Whole exome sequencing of patients with varicella-zoster virus and herpes simplex virus induced acute retinal necrosis reveals rare disease-associated genetic variants

Abstract

PurposeHerpes simplex virus (HSV) and varicella-zoster virus (VZV) are neurotropic human alphaherpesviruses endemic worldwide. Upon primary infection, both viruses establish lifelong latency in neurons and reactivate intermittently to cause a variety of mild to severe diseases. Acute retinal necrosis (ARN) is a rare, sight-threatening eye disease induced by ocular VZV or HSV infection. The virus and host factors involved in ARN pathogenesis remain incompletely described. We hypothesize an underlying genetic defect in at least part of ARN cases.MethodsWe collected blood from 17 patients with HSV-or VZV-induced ARN, isolated DNA and performed Whole Exome Sequencing by Illumina followed by analysis in Varseq with criteria of CADD score > 15 and frequency in GnomAD < 0.1% combined with biological filters. Gene modifications relative to healthy control genomes were filtered according to high quality and read-depth, low frequency, high deleteriousness predictions and biological relevance.ResultsWe identified a total of 50 potentially disease-causing genetic variants, including missense, frameshift and splice site variants and on in-frame deletion in 16 of the 17 patients. The vast majority of these genes are involved in innate immunity, followed by adaptive immunity, autophagy, and apoptosis; in several instances variants within a given gene or pathway was identified in several patients.DiscussionWe propose that the identified variants may contribute to insufficient viral control and increased necrosis ocular disease presentation in the patients and serve as a knowledge base and starting point for the development of improved diagnostic, prophylactic, and therapeutic applications.

Varicella zoster virus‐induced autophagy in human neuronal and hematopoietic cells exerts antiviral activity

“…Additionally, defects in the autophagy pathway have been proposed as novel IEI predisposing to severe viral disease in recurrent lymphocytic HSV2 Mollaret meningitis, 73 and poliomyelitis 53 . Recently, we reported findings of variants in genes encoding autophagy‐molecules in patients suffering from severe disease following VZV infection or ‐reactivation, including VZV encephalitis and VZV‐induced ARN 47,48 . Here, we show reduced, but not abolished, autophagy in MdMs together with increased VZV replication in PBMCs from two patients with VZV CNS infection harboring variants in ULK1 and MAP1LC3B2 .…”

“…To pursue our findings on VZV‐induced autophagy and a potential antiviral role of autophagy in neuronal cells, we asked the question whether autophagy defects may be present in patients suffering from severe CNS infection with VZV. We therefore investigated our previously described cohorts of patients with VZV encephalitis or meningoencephalitis (N = 17) 47 and VZV‐induced ARN (N = 17) 48 . Bioinformatic analysis resulted in the identification of 8 variants in genes involved in the autophagy pathway in 6 of 17 (35%) VZV encephalitis patients and in 6 autophagy‐related variants in 7 of 17 (41%) ARN patients 47,48 .…”

“…We therefore investigated our previously described cohorts of patients with VZV encephalitis or meningoencephalitis (N = 17) 47 and VZV-induced ARN (N = 17). 48 Bioinformatic analysis resulted in the identification of 8 variants in genes involved in the autophagy pathway in 6 of 17 (35%) VZV encephalitis patients and in 6 autophagy-related variants in 7 of 17 (41%) ARN patients. 47,48 Based on the bioinformatic predictions on deleteriousness of these variants, combined with the central role of autophagy proteins encoded by the respective genes, we went on to functionally investigate autophagy responses and VZV replication in two of these patients.…”

“…Additional results of the exome analysis in these VZV CNS infection cohorts is available in the respective publications. 47,48…”

“…P1 was included as P1 in a VZV encephalitis cohort described by Thomsen et al (2021), 47 and P2 was included as P2 in an ARN cohort described by Heinz et al (2023). 48 Whole blood was collected into EDTA tubes for DNA extraction and in lithium heparin tubes for peripheral blood mononuclear cell (PBMC) isolation.…”