Volume 133, 30 May 2024, 112083Author links open overlay panel, , , , , , Highlights•

Japanese encephalitis virus （JEV）activated the acid sphingomyelinase (ASM) and ceramide in the rats.

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ASM was involved in immune cell differentiation and activation, exerting proinflammatory effects.

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Intravenous immunoglobulin was an acid sphingomyelinase function inhibitor (FIASMA).

Abstract

Japanese encephalitis virus (JEV) infection is considered a global public health emergency. Severe peripheral neuropathy caused by JEV infection has increased disability and mortality rates in recent years. Because there are very few therapeutic options for JEV infection, prompt investigations of the ability of clinically safe, efficacious and globally available drugs to inhibit JEV infection and ameliorate peripheral neuropathy are urgently needed. In this study, we found that high doses of intravenous immunoglobulin, a function inhibitor of acid sphingomyelinase (FIASMA), inhibited acid sphingomyelinase (ASM) and ceramide activity in the serum and sciatic nerve of JEV-infected rats, reduced disease severity, reversed electrophysiological and histological abnormalities, significantly reduced circulating proinflammatory cytokine levels, inhibited Th1 and Th17 cell proliferation, and suppressed the infiltration of inflammatory CD4 + cells into the sciatic nerve. It also maintained the peripheral nerve-blood barrier without causing severe clinical side effects. In terms of the potential mechanisms, ASM was found to participate in immune cell differentiation and to activate immune cells, thereby exerting proinflammatory effects. Therefore, immunoglobulin is a FIASMA that reduces abnormal immune responses and thus targets the ASM/ceramide system to treat peripheral neuropathy caused by JEV infection.

Section snippetsBackground

Japanese encephalitis virus (JEV) is a mosquito-borne virus that belongs to the flavivirus family, which also includes dengue virus, West Nile virus, and Zika virus [1]. JEV is a neurotropic virus that threatens millions of people worldwide every year [2]. Patients with JEV infection suffer from high fever, status epilepticus, psychosis, impaired consciousness, and even coma, as well as paralysis [3]. We also found that clinically, peripheral neuropathy tends to accompany JEV infection [4]. Our

Experimental animals

Twelve-day-old Wistar rats were bred according to previously reported guidelines and in adherence with to Basel Declaration. Approval for all the experimental procedures was obtained from the animal ethics committee of CDC China (20210607040).

Modelling and assessment of motor function

JEV (NX1889) of the GI-b genotype (GenBank: MT134112.1) was obtained from the cerebrospinal fluid of patients with JEV infection in Ningxia in 2018 and from the mosquitoes captured in the same period. JEV (nx1887) (3 × 106 pfu/ml) was injected into the

Intravenous immunoglobulin (IVIG) reduces ASM activity and the serum levels of ASM, ceramide, IL-17 and IFN-γ in rats

ASM activity and ASM, ceramide, IL-17A, and IFN-γ levels were measured in the sera of rats in the sham, JEV-infected, and IVIG-treated groups at 6 dpi and 19 dpi. ASM activity and the serum levels of ASM, ceramide, IL-17A, and IFN-γ inflammatory cytokines were elevated on 6 days after JEV infection, whereas IVIG treatment significantly inhibited ASM activity and decreased ASM, ceramide, IL-17A, and IFN-γ inflammatory cytokine levels. ASM activity and ASM, ceramide, IFN-γ and IL-17A levels were

Discussion

ASM mediates the hydrolysis of sphingolipids to produce ceramide, which promotes the remodelling and repair of the membrane and restores its integrity. Microregions of the ceramide-rich membrane play a crucial role in viral invasion and transport [13] and may facilitate pathogen entry into cells [14]. Ceramide was found to significantly promote pseudotype JEV (JEVpv) infection and increase the replication of recombinant JEV (JEVrv) in an in vitro model [7], and sphingomyelin (SM) may also be

Conclusion

Intravenous immunoglobulin, a FIASMA, effectively reduced acid sphingomyelinase and ceramide levels in the serum and sciatic nerve in a rat model of JEV infection with peripheral nerve injury. We found that intravenous immunoglobulin alleviated early symptoms of peripheral nerve injury in rats infected with JEV. It reduced the loss of myelin fibres and axonal degeneration as well as the number of inflammatory cells infiltrating Peripheral nerves. Intravenous immunoglobulin also inhibited the

Author statement

ZHW, GWW, and NZ designed the study. NZ and GWW wrote the draft of the manuscript, NZ, LPY, and YPY performed the experiments; NZ,JYZ and LPY analyzed the data; NZ, LJM and GWW prepared all figures, ZHW, NZ, and GWW reviewed and edited the manuscript. The authors read and approved the final manuscript. The authors declares that there are no conflict of interest exists in the paper.

Zhenhai Wang had taken part in the study. We are from the General Hospital of Ningxia Medical University and the

CRediT authorship contribution statement

Na Zhang: Data curation. Guowei Wang: Writing – review & editing, Writing – original draft, Data curation. Liping Yang: Investigation, Data curation. Jinyuan Zhang: Data curation. YanPing Yuan: Investigation. Lijun Ma: Methodology, Formal analysis, Data curation. Zhenhai Wang: Writing – review & editing, Writing – original draft, Supervision, Methodology, Funding acquisition, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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