Von Willebrand Factor Gene Variants Associate with Herpes simplex Encephalitis

Abstract

Herpes simplex encephalitis (HSE) is a rare complication of Herpes simplex virus type-1 infection. It results in severe parenchymal damage in the brain. Although viral latency in neurons is very common in the population, it remains unclear why certain individuals develop HSE. Here we explore potential host genetic variants predisposing to HSE. In order to investigate this we used a rat HSE model comparing the HSE susceptible SHR (Spontaneously Hypertensive Rats) with the asymptomatic infection of BN (Brown Norway). Notably, both strains have HSV-1 spread to the CNS at four days after infection. A genome wide linkage analysis of 29 infected HXB/BXH RILs (recombinant inbred lines—generated from the prior two strains), displayed variable susceptibility to HSE enabling the definition of a significant QTL (quantitative trait locus) named Hse6 towards the end of chromosome 4 (160.89–174Mb) containing the Vwf (von Willebrand factor) gene. This was the only gene in the QTL with both cis-regulation in the brain and included several non-synonymous SNPs (single nucleotide polymorphism). Intriguingly, in human chromosome 12 several SNPs within the intronic region between exon 43 and 44 of the VWF gene were associated with human HSE pathogenesis. In particular, rs917859 is nominally associated with an odds ratio of 1.5 (95% CI 1.11–2.02; p-value = 0.008) after genotyping in 115 HSE cases and 428 controls. Although there are possibly several genetic and environmental factors involved in development of HSE, our study identifies variants of the VWF gene as candidates for susceptibility in experimental and human HSE.

The controversial natural history of oral herpes simplex virus type 1 infection

“…If the viral load that causes the primary infection is particularly high, and/or the infected subject is immunocompromised or lacks specific anti-viral activity (Abdelmagid et al, 2016;Casrouge et al, 2006;Pourchet, Modrek, Placantonakis, Mohr, & Wilson, 2017), HSV-1 particles surpass the Trigeminal Ganglion and reach the Geniculate Ganglion (Facial Nerve, CN-7) via the lingual nerve and, from there, the Vestibular Ganglion (Vestibulocochlear Nerve, anastomoses. Although latency can be induced into these ganglia, HSV-1 infection control by the host is less efficient and complications, such as Bell's palsy (Geniculate Ganglion), sudden hearing loss, and vestibular neuritis (Vestibular Ganglion) may occur (Arbusow et al, 2010;Himmelein et al, 2017).…”

Contribution of a European‐Prevalent Variant near CD83 and an East Asian–Prevalent Variant near IL17RB to Herpes Zoster Risk in Tofacitinib Treatment: Results of Genome‐Wide Association Study Meta‐Analyses

“…The levels of vWF rise in multiple types of infections ( 38 , 39 ). In a candidate gene study, VWF genetic variants were associated with human herpes simplex encephalitis, a rare complication following infection with herpes simplex virus type 1, which usually remains latent in neurons ( 40 ). Thus, the VWF gene may have roles in multiple infections; however, the mechanisms of vWF in HZ have not been directly studied.…”

Viruses in human central nervous system — invasion, transmission, and latency: a literature review

“…В последнее время все большее внимание уделяют генетической предрасположенности к заражению вирусами и клиническому течению заболевания. Так, одним из возможных факторов предрасположенности к HSV энцефалиту считают наличие генетических вариантов в гене фактора фон Виллебранда (Vwf ) [78]. Различное клиническое течение заболевания при заражении RABV зависит от регуляции экспрессии MHC II [79].…”