Bat Origins of MERS-CoV Supported by Bat Coronavirus HKU4 Usage of Human Receptor CD26

Abstract

The recently reported Middle East respiratory syndrome coronavirus (MERS-CoV) is phylogenetically closely related to the bat coronaviruses (BatCoVs) HKU4 and HKU5. However, the evolutionary pathway of MERS-CoV is still unclear. A receptor binding domain (RBD) in the MERS-CoV envelope-embedded spike protein specifically engages human CD26 (hCD26) to initiate viral entry. The high sequence identity in the viral spike protein prompted us to investigate if HKU4 and HKU5 can recognize hCD26 for cell entry. We found that HKU4-RBD, but not HKU5-RBD, binds to hCD26, and pseudotyped viruses embedding HKU4 spike can infect cells via hCD26 recognition. The structure of the HKU4-RBD/hCD26 complex revealed a hCD26-binding mode similar overall to that observed for MERS-RBD. HKU4-RBD, however, is less adapted to hCD26 than MERS-RBD, explaining its lower affinity for receptor binding. Our findings support a bat origin for MERS-CoV and indicate the need for surveillance of HKU4-related viruses in bats.

Coronavirus Host Range Expansion and Middle East Respiratory Syndrome Coronavirus Emergence: Biochemical Mechanisms and Evolutionary Perspectives

“…Unlike SARS-CoV, MERS-CoV utilizes dipeptidyl peptidase 4 (DPP4) as an entry receptor (45). Among the coronaviruses with characterized entry receptors, only MERS-CoV and BtCoV-HKU4 have been found to utilize DPP4 (46,47). Whereas MERS-CoV binds to human DPP4 (hDPP4) more efficiently than to bat DPP4 (bDPP4), BtCoV-HKU4 can use both hDPP4 and bDPP4 efficiently (47), suggesting that MERS-CoV has adapted specifically to hDPP4.…”

“…BtCoV-HKU4 replication in human cells may be restricted by the lack of appropriate entry proteases as well (47). Despite BtCoV-HKU5's sequence similarity to MERS-CoV, it is unable to utilize DPP4 for cell entry (46,47), and its actual receptor for entry remains unknown. The similarity between MERS-CoV, bat coronaviruses BtCoV-HKU4 and BtCoV-HKU5, and other group 2c bat coronaviruses (Figure 1) suggests that MERS-CoV originated from bats.…”

Activity and selectivity cliffs for DPP‐IV inhibitors: Lessons we can learn from SAR studies and their application to virtual screening

“…This figure shows that only Arg358, Tyr547, and Trp629 (in magenta) have different conformations depending on crystallization conditions: panel A complex with a fluoroolefin inhibitor (PDB code 3C45); panel B complex with alogliptin (PDB code 3G0B); panel C complex with a β‐substituted biarylphenylalanine amide inhibitor (PDB code 2FJP); panel D complex with the ABT‐341 inhibitor (PDB code 2I78); panel E superposition of apo chains; and panel F superposition of the 64 noncovalent DPP‐IV/inhibitor complexes currently available (one chain per PDB file; see Supporting Information Table ). The apo forms in panel E correspond to all available chains in Supporting Information Table that do not form a complex with any inhibitor (i.e., chains A and B for 1TK3 and 1PFQ; chains A, C, and D for 2I78, 2OAG, and 2OQI ; chains A, B, C, and D for 1W1I; chains A and C for 4QZV ; chain A for 4KR0 and 4L72; and chain B for 2OQV ). This figure was obtained with the help of the Maestro program…”

Genomic characterization of a novel poxvirus from a flying fox: evidence for a new genus?

“…The other possibility is that only flying foxes that have been captured following misadventure or illness and sent to wildlife care facilities are examined, leading to a very small sample size of the overall population, and subsequent misrepresentation of a disease of low prevalence. Current research into the virome of bat species is largely driven by the search for precursor species of known human pathogens such as MERS coronavirus (Wang et al, 2014), or scanning for species with zoonotic potential (Mortlock et al, 2015). As such, a key concern with PTPV is whether or not it has zoonotic potential, but due to the inability to isolate the virus, in vitro testing in human-derived cell lines could not be undertaken as an initial predictive test.…”