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.
Highlights
Human parechovirus (PeV-A) is a 28-nm diameter, non-enveloped, positive-sense, signal-stranded RNA virus that belongs to the Picornaviridae family [1]
This study used human GBM cells (DBTRG-05MG) and human neuroblastoma cells (IMR-32) to decipher the neuropathic effects of PeV-A type 3 (PeV-A3). These two cell lines were infected with PeV-A3 at multiplicity of infection (MOI) = 5 for 8 and 24 h, followed by immunofluorescence analysis conducted with anti-PeV VP0 antibody
The viral genome in GBM cells infected with PeV-A3 at MOI = 0.1, 1, 5, and 10 was measured
Summary
Human parechovirus (PeV-A) is a 28-nm diameter, non-enveloped, positive-sense, signal-stranded RNA virus that belongs to the Picornaviridae family [1]. In view of its nucleotide sequence in replication and translation elements being different from other members of the genus Enterovirus, the virus was reclassified as Parechovirus, and echoviruses 22 and 23 were e-named PeV-A1. Parechovirus A3 Causes Neuropathogenesis and PeV-A2, respectively [3,4,5]. 19 types PeV-A (PeVA1~PeV-A19) have been reported and recognized on the basis of their viral protein 1 (VP1) sequences [6]. PeV-A is a widespread viral pathogen that affects children’s health, causing gastroenteritis, respiratory disease, or severe nerve disease in children of younger age [7]. The actual incidence of PeV-A infection in clinical illnesses is unknown; and more importantly, delayed diagnosis and poor management in severe conditions remain unsolved
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