Abstract
Enterovirus 71 (EV71) is one of the main pathogens responsible for hand, foot, and mouth disease (HFMD). Infection with EV71 can lead to severe clinical disease via extensive infections of either the respiratory or alimentary tracts in children. Based on the previous pathological study of EV71 infections in neonatal rhesus macaques, our work using this animal model and an EV71 chimera that expresses enhanced green fluorescent protein (EGFP-EV71) primarily explored where EV71 localizes and proliferates, and the subsequent initiation of the pathological process. The chimeric EGFP-EV71 we constructed was similar to the wild-type EV71 (WT-EV71) virus in its biological characteristics. Similar clinical manifestations and histo-pathologic features were equally displayed in neonatal rhesus macaques infected with either WT-EV71 or EGFP-EV71 via the respiratory route. Fluorescent signal tracing in tissues from the animals infected with EGFP-EV71 showed that EV71 proliferated primarily in the respiratory tract epithelium and the associated lymphoid tissues. Immunofluorescence and flow cytometry analyses revealed that EV71 was able to enter a pre-conventional dendritic cell (DC) population at the infection sites. The viremia identified in the macaques infected by WT-EV71 or EGFP-EV71 was present even in the artificial presence of a specific antibody against the virus. Our results suggest that EV71 primarily proliferates in the respiratory tract epithelium followed by subsequent entry into a pre-cDC population of DCs. These cells are then hijacked by the virus and they can potentially transmit the virus from local sites to other organs through the blood circulation during the infection process. Our results suggest that the EV71 infection process in this DC population does not interfere with the induction of an independent immune response against the EV71 infection in the neonatal macaques.
Highlights
Enterovirus 71 (EV71), a member of the Enterovirus genus with a small viral RNA structure, is widely recognized as one of the major pathogens responsible for the large outbreaks of hand, foot, and mouth disease (HFMD) in children in the Asian-Pacific region (McMinn, 2002)
We investigated the dynamic interaction between dendritic cell (DC) and EV71 upon viral entry into macaques by using an EV71 chimera that expresses enhanced green fluorescent protein (EGFP)
A previous report indicated that biological properties of fluorescently-labeled EV71 chimera were indistinguishable from the parental virus in their plaque morphology and growth kinetics, and the chimera was useful for studying viral pathogenesis (Shang et al, 2013)
Summary
Enterovirus 71 (EV71), a member of the Enterovirus genus with a small viral RNA structure, is widely recognized as one of the major pathogens responsible for the large outbreaks of hand, foot, and mouth disease (HFMD) in children in the Asian-Pacific region (McMinn, 2002). Because infection with EV71 can induce a distinct specific immune response (Liu et al, 2013), the above data might support the hypothesis that EV71 infection of DCs is correlated with the interaction between the virus and immune system, thereby leading to up-regulated expression of cytokines such as IL6 and TNFα (Liu et al, 2013). The first step for investigating this is to focus on the dynamic interaction between the virus and dendritic cells during the infection Based on such analyses, we previously established a neonatal rhesus macaque model for EV71 infection, in which EV71 was capable of infecting the macaques through the respiratory tract. The typical clinical pathological process resulting in vesicular lesions in oral mucosa and limb skin, fever and viremia was observed (Dong et al, 2010; Liu et al, 2011)
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