Abstract

BackgroundThe increase of inflammation-inducing enterobacteria was recently observed in severe hand, foot, and mouth disease (HFMD) caused by Enterovirus A71 (EV-A71). This study aimed to verify the occurrence of bacterial translocation (BT) and further explore the contributory role of BT to severity of EV-A71-mediated HFMD cases.MethodsSerum specimens from 65 mild and 65 severe EV-A71-associated HFMD cases and 65 healthy children were collected. EV-A71 VP1 in serum, inflammatory mediators including C-reactive protein, IL-1β, IL-6, interferon-γ and tumor necrosis factor-α, BT related biomarkers including Claudin-3, intestinal fatty acid binding protein, lipopolysaccharide (LPS), soluble CD14 (sCD14) and endotoxin core antibody were measured by ELISA. Bacterial DNA (BactDNA) fragments were quantified by quantified PCR (qPCR). Rhabdomyosarcoma (RD) or SH-SY5Y cells, infected with LPS-pre-incubated EV-A71 or transfected with plasmid containing viral 2Apro or mRNA containing viral internal ribosomal entry site (IRES), were post-treated with or without LPS in vitro. EV-A71 RNA and viral or cellular proteins were determined by qPCR and western blot, respectively.ResultsCompared to mild HFMD patients, remarkably higher inflammatory mediators as well as BT-related biomarkers except BactDNA were observed in severe HFMD cases (all P < 0.05). In severe HFMD group, circulating concentrations of LPS and sCD14 showed statistical correlations with inflammation indices (all P < 0.05), serum levels of EV-A71 VP1 were found to be positively correlated with serum LPS (r = 0.341, P = 0.005) and serum sCD14 (r = 0.458, P < 0.001). In vitro, EV-A71 attachment and internalization were only slightly promoted by LPS pre-incubation; however, EV-A71 proliferation and viral 2Apro-mediated IRES activity were significantly accelerated by LPS post-treatment.ConclusionsOur results collectively indicate that gut-derived translocating LPS contributes to the severity of EV-A71-induced HFMD by driving inflammatory response and viral proliferation via viral 2Apro-mediated IRES.

Highlights

  • The increase of inflammation-inducing enterobacteria was recently observed in severe hand, foot, and mouth disease (HFMD) caused by Enterovirus A71 (EV-A71)

  • Three inactivated monovalent EV-A71 vaccines were licensed in China in 2016; the vaccines are only available in the private market in China and the vaccines’ effectiveness against severe HFMD remains yet unknown [4]

  • In present study, we focused on the correlations between leaky gut-related bacterial translocation (BT) and inflammation-driven severity of HFMD, and further assessed the possible mechanism of BT in EV-A71 infection, in the hope of providing more convincing evidence for BT-derived inflammatory pathogenesis of HFMD deterioration

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Summary

Introduction

The increase of inflammation-inducing enterobacteria was recently observed in severe hand, foot, and mouth disease (HFMD) caused by Enterovirus A71 (EV-A71). Enterovirus A71 (EV-A71) is well known to be the major etiological culprit causing hand, foot, and mouth disease (HFMD) in children aged five and below. In 1969, Schmidt et al [1] isolated the first strain of EV-A71 from the stool samples of children with disease of the central nervous system in California, USA. In China, it caused the death of 479 children during 2008–2009 and more than 1 million cases per year have been monitored since 2008 [2, 3]. Few established antiviral therapies are available for severe EV-A71 infection. EVA71-associated HFMD (especially the severe conditions) still pose a growing global public health and economic concern in affected areas

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