Saturday, April 27, 2024
4/27/2024
Project Summary Childhood herpes simplex encephalitis (HSE) is a life-threatening complication of primary infection with herpes simplex virus 1 (HSV-1), which is typically innocuous. Acyclovir-treated survivors often suffer from severe neurological sequelae. Most infections affect the forebrain, with only a minority affecting the brainstem. HSE is the most common sporadic viral encephalitis in Western countries. Its pathogenesis remained unclear until we showed that it results, in some children, from single-gene inborn errors of immunity to HSV-1 in the central nervous system (CNS). Using a candidate gene approach, we and others discovered the first six genetic etiologies of forebrain HSE: mutations of TLR3, UNC93B1, TRIF, TRAF3, TBK1, and IRF3. These disorders impair TLR3-dependent, IFN-a/ß- and IFN-l-mediated, cell-intrinsic immunity in iPSC-derived cortical neurons. With NIH R01AI088364 funding, we initiated a genome-wide approach to search for novel HSE-causing genes by a combination of genome-wide linkage (GWL) analysis and whole-exome sequencing (WES). This led to the discovery of 1) a novel genetic etiology of forebrain HSE, SNORA31 mutations, and 2) the first genetic etiology of brainstem HSE, DBR1 mutations. Both disorders impair cell-intrinsic immunity to HSV-1 by novel mechanisms, independent of TLR3. No genetic etiology has yet been identified for 258 of the 280 HSE patients studied. We now hypothesize that 1) other single-gene inborn errors of CNS-intrinsic immunity to HSV-1 can underlie HSE, and 2) mutations affecting different pathways are responsible for forebrain and brainstem HSE. In the work proposed in this renewal application, we will use next-generation sequencing (NGS), including WES, whole- genome sequencing (WGS), and RNA-seq, to search for novel genetic etiologies of HSE. We will analyze the NGS data at both the population and patient levels, following both a candidate gene approach and an unbiased hypothesis-generating approach. We will consider models based on both genetic homogeneity and genetic heterogeneity, while also testing both physiological homogeneity (HSE-causing genes being physiologically related) and heterogeneity (different pathways involved), making use of novel computational approaches. We will analyze the function of mutant alleles of candidate genes. We will also use the patients’ fibroblasts to investigate the impact of the candidate genotypes on anti-HSV-1 immunity. This application is innovative but supported by exciting preliminary data. We have established a unique international cohort of 450 HSE children and intend to enroll at least 600 patients. From the WES data for the first 280 patients, we have already identified biallelic mutations of MEX3B and IFNAR1 (in the TLR3-IFN-a/b circuit), RIPK1 and RIPK3 (in the TLR3- necroptosis pathway), and TMEFF1 (defining a novel pathway). Our research will decipher the pathogenesis of a devastating pediatric illness, paving the way for new therapeutic approaches. The genetic analysis of HSE will also provide proof-of-principle that sporadic, life-threatening infectious diseases striking an isolated organ in otherwise healthy children can result from single-gene inborn errors of non-hematopoietic cell-intrinsic immunity.
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