Species-Specific Colocalization of Middle East Respiratory Syndrome Coronavirus Attachment and Entry Receptors

Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) uses the S1 B domain of its spike protein to bind to dipeptidyl peptidase 4 (DPP4), its functional receptor, and its S1 A domain to bind to sialic acids. The tissue localization of DPP4 in humans, bats, camelids, pigs, and rabbits generally correlates with MERS-CoV tropism, highlighting the role of DPP4 in virus pathogenesis and transmission. However, MERS-CoV S1 A does not indiscriminately bind to all ␣2,3-sialic acids, and the species-specific binding and tissue distribution of these sialic acids in different MERS-CoV-susceptible species have not been investigated. We established a novel method to detect these sialic acids on tissue sections of various organs of different susceptible species by using nanoparticles displaying multivalent MERS-CoV S1 A . We found that the nanoparticles specifically bound to the nasal epithelial cells of dromedary camels, type II pneumocytes in human lungs, and the intestinal epithelial cells of common pipistrelle bats. Desialylation by neuraminidase abolished nanoparticle binding and significantly reduced MERS-CoV infection in primary susceptible cells. In contrast, S1 A nanoparticles did not bind to the intestinal epithelium of serotine bats and frugivorous bat species, nor did they bind to the nasal epithelium of pigs and rabbits. Both pigs and rabbits have been shown to shed less infectious virus than dromedary camels and do not transmit the virus via either contact or airborne routes. Our results depict species-specific colocalization of MERS-CoV entry and attachment receptors, which may be relevant in the transmission and pathogenesis of MERS-CoV. IMPORTANCE MERS-CoV uses the S1 B domain of its spike protein to attach to its host receptor, dipeptidyl peptidase 4 (DPP4). The tissue localization of DPP4 has been mapped in different susceptible species. On the other hand, the S1 A domain, the N-terminal domain of this spike protein, preferentially binds to several glycotopes of ␣2,3-sialic acids, the attachment factor of MERS-CoV. Here we show, using a novel method, that the S1 A domain specifically binds to the nasal epithelium of dromedary camels, alveolar epithelium of humans, and intestinal epithelium of common pipistrelle bats. In contrast, it does not bind to the nasal epithelium of pigs or rabbits, nor does it bind to the intestinal epithelium of serotine bats and frugivorous bat species. This finding supports the importance of the S1 A domain in MERS-CoV infection and tropism, suggests its role in transmission, and highlights its potential use as a component of novel vaccine candidates.KEYWORDS Middle East respiratory syndrome coronavirus, S1 A domain, common pipistrelle bats, dromedary camels, humans C oronaviruses use their spike (S) protein to attach to host cell surface molecules and enter target cells. The N-terminal part of this S protein, known as S1, is responsible for attachment to host cells, while the C-terminal part mediates virus fusion to host cells

The dipeptidyl peptidase-4 expression in some MERS-CoV naturally infected dromedary camels in Saudi Arabia 2018–2019

“…Viral replication and tropism is mainly governed by many factors including the availability of specific viral receptors and transcription factors. It is believed that MERS-CoV utilizes the DPP-4 as main receptors and sialic acid as accessory receptors [7]. MERS-CoV infection usually starts with the attachment of the virus by its spike glycoproteins to the target cell DPP4 ligands [7].…”

“…It is believed that MERS-CoV utilizes the DPP-4 as main receptors and sialic acid as accessory receptors [7]. MERS-CoV infection usually starts with the attachment of the virus by its spike glycoproteins to the target cell DPP4 ligands [7]. One study have found that DPP4 was detected on cells in the cortical apical proximal tubular epithelium and arteriolar smooth muscle of kidney of camel [8].…”

Glycine 29 Is Critical for Conformational Changes of the Spike Glycoprotein of Mouse Hepatitis Virus A59 Triggered by either Receptor Binding or High pH

“…S proteins of all CoVs contain both an NTD and a CTD, but different CoVs evolve to use either the NTD or CTD to bind their cognate receptor. Some CoVs, such as MERS-CoV, use their CTDs to bind protein receptors and NTDs to bind sugar moieties (45,46). One intriguing question is whether there is any cross-domain communication between the NTD and CTD during conformational changes of the S protein leading to virus entry.…”

Animal models for the risk assessment of viral pandemic potential

“…However, while dromedary camels and New World camelids could transmit MERS-CoV upon contact, rabbits could hardly transmit the virus [130,143]. MERS-CoV has been shown to use α-2,3 SA as a receptor assistant, which dromedary camels but not rabbits express in the nasal epithelium [130,151,152]. Humans do not express the primary receptor DPP4 in the upper respiratory tract but transmits MERS-CoV well [153].…”

“…It is now known that DPP4 is a functional cellular receptor for MERS-CoVs and that Vero cells express DPP4 [193]. Vero cells also express α-2,3 SA, which has been shown to assist receptor binding of MERS-CoVs [130,151,152,167]. Vero cells are well known for an impairment in the type I interferon pathways [194].…”