Peripheral nerve injury mediated by JEV strain NX1889 infection and impairment of Schwann cells

Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus primarily associated with central nervous system disorders. Recent studies have indicated that JEV infection can lead to Guillain-Barré syndrome (GBS), a peripheral nervous system (PNS) disorder; however, the underlying mechanisms remain unclear. In this study, we investigated the tropism of different genotypes of JEV strains for peripheral nerves and their potential impact on peripheral nerves. Four JEV strains-GI NX1889, GI GZ56, GIII P3, and GV XZ0934-representing three prevalent genotypes in China were selected for analysis. Compared with other JEV strains, NX1889 exhibited greater peripheral nerve tropism, leading to peripheral nerve dysfunction, severe pathological changes, and inflammatory responses. Further investigation revealed that Schwann cells (SCs) supported productive replication of GI JEV, but not GIII or GV strains. Although both GI strains infected SCs and caused proliferation inhibition and G1 phase arrest, only NX1889 induced apoptosis. At the symptomatic peak, NX1889-infected mice demonstrated significantly higher viral loads in sciatic nerves and dorsal root ganglia compared to peripheral non-neural tissues and organs. Sciatic nerves exhibited extensive infiltration of CD45 + inflammatory cells and upregulated pro-inflammatory mediators, and the viral load and CCL2 expression in sciatic nerves were positively correlated with limb motor deficits. These findings demonstrate that JEV strains exhibit distinct abilities to induce peripheral nerve injury (PNI), with the variation being a strain-specific characteristic of NX1889 rather than a genotype-specific feature of GI. The peripheral nerve is a vital site for JEV NX1889 replication, and the direct viral invasion of SCs leads to demyelinating neuropathy, with subsequent immune-inflammatory responses exacerbating this injury. This study broadens the spectrum of pathogens known to directly invade and damage peripheral nerves and provides new insights into the pathogenesis of JEV-associated PNI.