Innate immune response in neuronopathic forms of Gaucher disease confers resistance against viral-induced encephalitis

Sharon Melamed,Tomer Israely,Roy Avraham,Ziv Klausner,Nir Paran,Einat B Vitner,Noam Erez,Deborah E Rothbard,Anthony H Futerman

doi:10.1186/s40478-020-01020-6

Abstract

Both monogenic diseases and viral infections can manifest in a broad spectrum of clinical phenotypes that range from asymptomatic to lethal, suggesting that other factors modulate disease severity. Here, we examine the interplay between the genetic neuronopathic Gaucher’s disease (nGD), and neuroinvasive Sindbis virus (SVNI) infection. Infection of nGD mice with SVNI had no influence on nGD severity. However, nGD mice were more resistant to SVNI infection. Significantly different inflammatory responses were seen in nGD brains when compared with SVNI brains: the inflammatory response in the nGD brains consisted of reactive astrocytes and microglia with no infiltrating macrophages, but the inflammatory response in the brains of SVNI-infected mice was characterized by infiltration of macrophages and altered activation of microglia and astrocytes. We suggest that the innate immune response activated in nGD confers resistance against viral infection of the CNS.

Highlights

Brain inflammation is a common characteristic of many disorders of the central nervous system (CNS)
Accumulation of GlcCer confers resistant to infection with neuroinvasive Sindbis virus To determine whether GlcCer accumulation in the brain modulates viral pathogenesis, and/or whether viral infection of the CNS affects the severity of neuronopathic Gaucher’s disease (nGD) pathology, we infected nGD mice with a lethal dose of SVNI
In this study we identified two distinct innate immune responses in the brain: one is activated in response to a chronic intrinsic stimulus (i.e. GlcCer accumulation) and the other activated by an acute extrinsic stimulus (i.e. SVNI infection)

Summary

Introduction

Brain inflammation is a common characteristic of many disorders of the central nervous system (CNS). The innate immune response is critical for limiting pathogen invasion of the CNS and essential to mediate host resistance. The innate immune response is associated with genetic neurodegenerative diseases despite their different etiologies. In contrast to infectious diseases where immune activation is resolved by elimination of infectious agents, the immune response stimuli persist in genetic diseases and cannot be resolved, resulting in chronic inflammation. Epidemiologic studies, and meta-analysis suggest a neutral to moderately detrimental role of the innate immune response in neurodegenerative disease pathology, as observed by the limited or non-effectivity of nonsteroidal anti-inflammatory drugs (NSAIDs) and by genetic knock-out of immune pathways [37, 56, 79]

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Conclusion