Adaptive evolution of bat dipeptidyl peptidase 4 (dpp4): implications for the origin and emergence of Middle East respiratory syndrome coronavirus
© Cui et al.; licensee BioMed Central Ltd. 2013
Received: 3 September 2013
Accepted: 3 October 2013
Published: 10 October 2013
The newly emerged Middle East respiratory syndrome coronavirus (MERS-CoV) that first appeared in Saudi Arabia during the summer of 2012 has to date (20th September 2013) caused 58 human deaths. MERS-CoV utilizes the dipeptidyl peptidase 4 (DPP4) host cell receptor, and analysis of the long-term interaction between virus and receptor provides key information on the evolutionary events that lead to the viral emergence.
We show that bat DPP4 genes have been subject to significant adaptive evolution, suggestive of a long-term arms-race between bats and MERS related CoVs. In particular, we identify three positively selected residues in DPP4 that directly interact with the viral surface glycoprotein.
Our study suggests that the evolutionary lineage leading to MERS-CoV may have circulated in bats for a substantial time period.
Middle East respiratory syndrome coronavirus (MERS-CoV) , first described by the World Health Organization (WHO) on 23rd September 2012 [2, 3], has to date (20th September 2013) caused 130 laboratory-confirmed human infections with 58 deaths (http://www.who.int/csr/don/2013_09_20/en/index.html). MERS-CoV belongs to lineage C of the genus Betacoronavirus in the family Coronaviridae, and is closely related to Tylonycteris bat coronavirus HKU4 (BtCoV-HKU4), Pipistrellus bat coronavirus HKU5 (Bt-HKU5) [4, 5] and CoVs in Nycteris bats , suggestive of a bat-origin . Unlike severe acute respiratory syndrome (SARS) CoV which uses the angiotensin-converting enzyme 2 (ACE2) receptor for cell entry , MERS-CoV employs the dipeptidyl peptidase 4 receptor (DPP4; also known as CD26), and recent work has demonstrated that expression of both human and bat DPP4 in non-susceptible cells enabled viral entry .
Cell-surface receptors such as DPP4 play a key role in facilitating viral invasion and tropism. As a consequence, the long-term co-evolutionary dynamics between hosts and viruses often leave evolutionary footprints in both receptor-encoding genes of hosts and the receptor-binding domains (RBDs) of viruses in the form of positively selected amino acid residues (i.e. adaptive evolution). For example, signatures of recurrent positive selection have been observed in ACE2 genes in bats , supporting the past circulation of SARS related CoVs in bats. To better understand the origins of MERS-CoV, as well as their potentially long-term (compared to short-term which lacks virus-host interaction) evolutionary dynamics with bat hosts [5, 10], we studied the molecular evolution of DPP4 across the mammalian phylogeny.
Sequences used in the evolutionary analysis of DDP4
Odobenus rosmarus divergens
Mustela putorius furo
Large flying fox
Black flying fox
Common vampire bat
Little brown bat
Lesser Egyptian jerboa
Gorilla gorilla gorilla
Numbers of nonsynonymous (d N ) and synonymous (d S ) substitutions per site DPP4 genes in different mammals
Large flying fox
Black flying fox
Common vampire bat
Little brown bat
Lesser Egyptian jerboa
Putatively positive selected DPP4 codons in bats
Codon position a
Posterior probability b
Our analysis therefore suggests that the evolutionary lineage leading to current MERS-CoV co-evolved with bat hosts for an extended time period, eventually jumping species boundaries to infect humans and perhaps through an intermediate host. As such, the emergence of MERS-CoV may parallel that of the related SARS-CoV . Although one bat species, Taphozous erforatus, in Saudi Arabia has been found to harbour a small RdRp (RNA-Dependent RNA Polymerase) fragment of MERS-CoV , a larger viral sampling of bats and other animals with close exposure to humans, including dromedary camels were serological evidence for MERS-CoV has been identified , are clearly needed to better understand the viral transmission route. Alternatively, it is possible that the adaptive evolution present on the bat DPP4 was due to viruses other than MERS-CoVs, and which will need to be better assessed when a larger number of viruses are available for analysis. Overall, our study provides evidence that a long-term evolutionary arms race likely occurred between MERS related CoVs and bats.
We thank Christopher Cowled at CSIRO Australian Animal Health Laboratory for annotating the Pterous aleco DPP4. This word was supported in part by a grant from the National Research Foundation, Singapore (NRF2012NRF-CRP-001-056) and the CSIRO Office of the Chief Executive Science Leaders Award. ECH is supported by an NHMRC Australia Fellowship.
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