Cytosolic DNA Sensors and CNS Responses to Viral Pathogens

Abstract

Viral central nervous system (CNS) infections can lead to life threatening encephalitis and long-term neurological deficits in survivors. Resident CNS cell types, such as astrocytes and microglia, are known to produce key inflammatory and antiviral mediators following infection with neurotropic DNA viruses. However, the mechanisms by which glia mediate such responses remain poorly understood. Recently, a class of intracellular pattern recognition receptors (PRRs), collectively known as DNA sensors, have been identified in both leukocytic and non-leukocytic cell types. The ability of such DNA sensors to initiate immune mediator production and contribute to infection resolution in the periphery is increasingly recognized, but our understanding of their role in the CNS remains limited at best. In this review, we describe the evidence for the expression and functionality of DNA sensors in resident brain cells, with a focus on their role in neurotropic virus infections. The available data indicate that glia and neurons can constitutively express, and/or can be induced to express, various disparate DNA sensing molecules previously described in peripheral cell types. Furthermore, multiple lines of investigation suggest that these sensors are functional in resident CNS cells and are required for innate immune responses to viral infections. However, it is less clear whether DNA sensormediated glial responses are beneficial or detrimental, and the answer to this question appears to dependent on the context of the infection with regard to the identity of the pathogen, host cell type, and host species. Defining such parameters will be essential if we are to successfully target these molecules to limit damaging inflammation while allowing beneficial host responses to improve patient outcomes.

Keywords: DNA sensors; astrocytes; microglia; neuroinflammation; viral encephalitis.

Figure 1

Intracellular DNA sensors in resident CNS cell types. Intracellular nucleic acid sensing by DNA sensors in microglia, astrocytes, and neurons. AIM2 sensing of dsDNA leads to the recruitment of apoptosis-associated speck-like protein containing a CARD (ASC) that then cleaves pro-caspase 1. Active caspase 1 then cleaves the precursor forms of IL18 and IL-1β, causing their maturation and release from the cell. ZBP1 sensing of either dsDNA or RNA causes it to associate with RIPK3, activate the transcription factor NF-κB, and phosphorylate mixed lineage kinase domain-like protein (MLKL) in microglia and astrocytes. This results in pro-inflammatory cytokine expression and execution of necroptosis. In neurons, ZBP1 sensing results in the activation of IRF1, expression of IRG1, production of itaconate, and a reduction in succinate dehydrogenase (SDH) activity. Sensing of dsDNA by cGAS leads to the production of cGAMP, which binds to and activates STING causing the phosphorylation and translocation of interferon regulatory factor 3 (IRF3) to the nucleus. This results in the expression of IFN and ISGs in microglia and astrocytes. RNA pol III senses dsDNA and converts it into dsRNA that can then be sensed by RIG-I in microglia and astrocytes. RIG-I sensing of dsRNA causes it to associate with mitochondrial antiviral-signaling protein (MAVS) leading to activation and translocation of IRF3 and NF-κB, resulting in the expression of IFN, ISGs, and pro-inflammatory cytokines. This figure was created with BioRender.com.