CpG Oligonucleotides Protect Mice From Alphavirus Encephalitis: Role of NK Cells, Interferons, and TNF.

Mohanraj Manangeeswaran,Derek D.C Ireland,Tomer Israely,Daniela Verthelyi,Aaron P Lewkowicz

doi:10.3389/fimmu.2020.00237

Mohanraj Manangeeswaran, Derek D.C Ireland + Show 3 more

Open Access

https://doi.org/10.3389/fimmu.2020.00237

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Abstract

Arboviruses including alphavirus are responsible for most emerging infectious diseases worldwide. Recent outbreaks of chikungunya virus serve as a stark reminder to their pathogenic potential. There are no vaccines or therapeutics currently available to contain alphavirus outbreaks. In this study we evaluated the effect of immunomodulatory CpG ODN on the clinical progression of neurotropic Sindbis virus infection. Neonatal C57Bl-6 mice challenged with Sindbis virus AR339 (25 PFU Subcutaneous) infect neurons in the CNS leading to the development of ataxia, seizures, paralysis, and death. We show that systemic administration of CpG ODN modulates the cytokine and chemokine gene expression levels in the CNS and ultimately protects neonatal mice from lethal neurotropic infection. The protection conferred by CpG ODN is controlled by innate immune response and T and B cells were dispensable. Further, protection required Type I, Type II interferons, and TNF as well as functional NK cells, but did not involve iNOS. This study confirms that administration of innate immune modulators can be used as a strategy to boost host innate immune responses and protect against neurotropic viruses reducing their pathogenic footprint.

Highlights

A wide range of viruses can infect the central nervous system (CNS) causing acute encephalitis and long-term neurological sequelae, early in life
Infection with wild type Sindbis virus strain AR 339 (SINV) in adult C57BL/6 mice (B6- WT) leads to a short viremia with no evidence of virus in CNS, as all B6-WT mice survive the challenge without showing symptoms of disease (Supplementary Figures 1A,B), despite the virus being lethal in B6-IFNAR1 KO (Supplementary Figure 1C)
Since neonatal mice challenged with SINV showed neurological symptoms, we examined whether the virus infected the CNS

Summary

Introduction

A wide range of viruses can infect the CNS causing acute encephalitis and long-term neurological sequelae, early in life. Alphaviruses are enveloped, positive-strand, RNA viruses in the Togaviridae family, which includes Venezuelan (VEE), western (WEE) and eastern equine (EEE) encephalitis, and Chikungunya viruses. They are transmitted primarily by mosquitoes and known to cause widespread epidemics of fever, arthritis, and encephalitis. Alphavirus-induced encephalitis can result in incapacitating neurological damage and death [1, 2]. While these viruses have defined endemic areas, climate changes and increased travel are leading to outbreaks in new territories where there is no immunological memory to the infection in the population. There are no approved vaccines or therapeutics for these viruses, so there is a pressing need to establish preclinical models that allow for improved

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