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.

Department of Clinical Neuroscience Neuroimmunology Unit Karolinska Institutet Karolinska University Hospital SE 171 76 Stockholm Sweden

Department of Clinical Virology University of Gothenburg SE 413 46 Gothenburg Sweden

Department of Infectious Diseases Institute of Biomedicine Sahlgrenska Academy University of Gothenburg Gothenburg Sweden

Department of Medicine Unit of Infectious Diseases Karolinska Institutet Karolinska University Hospital SE 171 76 Stockholm Sweden

Department of Pharmacology University of Colorado Denver School of Medicine Denver United States of America

Division of Medicine Imperial College London London United Kingdom

Institut National de la Santé et de la Recherche Médicale UMR_S 1176 Univ Paris Sud Université Paris Saclay 94276 Le Kremlin Bicêtre France

Institute of Physiology Academy of Sciences of the Czech Republic Prague Czech Republic

Max Delbruck Center for Molecular Medicine Berlin Buch Berlin Germany

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