Coxsackievirus A6 Infection Causes Neurogenic Pathogenesis in a Neonatal Murine Model

Abstract

Coxsackievirus A6 (CVA6), a member of species A enterovirus, is associated with outbreaks of hand-foot-and-mouth disease and causes a large nationwide burden of disease. However, the molecular pathogenesis of CVA6 remains unclear. In the present study, we established a suckling Institute of Cancer Research (ICR) mouse infection model to explore the neural pathogenicity of CVA6. Five-day-old mice infected with CVA6 strain F219 showed lethargy and paralysis, and died 5 or 6 days after infection via IM injection. Cerebral edema and neuronal cell swelling were observed in the infected brain tissue, and we found that the CVA6 VP1 antigen could co-localize with GFAP-positive astrocytes in infected mouse brain using an immunofluorescence assay. CVA6 strain F219 can also infect human glioma (U251) cells. Transcriptome analysis of brain tissues from infected mice and infected U251 cells showed that significantly differentially expressed genes were enriched in antiviral and immune response and neurological system processes. These results indicate that CVA6 could cause neural pathogenesis and provide basic data for exploring the mechanism of how host–cell interactions affect viral replication and pathogenesis. Importance: Coxsackievirus A6 (CVA6) surpasses the two main pathogens, enterovirus 71 (EV-A71) and coxsackievirus A16 (CVA16), which are the leading pathogens causing HFMD in many provinces of China. In our study, CVA6 infection caused neurogenic pathogenesis in a neonatal murine model, manifesting as cerebral edema and neuronal cell swelling, CVA6 VP1 antigen could co-localize with GFAP-positive astrocytes in the infected mouse brain. Based on CVA6-infected brain tissue and U251 cell transcriptome analysis, we found upregulated antiviral and immune response-related genes such as Zbp1, Usp18, Oas2, Irf7, Ddx60, Ifit3, Ddx58, and Isg15, while the neurological system process-related genes were downregulated, including Fcrls, Ebnrb, Cdk1, and Anxa5.

Bulk and single cells transcriptomes with experimental validation identify USP18 as a novel glioma prognosis and proliferation indicator

“…The role of USP18 in viral infectious diseases, particularly those related to the central nervous system (CNS), has been the focus of previous research ( 33 , 34 ). The role of USP18 in the IFN pathway has therefore encouraged research in the field of malignant tumors ( 35 ).…”

ZBP1 inhibits the replication of Senecavirus A by enhancing NF-κB signaling pathway mediated antiviral response in porcine alveolar macrophage 3D4/21 cells

“…As a nucleic acid sensor, the Zα domain of ZBP1 triggers inflammatory response by binding to Z-conformational nucleic acids (Z-DNA/ Z-RNA) [29], however, whether SVA can form Z-RNA during replication needs to be further tested. In addition, the expression of ZBP1 is upregulated in the infection of a variety of viruses, such as influenza virus [30], coxsackievirus A6 [31], and HSV-1 [17]. ZBP1 is also considered to be a limiting factor of HSV-1, indicating that ZBP1 is an important antiviral molecule.…”

Molecular epidemiology and clinical characteristics of enteroviruses associated HFMD in Chengdu, China, 2013–2022

“…Over the past decade, the majority of EV71-associated HFMD outbreaks occurred in China among the Asia–Pacific countries [ 10 ]. Recent epidemic analysis has shown that CV-A6 has replaced CV-A16 and EV-A71 as the leading epidemic serotypes in many provinces of China [ 11 ]. This demonstrates that CV-A6 is a major cause of HFMD in patients after the launch of EV-A71 vaccination in Chengdu [ 12 ].…”