The heptad repeat region is a major selection target in MERS-CoV and related coronaviruses

Diego Forni,Uberto Pozzoli,Mario Clerici,Giulia Filippi,Luca De Gioia,Nasser Al-Daghri,Rachele Cagliani,Manuela Sironi

doi:10.1038/srep14480

Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) originated in bats and spread to humans via zoonotic transmission from camels. We analyzed the evolution of the spike (S) gene in betacoronaviruses (betaCoVs) isolated from different mammals, in bat coronavirus populations, as well as in MERS-CoV strains from the current outbreak. Results indicated several positively selected sites located in the region comprising the two heptad repeats (HR1 and HR2) and their linker. Two sites (R652 and V1060) were positively selected in the betaCoVs phylogeny and correspond to mutations associated with expanded host range in other coronaviruses. During the most recent evolution of MERS-CoV, adaptive mutations in the HR1 (Q/R/H1020) arose in camels or in a previous host and spread to humans. We determined that different residues at position 1020 establish distinct inter- and intra-helical interactions and affect the stability of the six-helix bundle formed by the HRs. A similar effect on stability was observed for a nearby mutation (T1015N) that increases MERS-CoV infection efficiency in vitro. Data herein indicate that the heptad repeat region was a major target of adaptive evolution in MERS-CoV-related viruses; these results are relevant for the design of fusion inhibitor peptides with antiviral function.

Highlights

Middle East respiratory syndrome coronavirus (MERS-CoV), a newly emerged virus that can cause severe lower respiratory tract infection in humans, was first identified in Saudi Arabia in 20121
High titers of MERS-CoV neutralizing antibodies have been detected in camels from various countries and MERS-CoV has been isolated from these animals in Saudi Arabia and Qatar[10]
We first investigated whether positive selection drove the evolution of MERS-CoV-related coronavirus spike proteins

Summary

Introduction

Middle East respiratory syndrome coronavirus (MERS-CoV), a newly emerged virus that can cause severe lower respiratory tract infection in humans, was first identified in Saudi Arabia in 20121. A virus belonging to the same species as MERS-CoV was isolated in Neoromicia bats (NeoCoV), supporting a bat-origin for MERS-CoV6. This hypothesis received further confirmation by the identification of dipeptidyl-peptidase 4 (DPP4, known as CD26) as the cellular receptor used by both Ty-BatCoV HKU4 and MERS-CoV7–9. The most likely scenario envisages that a bat-derived MERS-CoV spread to humans via the zoonotic transmission from dromedary camels. Coronaviruses use their spike (S) protein to bind a host receptor and to promote membrane fusion. Class I fusion proteins are found in many other virus genera including retroviruses, orthomyxoviruses, paramyxoviruses, and filoviruses and share similar domain organization, as well as common functional properties[12]

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