Japanese Encephalitis Virus Infects the Thalamus Early Followed by Sensory-Associated Cortex and Other Parts of the Central and Peripheral Nervous Systems

Abstract

Japanese encephalitis (JE) is a known CNS viral infection that often involves the thalamus early. To investigate the possible role of sensory peripheral nervous system (PNS) in early neuroinvasion, we developed a left hindlimb footpad-inoculation mouse model to recapitulate human infection by a mosquito bite. A 1–5 days postinfection (dpi) study, demonstrated focal viral antigens/RNA in contralateral thalamic neurons at 3 dpi in 50% of the animals. From 4 to 5 dpi, gradual increase in viral antigens/RNA was observed in bilateral thalami, somatosensory, and piriform cortices, and then the entire CNS. Infection of neuronal bodies and adjacent nerves in dorsal root ganglia (DRGs), trigeminal ganglia, and autonomic ganglia (intestine, etc.) was also observed from 5 dpi. Infection of explant organotypic whole brain slice cultures demonstrated no viral predilection for the thalamus, while DRG and intestinal ganglia organotypic cultures confirmed sensory and autonomic ganglia susceptibility to infection, respectively. Early thalamus and sensory-associated cortex involvement suggest an important role for sensory pathways in neuroinvasion. Our results suggest that JE virus neuronotropism is much more extensive than previously known, and that the sensory PNS and autonomic system are susceptible to infection.

Efficient control of Japanese encephalitis virus in the central nervous system of infected pigs occurs in the absence of a pronounced inflammatory immune response

“…A hematogenous entry of JEV in the OB would be in line with the observation that LaCrosse virus, another mosquito-borne virus, also spreads via the hematogenous route to the OB in mice and that capillaries in the OB could be hot spots for neuroinvasion [38]. Also the thalamus has already been shown to constitute an important tissue for JEV replication in the brain of mice [39], piglets [5], and macaques [40], and thalamic lesions are the most commonly described abnormality based on magnetic resonance imaging (MRI) of JEV patients [41][42][43]. Entry to the thalamus probably occurs via infection of the sensory neurons of the dorsal route ganglion which connects directly to the thalamus [23,39].…”

“…Also the thalamus has already been shown to constitute an important tissue for JEV replication in the brain of mice [39], piglets [5], and macaques [40], and thalamic lesions are the most commonly described abnormality based on magnetic resonance imaging (MRI) of JEV patients [41][42][43]. Entry to the thalamus probably occurs via infection of the sensory neurons of the dorsal route ganglion which connects directly to the thalamus [23,39]. Besides the significantly higher viral RNA loads in the olfactory bulb and thalamus, a few intradermal inoculated pigs also showed higher JEV RNA loads in the brain stem and cerebrum, and thus, it cannot be excluded that these brain tissues can also play a role in JEV replication in the CNS.…”

Brain Microvascular Endothelial Cells-Derived HMGB1 Facilitates Monocyte Transendothelial Migration Favoring JEV Neuroinvasion

“…Although evidence revealed that inverse neural pathway is also employed in JEV neuroinvasion [67], neurotropic viruses might spread via multiple pathways to achieve the CNS invasion [19]. Our results suggested that CNS invading immune cells such as JEV-carried monocytes and T cells, caused the occurrence of obvious clinical symptoms of JE early, which was contributed by BMEC-derived HMGB1…”

Japanese Encephalitis Virus-Induced Peripheral Neuropathy in the Rat Model

“…GBS is a rare, but potentially fatal, immune-mediated disease of the peripheral nerves and nerve roots that is usually triggered by infections [18,19] . In ZIKA mouse model, dorsal root ganglion(DRG)was also found to support viral infection [20] .The mechanism of how JEV damages peripheral nerves is unknown,we created an JEV infected rat model to study peripheral nerve damage.In our study ,we found CMAP amplitudes in the JEV infected group rats were signi cantly and strongly reduced at 3dpi and 6 dpi and were increased at 12 and 19 dpi ,the motor nerve conduction velocity (MNCV) for JEV infected rats and strongly decreased at 3 dpi and no recovery was observed at 6 or 12 dpi ,and it was not signi cant compared to 19 dpi,CAMP latency was extended only in the 6dpi.The nature of the cellular and structural injury in the nerve de es imaging in most scenarios, and electrodiagnostic testing is currently the most sensitive and speci c method to evaluate peripheral nerve injure(PNI). Nerve conduction study(NCS)determines nerve conduction velocities to help evaluate axonal degeneration from demyelinating disorders [21] .Electron microscopy showed that the myelin lamella was loose, the structure was damaged, and the bulge was myelin ball at 3dpi and 19dpi.Semi-thin transverse sections of sciatic nerves demonstrated that clinical disability of JEV infected rats were associated with marked reduction of myelinated bers at 6 dpi and 19dpi when compared to control group' sciatic nerves.…”