Wednesday, August 13, 2014

PNAS: Receptor Usage & Cell Entry Of Bat Coronaviruses


More than one way to jump species


# 8949


In 2011 Hollywood director Stephen Soderbergh brought his pandemic thriller `Contagion’ to the big screen, with a fictionalized  MEV-1 bat virus as the viral villain (see Why You Should Catch `Contagion’). The following summer we became aware of a new, often deadly, respiratory virus in the Middle East – apparently also with bat origins – called MERS-CoV.


While one might simply assume Hollywood got `lucky’ and guessed right, the truth is the fictional MEV-1 used in the film was envisioned by the director of Columbia University’s Center for Infection and Immunity in New York – Dr. Ian Lipkin - who served as technical advisor for the film.


Bats, increasingly, are being viewed as substantial reservoirs for dangerous viruses. While long known to vector rabies, in the 1990s outbreaks of Hendra in Australia and Nipah in Malaysia and parts of Asia were eventually traced to bats, and while conclusive evidence is still lacking, the Ebola virus (and its cousin Marburg) are all believed to have bat origins


Bats are abundant (roughly 1/4th of all mammal species), mobile and wide ranging, and have adapted over millions of years to carry a variety of highly pathogenic viruses without ill effect.

Over the past couple of years we’ve also seen two new subtypes of influenza identified in bats (see A New Flu Comes Up To Bat & PLoS Pathogens: New World Bats Harbor Diverse Flu Strains).  All things considered, the past 20 years have been a Chiropterist’s delight.


While the world is riveted to the Ebola tragedy playing out in Africa, the bat viruses that with the most pandemic potential are those that once acquired, can spread via the respiratory route.  SARS and MERS are the two best known examples, but there are other similar coronaviruses circulating in bat that have the potential to jump species as well.


In September of 2012, shortly after the announced discovery of the MERS virus, I wrote that researchers from the University of Hong Kong had compared the genetic structure of the newly discovered coronavirus with other coronaviruses, and found it to be a 90% match to the HKU4 and HKU5 strains collected in the middle of the last decade in Hong Kong (see Coronavirus `Closely Related’ To HK Bat Strains.)


Earlier 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. 


All of which serves as prelude to a new study, published yesterday in PNAS  that looks at the ability of the HKU4 coronavirus, and MERS-CoV, to attach to, and enter human cells. While both use the same dipeptidyl peptidase 4 (DPP4) receptor, the MERS coronavirus is far more adept at actually entering human cells than its HKU4 cousin.



Receptor usage and cell entry of bat coronavirus HKU4 provide insight into bat-to-human transmission of MERS coronavirus

Yang Yang, Lanying Du, Chang Liu, Lili Wang, Cuiqing Ma, Jian Tang, Ralph S. Baric, Shibo Jiang, and Fang Li


Middle East respiratory syndrome coronavirus (MERS-CoV) currently spreads in humans and causes ∼36% fatality in infected patients. Believed to have originated from bats, MERS-CoV is genetically related to bat coronaviruses HKU4 and HKU5. To understand how bat coronaviruses transmit to humans, we investigated the receptor usage and cell entry activity of the virus-surface spike proteins of HKU4 and HKU5.

We found that dipeptidyl peptidase 4 (DPP4), the receptor for MERS-CoV, is also the receptor for HKU4, but not HKU5.

Despite sharing a common receptor, MERS-CoV and HKU4 spikes demonstrated functional differences.

First, whereas MERS-CoV prefers human DPP4 over bat DPP4 as its receptor, HKU4 shows the opposite trend. Second, in the absence of exogenous proteases, both MERS-CoV and HKU4 spikes mediate pseudovirus entry into bat cells, whereas only MERS-CoV spike, but not HKU4 spike, mediates pseudovirus entry into human cells.

Thus, MERS-CoV, but not HKU4, has adapted to use human DPP4 and human cellular proteases for efficient human cell entry, contributing to the enhanced pathogenesis of MERS-CoV in humans. These results establish DPP4 as a functional receptor for HKU4 and host cellular proteases as a host range determinant for HKU4. They also suggest that DPP4-recognizing bat coronaviruses threaten human health because of their spikes’ capability to adapt to human cells for cross-species transmissions.


Although the full study is behind a pay wall, the University of Minnesota Academic Health Center has published the following press release with additional details.


UMN and NYBC research finds potential MERS transmission mechanism between bats and humans


Researchers have identified the mechanism used by the deadly MERS virus to transmit from bats to humans. Bats are a native reservoir for MERS and the finding could be critical for understanding the animal origins of the virus, as well as preventing and controlling the spread of MERS and related viruses in humans.


Researchers have known the MERS virus infects human cells by attaching itself to a receptor molecule called dipeptidyl peptidase 4 (DPP4) and then entering human cells. However, it was not known how MERS was being transmitted from bats to humans.

"We wanted to better understand what prompted MERS to jump from bats to humans, and knew we needed to find a virus that was isolated in bats but had the potential to move into a human model," said Li. "HKU4 virus is related to MERS and has, so far, infected bats but not humans. It provided a good model for understanding the bat-to-human transmission process of MERS and related viruses."

After investigating both MERS and HKU4, researchers observed two major indicators MERS had adapted to human cells in a way HKU4 had not done yet.

The first discovery was that HKU4 virus recognizes the same receptor, DPP4, as MERS virus.. However, MERS virus uses the DPP4 molecule from human origin better, whereas HKU4 virus uses the DPP4 molecule from bat origin better. HKU4 also struggles to enter human cells once attached to the DPP4 receptor on the human cell surface. MERS does not have such a problem, though both viruses are able to enter bat cells.

"Overall, our findings suggest that MERS virus has successfully adapted to human cells for efficient infections, and HKU4 virus can potentially infect human cells," said Li. "MERS and MERS-related bat viruses present a constant and long-term threat to human health. So far little is known about these bat viruses that are evolutionary ancestors to human viruses. We need to look at bat viruses carefully, learn how they infect cells and jump species, and then develop strategies to block their transmission to humans."

For more on MERS, and its use of DPP4 receptors, you may wish to revisit:

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

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