Abstract
The innate immune system has evolved endosomal and cytoplasmic receptors for the detection of viral nucleic acids as sensors for virus infection. Some of these pattern recognition receptors (PRR) detect features of viral nucleic acids that are not found in the host such as long stretches of double-stranded RNA (dsRNA) and uncapped single-stranded RNA (ssRNA) in case of Toll-like receptor (TLR) 3 and RIG-I, respectively. In contrast, TLR7/8 and TLR9 are unable to distinguish between viral and self-nucleic acids on the grounds of distinct molecular patterns. The ability of these endosomal TLR to act as PRR for viral nucleic acids seems to rely solely on the mode of access to the endolysosomal compartment in which recognition takes place. The current dogma states that self-nucleic acids do not enter the TLR-sensing compartment under normal physiological conditions. However, it is still poorly understood how dendritic cells (DC) evade activation by self-nucleic acids, in particular with regard to specific DC subsets, which are specialized in taking up material from dying cells for cross-presentation of cell-associated antigens. In this review we discuss the current understanding of how the immune system distinguishes between foreign and self-nucleic acids and point out some of the key aspects that still require further research and clarification.
Highlights
Reviewed by: Bastian Opitz, Charite University Medicine Berlin, Germany Melanie M
Recognition by cytoplasmic pattern recognition receptors (PRR) partially depends on features of viral nucleic acids that are absent from mammalian nucleic acids such as 5 triphosphate groups on short blunt-ended double-stranded RNA structures recognized by RIG-I and long dsRNA structures recognized by MDA5 (Goubau et al, 2013)
Mechanisms that would allow the innate immune system to discriminate between self and viral nucleic acids could be based on the following characteristics: (1) as discussed above total cellular nucleic acids contain enough modified RNA species such as transfer RNA (tRNA) and ribosomal RNA (rRNA) which inhibit the activation of endosomal Toll-like receptor (TLR) in the presence of stimulatory selfnucleic acid such as messenger RNA (mRNA); (2) sequestration of cellular nucleic acids through binding to cellular components may prevent binding to endosomal TLR and/or (3) the recruitment of nucleic acid-sensing TLR to the endolysosomal compartment or their functional activation by cleavage may be regulated by gatekeeper molecules sensing pathogen-associated molecular patterns (PAMP) and/or damage-associated molecular patterns (DAMP) absent from uninfected dead cells or DAMP absent from infected dead cells
Summary
The innate immune system has evolved endosomal and cytoplasmic receptors for the detection of viral nucleic acids as sensors for virus infection Some of these pattern recognition receptors (PRR) detect features of viral nucleic acids that are not found in the host such as long stretches of double-stranded RNA (dsRNA) and uncapped single-stranded RNA (ssRNA) in case of Toll-like receptor (TLR) 3 and RIG-I, respectively. Viral replication leads to the accumulation of viral replication intermediates in the cytoplasm of infected cells, which trigger cytoplasmic PRR such as the RIG-I-like receptors and various DNA sensors such as DAI, DExD/H box family helicases, AIM2-like receptors and cGAS (Kato et al, 2011; Keating et al, 2011; Sun et al, 2013; Wu et al, 2013) These cytoplasmic nucleic acid-sensing PRR initiate the local anti-viral response in the infected tissue.
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