Genetic defects of brain immunity in childhood herpes simplex encephalitis

Abstract

Herpes simplex virus 1 (HSV-1) encephalitis (HSE) is the most common sporadic viral encephalitis in humans. It is life-threatening and has a first peak of incidence in childhood, during primary infection. Children with HSE are not particularly prone to other infections, including HSV-1 infections of tissues other than the brain. About 8-10% of childhood cases are due to monogenic inborn errors of 19 genes, two-thirds of which are recessive, and most of which display incomplete clinical penetrance. Childhood HSE can therefore be sporadic but genetic, enabling new diagnostic and therapeutic approaches. In this Review, we examine essential cellular and molecular mechanisms of cell-intrinsic antiviral immunity in the brain that are disrupted in individuals with HSE. These mechanisms include both known (such as mutations in the TLR3 pathway) and previously unknown (such as the TMEFF1 restriction factor) antiviral pathways, which may be dependent (for example, IFNAR1) or independent (for example, through RIPK3) of type I interferons. They operate in cortical or brainstem neurons, and underlie forebrain and brainstem infections, respectively. Conversely, the most severe inborn errors of leukocytes, including a complete lack of myeloid and/or lymphoid blood cells, do not underlie HSE. Thus congenital defects in intrinsic immunity in brain-resident neurons that underlie HSE broaden natural host defences against HSV-1 from the leukocytes of the immune system to other cells in the organism.

Figure 1.. Anatomic structure of the human brain and images displaying typical forebrain lesions in patients with genetically defined HSE

Anatomic structure of the human brain (left panel), and brain MRI scans from two patients with typical forebrain HSE enrolled in our study who were found to have deficiencies of IFNAR1 (middle panel, post-contrast T2-FLAIR imaging, adapted from Bastard et al., JCI 2021) or RIPK3 (right panel, post-contrast T2-weighted imaging, adapted from Liu et al., Sci Immunol 2023). Yellow arrows indicate the lesions detected, affecting the temporo-occipital regions, the left thalamus and base of the frontal lobes (middle panel), or the left insula (right panel).

Figure 2.. Monogenic inborn errors of immunity disrupt type I IFN-dependent and -independent cell-intrinsic antiviral mechanisms, conferring a predisposition to childhood HSE

Monogenic inborn errors of the type I IFN production or response pathways, or of snoRNA31-, RIPK3- or TMEFF1-mediated antiviral immunity confer susceptibility to forebrain HSE. Inborn errors of DBR1 underlie brainstem HSE. TLR3, UNC93B1 and TRIF govern the dsRNA-sensing TLR3-IFN production pathway, which is also controlled by the downstream molecules TRAF3, NEMO, TBK1 and IRF3. TFIIIA is a component of the POL III complex that generates the endogenous RIG-I agonist RNA5SP141 during HSV-1 infection, thereby controlling RIG-I-dependent IFN production in HSV-1-infected cells. IFNAR1/IFNAR2 govern the type I IFN response pathway, which is also controlled by the downstream molecules JAK1, TYK2, STAT1, and STAT2. SnoRNA31, RIPK3, DBR1 and TMEFF1 control cell-intrinsic antiviral immunity independently of type I IFNs. RIPK3 deficiency impairs cortical neuron-intrinsic necroptotic and apoptotic cell death-mediated antiviral immunity to HSV-1. SnoRNA31 is a previously unknown HSV-1 restriction factor in cortical neurons. Its genetic deficiency results in uncontrolled HSV-1 replication in neurons, thereby underlying HSE. DBR1 deficiency results in an accumulation of RNA lariats within cells, leading to an impairment of PKR-mediated cell-intrinsic immunity to HSV-1 and other viruses in the brainstem. TMEFF1 blocks HSV-1 entry by interacting with NECTIN-1 at the cell surface. In pink: gene mutations found in patients with forebrain HSE. In dark purple: gene mutations found in patients with brainstem HSE. In light pink: other known important molecules of the pathways implicated that have yet to be shown to be related to HSE.

Figure 3.. Inborn errors of immunity and their autoimmune phenocopies underlie HSE and WNV encephalitis, respectively

Inborn errors of immunity (IEI) have been found in about 10% of the patients with childhood HSE studied (on the left), whereases autoantibodies neutralizing type I IFNs (AAB-IFN I) have been found in about 40% of patients with WNV encephalitis during adulthood (on the right). The roles of AAB-IFN I in HSE and of IEIs in WNV encephalitis remain to be investigated.