Characterization of Pathogenesis and Inflammatory Responses to Experimental Parechovirus Encephalitis

Abstract

Human parechovirus type 3 (PeV-A3) infection has been recognized as an emerging etiologic factor causing severe nerve disease or sepsis in infants and young children. But the neuropathogenic mechanisms of PeV-A3 remain unknown. To understand the pathogenesis of PeV-A3 infection in the neuronal system, PeV-A3-mediated cytopathic effects were analyzed in human glioblastoma cells and neuroblastoma cells. PeV-A3 induced interferons and inflammatory cytokine expression in these neuronal cells. The pronounced cytopathic effects accompanied with activation of death signaling pathways of apoptosis, autophagy, and pyroptosis were detected. A new experimental disease model of parechovirus encephalitis was established. In the disease model, intracranial inoculation with PeV-A3 in C57BL/6 neonatal mice showed body weight loss, hindlimb paralysis, and approximately 20% mortality. PeV-A3 infection in the hippocampus and cortex regions of the neonatal mouse brain was revealed. Mechanistic assay supported the in vitro results, indicating detection of PeV-A3 replication, inflammatory cytokine expression, and death signaling transduction in mouse brain tissues. These in vitro and in vivo studies revealed that the activation of death signaling and inflammation responses is involved in PeV-A3-mediated neurological disorders. The present results might account for some of the PeV-A3-associated clinical manifestations.

Parechovirus infections in human brain organoids: host immune response and not neuro-infectivity as a correlate of neuropathology

“…This could also explain why this disease is usually associated with young neonates as their immature immune system may not yet be capable of controlling viral spread 64 . This hypothesis is supported by other ndings in vivo and in vitro 23 , suggesting an increased innate antiviral immune response as a possible explanation for the clinical manifestations of PeV-A3.…”

“…Although immortalized cell lines and an animal model have been used to study PeV-A neuropathology 23 , they come with several limitations. Models based on cell lines lack complexity and biological relevance 24 , while animal models are often not susceptible to human viruses and do not recapitulate the human neurodevelopment 25,26 .…”

Update on nonpolio enterovirus and parechovirus infections in neonates and young infants

“…Investigators showed that type-I interferon treatment was able to activate host innate immunity against PeVA3 in vitro . This proposed model should serve as a platform to elucidate pathogenesis and evaluate efficacy of antiviral compounds [56].…”

A Neonate With Seizures

“…10 In experimental cell-culture and animal models, neuronal damage from HPeV3 resulted from infection-induced interferon and cytokine expression as confirmed by RT-PCR in the affected neurons with resultant increased expression of cell-death cytokines (as confirmed by Western blot) leading to activation of apoptosis, autophagy, and pyroptosis, though the full mechanism of HPeV3 pathogenesis is still being investigated. 13…”

“…10 In experimental cell-culture and animal models, neuronal damage from HPeV3 resulted from infection-induced interferon and cytokine expression as confirmed by RT-PCR in the affected neurons with resultant increased expression of cell-death cytokines (as confirmed by Western blot) leading to activation of apoptosis, autophagy, and pyroptosis, though the full mechanism of HPeV3 pathogenesis is still being investigated. 13 Infection with HPeV, particularly serotype HPeV3, should be considered in any infant less than 3 months of age presenting with sepsis and signs of meningoencephalitis and/or seizures. CSF analysis of affected infants is likely to reveal an absence of pleocytosis and RT-PCR positive for HPeV.…”