Nucleic Acid Immunity

Abstract

Organisms throughout biology need to maintain the integrity of their genome. From bacteria to vertebrates, life has established sophisticated mechanisms to detect and eliminate foreign genetic material or to restrict its function and replication. Tremendous progress has been made in the understanding of these mechanisms which keep foreign or unwanted nucleic acids from viruses or phages in check. Mechanisms reach from restriction-modification systems and CRISPR/Cas in bacteria and archaea to RNA interference and immune sensing of nucleic acids, altogether integral parts of a system which is now appreciated as nucleic acid immunity. With inherited receptors and acquired sequence information, nucleic acid immunity comprises innate and adaptive components. Effector functions include diverse nuclease systems, intrinsic activities to directly restrict the function of foreign nucleic acids (e.g., PKR, ADAR1, IFIT1), and extrinsic pathways to alert the immune system and to elicit cytotoxic immune responses. These effects act in concert to restrict viral replication and to eliminate virus-infected cells. The principles of nucleic acid immunity are highly relevant for human disease. Besides its essential contribution to antiviral defense and restriction of endogenous retroelements, dysregulation of nucleic acid immunity can also lead to erroneous detection and response to self nucleic acids then causing sterile inflammation and autoimmunity. Even mechanisms of nucleic acid immunity which are not established in vertebrates are relevant for human disease when they are present in pathogens such as bacteria, parasites, or helminths or in pathogen-transmitting organisms such as insects. This review aims to provide an overview of the diverse mechanisms of nucleic acid immunity which mostly have been looked at separately in the past and to integrate them under the framework nucleic acid immunity as a basic principle of life, the understanding of which has great potential to advance medicine.

Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression

“…Figure S3A). The particularly strong induction of Tlr7 as sensor (at endosomes or lysosomes) for toxic single-stranded RNA and miRNA (3.5-fold), in comparison to Tlr9 as sensor of single-stranded DNA sequences (2.3-fold) and Tlr3 as sensor of double-stranded RNA (1.3-fold) underlined and elucidated the RNA-toxicity [68, 74, 100] present in the spinal cord tissue of our SCA2 model. It is interesting to note that Ataxin-2 domains were reported to play a role in the miRNA-mediated mRNA degradation [90] and to interact with the microRNA effector DDX6 to mediate quality control of mRNAs [4, 120, 132, 198].…”

Perception of double‐stranded RNA in plant antiviral immunity

“…PTI has only recently been discovered to act against viruses in plants ( Kørner et al, 2013;Nicaise and Candresse, 2017;Niehl et al, 2016;Yang et al, 2010;Zvereva et al, 2016). RNA-based pathogen-associated molecular patterns (PAMPs) are well-known inducers of immunity in animals (Chow et al, 2018;Hartmann, 2017;Tan et al, 2015;Vabret et al, 2017), and have been shown to induce immunity upon viral and bacterial infection also in plants (Lee et al, 2016;Niehl et al, 2016). The mechanism of dsRNA recognition leading to PTI as well as the mode of action against the infecting virus is unknown.…”

The Role of Nucleic Acid Sensing in Controlling Microbial and Autoimmune Disorders

“…Of note, human TLR9 is predominantly expressed in plasmacytoid dendritic cells and B cells, resulting in a strong type I IFN response via MyD88/IRF7 signaling. Conversely, murine TLR9 is expressed abundantly in myeloid immune cells and can also result in IFN-γ production and the recruitment of NK, αβ-, and γδ-T cells (Hartmann, 2017; Hornung et al, 2002; Krug et al, 2004; Walker et al, 2010). For example, it has been shown that CMV infection in mice activates a TLR9/MyD88 response that occurs selectively in CD11 + dendritic cells (Krug et al, 2004; Puttur et al, 2016).…”