Broad receptor engagement of an emerging global coronavirus may potentiate its diverse cross-species transmissibility

Abstract

Porcine deltacoronavirus (PDCoV), identified in 2012, is a common enteropathogen of swine with worldwide distribution. The source and evolutionary history of this virus is, however, unknown. PDCoV belongs to the genus that comprises predominantly avian CoV. Phylogenetic analysis suggests that PDCoV originated relatively recently from a host-switching event between birds and mammals. Insight into receptor engagement by PDCoV may shed light into such an exceptional phenomenon. Here we report that PDCoV employs host aminopeptidase N (APN) as an entry receptor and interacts with APN via domain B of its spike (S) protein. Infection of porcine cells with PDCoV was drastically reduced by APN knockout and rescued after reconstitution of APN expression. In addition, we observed that PDCoV efficiently infects cells of unusual broad species range, including human and chicken. Accordingly, PDCoV S was found to target the phylogenetically conserved catalytic domain of APN. Moreover, transient expression of porcine, feline, human, and chicken APN renders cells susceptible to PDCoV infection. Binding of PDCoV to an interspecies conserved site on APN may facilitate direct transmission of PDCoV to nonreservoir species, including humans, potentially reflecting the mechanism that enabled a virus, ancestral to PDCoV, to breach the species barrier between birds and mammals. The APN cell surface protein is also used by several members of the genus. Hence, our data constitute the second identification of CoVs from different genera that use the same receptor, implying that CoV receptor selection is subjected to specific restrictions that are still poorly understood.

Susceptibility of porcine IPEC-J2 intestinal epithelial cells to infection with porcine deltacoronavirus (PDCoV) and serum cytokine responses of gnotobiotic pigs to acute infection with IPEC-J2 cell culture-passaged PDCoV

“…However, our current study verified that PDCoV previously grown in other swine cell cultures such as LLC-PK cells can be propagated and passaged in IPEC-J2 cells. Recently, porcine aminopeptidase N (pAPN) was identified as a major cell entry receptor for PDCoV (Li et al, 2018;Wang et al, 2018;Zhu et al, 2018). Therefore, possible differences in pAPN expression levels among the LLC-PK, ST, and IPEC-J2 cells of swine origin could influence their susceptibility to infection with PDCoV.…”

Emerging and re-emerging coronaviruses in pigs

“…Most recent phylogenetic analyses have confirmed that quail deltacoronavirus UAE-HKU30 belongs to the same deltacoronavirus species as porcine coronavirus HKU15 (Por CoV HKU15) and sparrow coronavirus HKU17 (SpCoV HKU17) [46]. In addition, PDCoV was shown to efficiently infect cells of broad host range, including swine, humans, and chickens (Table 1) [53 ]. Accordingly, PDCoV S protein was found to target the phylogenetically conserved catalytic domain of APN [53 ].…”

“…In addition, PDCoV was shown to efficiently infect cells of broad host range, including swine, humans, and chickens (Table 1) [53 ]. Accordingly, PDCoV S protein was found to target the phylogenetically conserved catalytic domain of APN [53 ]. Moreover, transient expression of porcine, feline, human, and chicken APN renders cells susceptible to PDCoV infection [53 ].…”

“…Accordingly, PDCoV S protein was found to target the phylogenetically conserved catalytic domain of APN [53 ]. Moreover, transient expression of porcine, feline, human, and chicken APN renders cells susceptible to PDCoV infection [53 ].…”

Structural insights into coronavirus entry

“…Remarkably, viruses from different genera, such as HCoV-NL63 (α-CoV) and SARS-CoV (β-CoV), can recognize the same region of ACE2 (entry receptor) using structurally distinct B domains (Hofmann et al, 2005;Li et al, 2005aLi et al, , 2003Wu et al, 2009). Many α-CoVs, including HCoV-229E, TGEV and PRCV, as well as porcine δ-CoV (PDCoV) utilize aminopeptidase N (APN) as entry receptor (Delmas et al, 1992;Delmas et al, 1993;Li et al, 2018;Reguera et al, 2012;Wong et al, 2017;Yeager et al, 1992) whereas MERS-CoV uses dipeptidyl peptidase 4 (DPP4) Raj et al, 2013;Wang et al, 2013). Crystal structures of SARS-CoV, HCoV-NL63, MERS-CoV, HCoV-229E B domains in complex with their cognate receptors provided atomic details of the interacting-interface and identified key residues for cross-species transmission and infection (Fig.…”