Increased level of compleasomes in cerebrospinal fluid of patients with herpes simplex encephalitis

Ewa Johansson,Stefan Lange,Merna Oshalim,Marie Studahl,Ivar Lönnroth,Tomas Bergström

doi:10.1007/s13365-018-0665-x

Ewa Johansson, Stefan Lange + Show 4 more

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https://doi.org/10.1007/s13365-018-0665-x

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Abstract

Herpes simplex encephalitis (HSE) is a common cause of viral encephalitis (HSV-1) characterised by pronounced inflammation and elevated intracranial pressure. We have shown in a rat model that HSV-1 infection causes an interaction between complement factors and proteasomes, leading to formation of proteasome/complement complexes (compleasomes). Exposure of the proteasome regulatory subunit antisecretory factor 1 (AF1) leads to a decrease in intracranial pressure. The aim of this study was to evaluate the acute and prolonged formation of compleasomes in cerebrospinal fluid (CSF) from patients with HSE. Cerebrospinal fluid samples (n = 55) from 24 HSE patients were analysed for compleasome complexes. Samples from healthy controls (n = 23) and patient controls (n = 27) served as baseline information. Sandwich enzyme-linked immunosorbent assay (ELISA) for proteasomes and their complex formation with complement factor 3 or 4, and Western blot for C3 activation were performed on CSF samples. Increased compleasome formation, both presenting as an initial formation and showing exposure of subunit AF1 in the compleasomes, was found in CSF samples drawn from patients with HSE compared with samples from the control groups (p < 0.0005). The total protein CSF concentration was equal in all groups. The levels were higher in the acute phase compared with late in the disease course (p < 0.0005). Complement 3 breakdown product iC3b was detected in CSF samples of the HSE patients. The early increased formation of compleasomes in CSF suggests that this complex may be involved in host defence against HSE.

Highlights

Herpes simplex encephalitis (HSE), most often caused by herpes simplex virus type 1 (HSV-1), induces an acute focal, necrotizing inflammation with a predilection for the frontotemporal regions of the brain
The role of a high intracranial pressure (ICP) is scarcely investigated in human HSE, but since a high ICP leads to decreased consciousness which is associated to poor prognosis in HSE (Singh et al 2016), a high ICP might be a bad prognostic factor (Jouan et al 2015; Barnett et al 1988) and a target for therapy
The levels detected in samples collected from patient controls (PC) were somewhat increased compared with cerebrospinal fluid (CSF) obtained from healthy controls (HC)

Summary

Introduction

Herpes simplex encephalitis (HSE), most often caused by herpes simplex virus type 1 (HSV-1), induces an acute focal, necrotizing inflammation with a predilection for the frontotemporal regions of the brain. In CSF, extracellular proteasomes have been suggested to play a role in neurodegenerative inflammatory diseases of the CNS (Mueller et al 2012). The 43-kD ubiquitously expressed AF1 protein has been shown to exert a potent antisecretory and anti-inflammatory effect (Davidson and Hickey 2004; Johansson et al 1995; Lange and Lonnroth 2001). Administered AF-16 in rats experimentally infected with HSV-1 has been demonstrated to abolish sickness and death during time course of infection (Jennische et al 2008), most likely accomplished by an AF-16-mediated absence of increased intracranial pressure (ICP) ubiquitously found in HSE-affected rats. Decreasing of a high ICP in infected rats has been achieved by a diet-induced rise in endogenous AF1 (Johansson et al 2013). The role of a high ICP is scarcely investigated in human HSE, but since a high ICP leads to decreased consciousness which is associated to poor prognosis in HSE (Singh et al 2016), a high ICP might be a bad prognostic factor (Jouan et al 2015; Barnett et al 1988) and a target for therapy

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