Asymptomatic Herpes Simplex Virus Type 1 Infection Causes an Earlier Onset and More Severe Experimental Autoimmune Encephalomyelitis.

Luisa F Duarte,Pablo A González,Jorge H Tabares-Guevara,Omar P Vallejos,Susan M Bueno,Romina Navarrete,Claudia A Riedel,Máximo Díaz,Catalina Muza,Alexis M Kalergis,Ma Cecilia Opazo,María J Altamirano-Lagos

doi:10.3389/fimmu.2021.635257

Abstract

Multiple sclerosis (MS) is an increasingly prevalent progressive autoimmune and debilitating chronic disease that involves the detrimental recognition of central nervous system (CNS) antigens by the immune system. Although significant progress has been made in the last decades on the biology of MS and the identification of novel therapies to treat its symptoms, the etiology of this disease remains unknown. However, recent studies have suggested that viral infections may contribute to disease onset. Interestingly, a potential association between herpes simplex virus type 1 (HSV-1) infection and MS has been reported, yet a direct relationship among both has not been conclusively demonstrated. Experimental autoimmune encephalomyelitis (EAE) recapitulates several aspects of MS in humans and is widely used to study this disease. Here, we evaluated the effect of asymptomatic brain infection by HSV-1 on the onset and severity of EAE in C57BL/6 mice. We also evaluated the effect of infection with an HSV-1-mutant that is attenuated in neurovirulence and does not cause encephalitis. Importantly, we observed more severe EAE in mice previously infected either, with the wild-type (WT) or the mutant HSV-1, as compared to uninfected control mice. Also, earlier EAE onset was seen after WT virus inoculation. These findings support the notion that a previous exposure to HSV-1 can accelerate and enhance EAE, which suggests a potential contribution of asymptomatic HSV-1 to the onset and severity of MS.

Highlights

Multiple sclerosis (MS) is an autoimmune inflammatory disorder of the central nervous system (CNS) that affects both, the brain and spinal cord in which multifocal autoreactive lymphocytic infiltrations lead to the damage of the myelin and the axons of neurons [1, 2]
To assess a potential effect of asymptomatic Herpes simplex virus type 1 (HSV-1) infection of the CNS over the onset and severity of EAE in the mouse model, we performed experiments with C57BL/6 mice. This mouse strain has been reported to be resistant to acute HSV1 encephalitis and could better reflect circumstances related to asymptomatic and latent CNS infections reported in humans that do not show clinical manifestations, despite having the virus in the brain [11, 40]
Infections with human herpesviruses have been suggested as potential triggers or enhancers of MS in recent reports [21, 23], yet studies that assess or support a role for HSV-1 infection are relatively scarce and a direct relationship between this virus and MS disease has not been reported before [25, 46,47,48]

Summary

Introduction

Multiple sclerosis (MS) is an autoimmune inflammatory disorder of the central nervous system (CNS) that affects both, the brain and spinal cord in which multifocal autoreactive lymphocytic infiltrations lead to the damage of the myelin and the axons of neurons [1, 2]. Increased levels of the matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) have been detected in HSV-1 latently-infected CNS, which could contribute to the degradation of the surrounding extracellular matrix and cell surface proteins leading to a partial breakdown of the bloodbrain barrier (BBB), which plays an important role in MS [16, 17] This inflammatory response could arise due to low-level expression of viral genes during HSV-1 latency of the CNS [18], which could promote or facilitate an inflammatory environment that modulates the onset and severity of neurological disorders [12, 19]

Methods

Results

Conclusion