Dynamic Interaction of Enterovirus 71 and Dendritic Cells in Infected Neonatal Rhesus Macaques

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.

microRNA-4516 Contributes to Different Functions of Epithelial Permeability Barrier by Targeting Poliovirus Receptor Related Protein 1 in Enterovirus 71 and Coxsackievirus A16 Infections

“…Nevertheless, EV-A71 and CV-A16 transmission via respiratory droplets has been reported (Wang et al, 2011 ). Moreover, our previous study also confirmed that EV-A71 infection presented more typical pathologic changes in the respiratory tract than those in the alimentary tract (Zhao et al, 2017 ). Thus, we speculate that variations in pathogenesis induced by EV-A71 and CV-A16 infections might be originally derived from different epithelial alterations.…”

Hand, foot and mouth disease and herpangina caused by enterovirus A71 infections: a review of enterovirus A71 molecular epidemiology, pathogenesis, and current vaccine development

“…Inflammation was the most profound in the spinal cord gray matter, brainstem, hypothalamus, subthalamic and dentate nuclei in autopsy samples investigated in Malaysia 35 . Previous studies 36 , 37 have found that the EV-A71 virus mechanism of infection is primarily focused on the respiratory tract epithelium, from which it is subsequently able to enter a pre-existing population of dendritic cells at the infection site; these cells could potentially transmit the virus from local sites to other organs through the blood stream during the infectious process.…”

Role of innate lymphoid cells and dendritic cells in intradermal immunization of the enterovirus antigen

“…Enterovirus type 71 (EV71) and coxsackievirus A 16 (CA16), which are both major pathogens of human hand, foot, and mouth disease (HFMD), were deemed capable of inducing a systemic, clinical, and pathogenic response based on their ability to infect the epithelium of the respiratory or alimentary tract. 15,16 However, studies of vaccine development with these two viruses suggested that the immunization provided by intramuscular inoculation of the inactivated EV71 vaccine in mice and macaques elicited effective immunity with clinical protection against viral challenge, 17 while the immunization provided by inoculation of the inactivated CA16 vaccine via the same route in macaques was not effective, especially in viral challenge tests. 18 This interesting immunological difference induced by two inactivated viral antigens that possess similar structural characteristics was addressed by analyzing the innate immune response, especially the responses of DCs and ILCs and the activation of adaptive immunity.…”