Thursday, October 10, 2013

Virology Journal: Bats, DPP4 Receptors, and MERS-CoV


Photo Credit NIAID



# 7849


From the moment the first MERS (then called nCoV) coronavirus was isolated, bats were considered likely host reservoirs, since other beta-coronaviruses have been linked to those winged mammals (see EID Journal: EMC/2012–related Coronaviruses in Bats and mBio: New Coronavirus Linked To Bats).  


While no live MERS virus has yet been isolated from a bat, last August this bat connection was strengthened when Dr. Ian Lipkin’s team at Columbia University, and researchers from EcoHealth Alliance – announced they had detected a viral fragment from a bat sample that was a 100% match to a conserved area of the MERS coronavirus (see EID Journal: Detection Of MERS-CoV In Saudi Arabian Bat).

Other research (see Nature: Receptor For NCoV Found) determined that MERS-CoV uses a well known cell surface protein called dipeptidyl peptidase 4 (DPP4) to enter and infect human cells. 


This DPP4 cell surface protein (also called CD26) is evolutionarily conserved in other species, including bats, non-human primates, and other animals – all of which suggests that this virus might be able to infect a wide range of hosts.  The discovery of MERS antibodies in camels over the summer provides additional evidence of this virus’ ability to infect a variety of hosts.


Today, another study that looks at the connection between bats and the MERS coronavirus - but this time from the perspective of evolutionary genomic changes in bats - that suggest that MERS and these nocturnal mammals have had a cozy relationship for quite some time.  The article is dauntingly called:


Adaptive evolution of bat dipeptidyl peptidase 4 (dpp4): implications for the origin and emergence of Middle East respiratory syndrome coronavirus

Jie Cui, John-Sebastian Eden, Edward C Holmes and Lin-Fa Wang

Virology Journal 2013, 10:304 doi:10.1186/1743-422X-10-304

Published: 10 October 2013

Abstract (provisional)


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.

Findings 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.

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.



Although you’ll probably want to read this article in its entirety, BioMed Central published a brief press release that explains some of the high points. Despite the air of certainty expressed in the title of this press release, the authors leave a little room in their article for an alternate explanation for the genetic evolution they charted in bats.  They write:


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.


This from the BioMed Central press room.


Origin of MERS coronavirus identified

10 Oct 2013

The newly emerged Middle East respiratory syndrome coronavirus (MERS-CoV) has circulated in bats for a substantial time, before making the species leap to humans, according to research published in BioMed Central’s open access publication Virology Journal. By analysing the genome of various bat species, scientists show that bat DPP4 genes have adapted significantly as they evolved, suggesting a long-term arms race between the bat and the virus.


Previous work has shown that MERS-CoV uses the DPP4 receptor to enter the cell and it is well known that viruses can leave evolutionary footprints in receptor-encoding genes of hosts and their binding domains during long battles with the hosts. Jie Cui, colleagues from the University of Sydney and collaborators from the Duke-NUS Graduate Medical School and CSIRO analysed the sequence of DPP4 from seven bat genomes. They then compared the findings to those of a range of non-bat mammalian species. They go on to identify three residues in bat DPP4 under positive selection that directly interact with the viral surface glycoprotein.


Their findings show more pressure on the bat genes than in other species, with mutations occurring at a faster rate, suggesting that the newly emerged MERS-CoV not only has a bat origin, but also evolved over an extended time period in bat populations before making the leap to infect humans.  Further research will be needed to understand the transmission route by collecting more bat MERS-CoVs.


Jie Cui, lead author on the paper, says: “Our analysis suggests that an evolutionary lineage leading to the current MERS-CoV co-evolved with bat hosts for an extended time period, eventually jumping species boundaries to infect humans, perhaps through an intermediate host.”