Neuron-intrinsic immunity to viruses in mice and humans

Abstract

Viral encephalitis is a major neglected medical problem. Host defense mechanisms against viral infection of the central nervous system (CNS) have long remained unclear. The few previous studies of CNS-specific immunity to viruses in mice in vivo and humans in vitro have focused on the contributions of circulating leukocytes, resident microglial cells and astrocytes, with neurons long considered passive victims of viral infection requiring protection from extrinsic antiviral mechanisms. The last decade has witnessed the gradual emergence of the notion that neurons also combat viruses through cell-intrinsic mechanisms. Forward genetic approaches in humans have shown that monogenic inborn errors of TLR3, IFN-α/β, or snoRNA31 immunity confer susceptibility to herpes simplex virus 1 (HSV-1) infection of the forebrain, whereas inborn errors of DBR1 underlie brainstem infections due to various viruses, including HSV-1. The study of human pluripotent stem cell (hPSC)-derived CNS-resident cells has unraveled known (i.e. TLR3-dependent IFN-α/β immunity) and new (i.e. snoRNA31-dependent or DBR1-dependent immunity) cell-intrinsic antiviral mechanisms operating in neurons. Reverse genetic approaches in mice have confirmed that some known antiviral mechanisms also operate in mouse neurons (e.g. TLR3 and IFN-α/β immunity). The search for human inborn errors of immunity (IEIs) underlying various forms of viral encephalitis, coupled with mouse models in vivo, and hPSC-based culture models of CNS and peripheral nervous system cells and organoids in vitro, should shed further light on the cell-specific and tissue-specific mechanisms of host defense against viruses in the human brain.

Figure 1.. Illustration of neuron-intrinsic type I IFN immunity or new antiviral mechanisms crucial for defense against viral infection of the central nervous system in humans.

TLR3-type I IFN circuit and snoRNA31 immunity in forebrain HSV-1 infection (left), and DBR1-mediated RNA lariat metabolism in brainstem viral infection (right). TLR3 controls basal levels of IFN-β-mediated anti-HSV-1 immunity in cortical neurons and oligodendrocytes. DBR1 controls brainstem-specific immunity to viruses (HSV-1, influenza virus, norovirus), presumably in neurons and other cells of the brainstem, which is composed of the midbrain and hindbrain. In red: molecules shown to be involved in TLR3-IFN-α/β-mediated or snoRNA31-mediated immunity to HSV-1 in cortical neurons (left), or involved in DBR1-mediated RNA lariat metabolism controls brainstem viral encephalitis due to HSV-1, influenza virus and norovirus (right). In dark gray: other key molecules of the TLR3-type I IFN circuit that have not been shown to be involved in central nervous system antiviral immunity in humans.