Polarized Entry of Human Parechoviruses in the Airway Epithelium.

Eveliina Karelehto,Rens Hulsdouw,Dasja Pajkrt,Katja C Wolthers,Karen De Haan,Adithya Sridhar,Cosimo Cristella,Hetty Van Eijk,Xiao Yu,Sylvie Koekkoek,Menno D De Jong

doi:10.3389/fcimb.2018.00294

Eveliina Karelehto, Rens Hulsdouw + Show 9 more

Open Access

https://doi.org/10.3389/fcimb.2018.00294

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Abstract

Human parechoviruses (HPeVs), a poorly studied genus within the Picornaviridae family, are classified into 19 genotypes of which HPeV1 and HPeV3 are the most often detected. HPeV1 VP1 C terminus contains an arginine-glycine-aspartic acid (RGD) motif and has been shown to depend on the host cell surface αV integrins (αV ITGs) and heparan sulfate (HS) for entry. HPeV3 lacks this motif and the receptors remain unknown. HPeVs can be detected in patient nasopharyngeal and stool samples, and infection is presumed to occur after respiratory or gastro-intestinal transmission. HPeV pathogenesis is poorly understood as there are no animal models and previous studies have been conducted in immortalized monolayer cell cultures which do not adequately represent the characteristics of human tissues. To bridge this gap, we determined the polarity of infection, replication kinetics, and cell tropism of HPeV1 and HPeV3 in the well-differentiated human airway epithelial (HAE) model. We found the HAE cultures to be permissive for HPeVs. Both HPeV genotypes infected the HAE preferentially from the basolateral surface while the progeny virus was shed toward the apical side. Confocal microscopy revealed the target cell type to be the p63+ basal cells for both viruses, αV ITG and HS blocking had no effect on the replication of either virus, and transcriptional profiling suggested that HPeV3 infection induced stronger immune activation than HPeV1. Genotype-specific host responses may contribute to the differences in pathogenesis and clinical outcomes associated with HPeV1 and HPeV3.

Highlights

Parechovirus A species within the Picornaviridae family comprises of 19 genotypes, of which human parechovirus 1 and 3 (HPeV1 and HPeV3, respectively) are the most often detected in clinical samples (Harvala et al, 2010; Romero and Selvarangan, 2011)
Infectious virus titers detected from the basolateral compartment were low with no significant difference between the apical and basolateral inoculation (Figure 1B)
Efficient apical infection in the human airway epithelial (HAE) cultures could be established with the respiratory picornavirus enterovirus 68 (EV68; data not shown)

Summary

Introduction

Parechovirus A species within the Picornaviridae family comprises of 19 genotypes, of which human parechovirus 1 and 3 (HPeV1 and HPeV3, respectively) are the most often detected in clinical samples (Harvala et al, 2010; Romero and Selvarangan, 2011). When compared to HPeV1, HPeV3 infects younger patients and often causes more severe diseases, such as sepsis-like illness or central nervous system (CNS) infections The reason for these differences remains elusive (Benschop et al, 2006; Romero and Selvarangan, 2011). Analogous to virus species in the closely related Enterovirus genus, HPeVs are detected in patient nasopharyngeal and stool specimens, and are assumed to initiate their replication in the host respiratory and intestinal tracts (Semler and Wimmer, 2002). It is not known whether the epithelium lining these anatomical sites can support HPeV replication nor which cell types are involved

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