected for CXCL9 (p = 0.0703) and for the receptor CXCR3 (p = 0.0447) in EBV-positive BL cells (Figure 3C). In contrast, a statistically significant downregulation in BL cells was found for some components of the type I interferon (IFN) signaling, such as IFNAR1 (p = 0.0002), JAK1 (p = 0.0004) and STAT2 (p = 0.0011), while RIG-1 (DDX58; p = 0.0001) and MDA5 (IFIH1; p = 0.0018) were downregulated in BL cells (Figure 3C).
Immunobiology and nanotherapeutics of severe acute respiratory syndrome 2 (SARS-CoV-2): a current update
Published in Infectious Diseases, 2021
Ifeanyi Elibe Mba, Hyelnaya Cletus Sharndama, Goodness Ogechi Osondu-chuka, Onyekachi Philomena Okeke
Other receptors such as the RIG-I-like receptors (RLRs) [100], C-type lectin-like receptors (CLRs) [53], NOD-like receptor (NLR) such as NLRP3 inflammasome [118], and free molecule receptors such as STING, cGAS, IFI16, and DAI are active in recognition of viruses and mediation of immune response-related signalling pathway [81]. RLRs are comprised of the H family members RIG-I (DDX58), MDA5 (IFIH), and LGP2, which recognize the genomic structure of RNA viruses such as SARS-CoV-2 [100]. NLRs are divided into three classes, mainly the inflammasomes (NLRP1, NLRP3, NLRP6, NLRC4, NLRC5W, and AY2), the embryo regenerative and regulatory NLRs [80,118]. They are a subclass of PRRs made up of conserved NOD structure. CLRs are soluble PRRs expressed majorly in myeloid cells. They are responsible for phagocytosis, maturation of DCs, and chemotaxis. Moreover, Toll-like receptors (TLRs) recognize PAMPs, RIG-I-Like receptors recognize nucleic acids, C-type Lectin-like receptors (CLRs), and NOD-like receptors (NLRs) are pattern recognition receptors (PRRs) responsible for identifying the viral antigens [81]. RNA fragment of SAR-CoV-2 can activate RIG-1 and mitochondrial antiviral signalling (MAV) platforms in the cytosol [119].
SARS-CoV-2 subunit vaccine adjuvants and their signaling pathways
Published in Expert Review of Vaccines, 2022
Daniel Mekonnen, Hylemariam Mihiretie Mengist, Tengchuan Jin
The RLR, melanoma differentiation associated gene 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2) are members of RNA helicase and sensors of RNA of the pathogen source in the cytoplasm [130,144]. The interaction of RLR–RNA activates type I interferons (IFN-α) and proinflammatory cytokines, which are known effectors of the innate immune system [144,145]. However, the RLR signaling pathway is very prone to overactivate and leads to autoimmunity. Hence, it is under strict regulation to keep the immune homeostasis [146] (Figure 3). Signaling pathways by RLR are employed by several viruses including SARS-CoV-2 [147].