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Background: Little is known of the pathogenetic mechanisms of enterovirus type 70 (EV70), a causative agent of acute hemorrhagic conjunctivitis. However, virus- or cytokine-induced perturbation of vascular endothelial cells are potential triggering events. Objective: To determine whether EV70 infection of human umbilical vascular endothelial cells (HUVECs) and human corneal epithelial cells (HCEs) causes the release of vasoactive cytokines, capable of triggering vascular endothelial cell activation. Study design: Susceptibility of cultured HUVECs and HCEs to EV70 was tested by observing the appearance of cytopathic effect or immunoprecipitation of viral protein in infected cells. The culture fluids from the virus-infected cells were tested for their ability to stimulate the expression of intercellular adhesion molecule-1 (ICAM-1) on uninfected HUVECs. Anti-cytokine antibodies were used to identify ICAM-1-activating cytokine(s). Results: Both HUVECs and HCEs were susceptible to EV70 infection. Culture fluids from EV70-infected HUVECs and HCEs stimulated ICAM-l expression on uninfected HUVECs, which was completely blocked by anti-interleukin-1α (IL-1α) antibody but not by interleukin-1β (IL-1β) or anti-tumor necrosis factor α (TNFα) antibodies. Conclusion: This study provides the first evidence of EV70 infection of both HCEs and HUVECs, and furthermore, identifies IL-1α as the predominant endothelial cell-activating factor produced by EV70-infected cells. Since endothelial cell activation is often an initiating step towards vascular permeability and/or inflammation, the perturbation of endothelial cell function through EV70 induced IL-1α is thus a potential contributory factor in the pathogenesis of EV70-associated hemorrhagic conjunctivitis. [Copyright &y& Elsevier]

Abstract: Background: Epidemics of acute hemorrhagic conjunctivitis (AHC) caused by a coxsackievirus A24 variant (CA24v) appeared in Taiwan in 2000–2002 and again in 2006–2007. Objective: To analyze the molecular epidemiology of CA24v in recent outbreaks in Taiwan. Study design: A 510bp fragment of 3Cpro region was analyzed in 30 CA24v isolates during 2000–2007. Phylogenetic tree was constructed along with 130 CA24v isolates available from the GenBank. Moreover, the 235bp of 3′VP1 region was similarly analyzed in 15 randomly selected strains isolated during 1985–2007. Phylogenetic dendrogram was constructed for the 3′VP1 region in 105 CA24v strains worldwide. Genetic distances were calculated using Kimura 2-parameter model, and phylogenetic trees were constructed by neighbor-joining method. Results: The 3Cpro dendrogram depicted genotype IV (GIV), a new genotype that can be further divided into three clusters (C1–C3). The 2000–2002 outbreaks were caused by genotype IV-cluster 1 (GIV-C1) and GIV-C2. Strains isolated in the 2006–2007 outbreak belong to GIV-C3, also in the same cluster as Singapore strains from 2005. Analysis on 3′VP1 revealed only GI, GIII and GIV in line with the classification in 3Cpro dendrogram. All genotype IV strains were also divided into three clusters, though the GIV-C 2′ were isolated from broader geographic areas and over a longer period of time. Conclusions: Analysis of the 3Cpro region is more insightful than the 3′VP1 region in the molecular epidemiology of CA24v. The 3Cpro dendrogram accurately and chronologically identified all stains involved in the worldwide outbreaks. [Copyright &y& Elsevier]