Genetic defects of brain immunity in childhood herpes simplex encephalitis

• 成果类型: Review
• 署名作者: Zhang, Shen-Ying; Casanova, Jean-Laurent
• 署名单位: Rockefeller University; Institut National de la Sante et de la Recherche Medicale (Inserm); Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Necker-Enfants Malades - APHP; Universite Paris Cite; Institut National de la Sante et de la Recherche Medicale (Inserm); Howard Hughes Medical Institute; Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Necker-Enfants Malades - APHP
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5755
• DOI: 10.1038/s41586-024-08119-z
• 发表日期: 2024-11-21
• 页码: 563-573
• 关键词: nf-kappa-b; pyogenic bacterial-infections; neuron-intrinsic immunity; lariat-debranching enzyme; toll-like receptor-3; human inborn-errors; double-stranded-rna; tlr3 deficiency; virus encephalitis; primary immunodeficiencies

摘要

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. This article reviews evidence that has emerged over the past two decades indicating that herpes simplex encephalitis in children can result from monogenic defects of brain immunity to herpes simplex virus 1.