Abstract
Herpes simplex encephalitis (HSE) is a fatal infection of the central nervous system (CNS) predominantly caused by Herpes simplex virus type 1. Factors regulating the susceptibility to HSE are still largely unknown. To identify host gene(s) regulating HSE susceptibility we performed a genome-wide linkage scan in an intercross between the susceptible DA and the resistant PVG rat. We found one major quantitative trait locus (QTL), Hse1, on rat chromosome 4 (confidence interval 24.3–31 Mb; LOD score 29.5) governing disease susceptibility. Fine mapping of Hse1 using recombinants, haplotype mapping and sequencing, as well as expression analysis of all genes in the interval identified the calcitonin receptor gene (Calcr) as the main candidate, which also is supported by functional studies. Thus, using unbiased genetic approach variability in Calcr was identified as potentially critical for infection and viral spread to the CNS and subsequent HSE development.
Highlights
Herpes simplex type 1 virus (HSV-1) is a member of the Herpesviridae family (Alphaherpesvirinae subfamily) that infects a large fraction of humans resulting in transient cold sores or nonsymptomatic infection that persists lifelong in the sensory ganglia
Further support for a role of CalcR in regulating HSV-1 replication and propagation is provided by strain-dependent differences in the calcitonin receptor protein tissue localization and in functional studies
Using an unbiased genetic mapping approach this study identifies calcitonin receptor gene (Calcr) as a candidate for regulating susceptibility to Herpes simplex encephalitis (HSE)
Summary
Herpes simplex type 1 virus (HSV-1) is a member of the Herpesviridae family (Alphaherpesvirinae subfamily) that infects a large fraction of humans resulting in transient cold sores or nonsymptomatic infection that persists lifelong in the sensory ganglia. Recurrent herpetic disease results from reactivation of HSV-1 in the sensory ganglia subsequently leading to axonal transport of the virus to the periphery where it causes skin lesions, cold sores, often located around the mouth. HSV-1 can cause a much more severe condition, Herpes simplex encephalitis (HSE), an acute inflammatory condition of the brain. Even though Herpes simplex is a neurotropic virus, HSE occurs in only 2–3 previously healthy individuals/million/year in all age groups [1]. HSE is characterized by acute onset of focal infection, inflammation and necrosis, mostly starting unilaterally in the fronto-medio-basal temporal lobe. The mortality is high and there is significant morbidity among the survivors
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