Tuesday, May 15, 2018

PNAS: Broad Receptor Engagement of PDCoV May Potentiate Its Cross-Species Transmissibility


Until SARS emerged on the world stage just over 15 years ago (see SARS and Remembrance), coronaviruses were only believed capable of producing mild `cold-like’ illnesses in humans. Today, we know of six coronaviruses with the ability to infect humans, two of which (MERS-CoV & SARS-CoV) are also known to produce severe, sometimes fatal, illness in humans. 
There are many other coronaviruses that infect other non-human  species - including horses, cattle, swine and bats (see Nature: Fatal Swine Acute Diarrhoea Syndrome Caused By An HKU2-related Coronavirus Of Bat Origin).
With both SARS and MERS having (presumably) jumped from bats to intermediate hosts (civets, raccoon dogs, and camels), and then on to humans, there are concerns that other - currently non-zoonotic - coronaviruses could evolve and do the same in the future (see PNAS: SARS-like WIV1-CoV Poised For Human Emergence).

Five years ago a new and deadly (to swine, at least) coronavirus made its first appearance in North America, and since then has swept across 39 states, killing millions of pigs.  We looked at that emerging threat in mBio: PEDV - Porcine Epidemic Diarrhea Virus - An Emerging Coronavirus.

While distantly related to SARS and MERS (both are betacoronaviruses),  PEDV is an alphacoronavirus. We’ve seen no evidence of human infection due to PEDV coronavirus, so PEDV is not currently considered a zoonotic disease.
Two other genera also exist; Gammacoronaviruses & Deltacoronaviruses.  The first two (alpha & beta) are believed to originate in bats (but are found in many other species), with the second two (Gamma & Delta) are believed to have an avian origin.

In February of 2014, the Ohio Department of Agriculture officially announced that a never-before-seen porcine deltacoronavirus (PDCoV) had been identified in the United States (see New, non-PED Coronavirus detected in pigs with diarrhea). From the announcement:
Sequence analysis of the new coronavirus shows that it is a deltacoronavirus, distinct from PED and TGE viruses.  The new virus has been designated as Swine DeltaCoronavirus (SDCV). This virus is closely related to a coronavirus which was detected in Hong Kong in 2012. The virus cannot spread to humans or other species and poses no risk to food safety. Further study is needed to confirm whether or not this virus is the cause of diarrheal disease in affected pigs.  
With a plethora of porcine pathogens to deal with, the USDA has lumped them together in the general category of SECD – or Swine Enteric Coronavirus Diseases. In 2014 the USDA announced the mandatory reporting of SECDs by all farmers, veterinarians, and diagnostic labs.

While it is absolutely true that PDCoV & PDCoV  have not been shown to infect humans, what is left largely unsaid is that viruses – particularly RNA viruses (which include coronaviruses) – tend to evolve over time. 
And what can be said about a particular virus today may not necessarily hold true tomorrow.
All of which brings us to a new study (alas, mostly behind a pay wall) in PNAS, that looks at the potential for PDCoV to bind to human (and other mammalian and avian) receptor cells, opening the door - at least a little - to it having some zoonotic potential.
The article is submitted by senior author Dr. Linda J. Saif, whose excellent 2014 presentation CORONAVIRUSES: Lessons for. SARS and MERS Human Coronaviruses, we've had occasion to look at in the past.
First the link to the study and abstract, and then some excerpts from an Ohio State University press release.
Broad receptor engagement of an emerging global coronavirus may potentiate its diverse cross-species transmissibility 
Wentao Li, Ruben J. G. Hulswit, Scott P. Kenney, Ivy Widjaja, Kwonil Jung, Moyasar A. Alhamo, Brenda van Dieren, Frank J. M. van Kuppeveld, Linda J. Saif, and Berend-Jan Bosch
PNAS May 14, 2018. 201802879; published ahead of print May 14, 2018. https://doi.org/10.1073/pnas.1802879115


Porcine deltacoronavirus (PDCoV), identified in 2012, is a common enteropathogen of swine with worldwide distribution. The source and evolutionary history of this virus is, however, unknown.

PDCoV belongs to the Deltacoronavirus genus that comprises predominantly avian CoV. Phylogenetic analysis suggests that PDCoV originated relatively recently from a host-switching event between birds and mammals. Insight into receptor engagement by PDCoV may shed light into such an exceptional phenomenon.

Here we report that PDCoV employs host aminopeptidase N (APN) as an entry receptor and interacts with APN via domain B of its spike (S) protein. Infection of porcine cells with PDCoV was drastically reduced by APN knockout and rescued after reconstitution of APN expression. In addition, we observed that PDCoV efficiently infects cells of unusual broad species range, including human and chicken.

Accordingly, PDCoV S was found to target the phylogenetically conserved catalytic domain of APN. Moreover, transient expression of porcine, feline, human, and chicken APN renders cells susceptible to PDCoV infection. Binding of PDCoV to an interspecies conserved site on APN may facilitate direct transmission of PDCoV to nonreservoir species, including humans, potentially reflecting the mechanism that enabled a virus, ancestral to PDCoV, to breach the species barrier between birds and mammals.

The APN cell surface protein is also used by several members of the Alphacoronavirus genus. Hence, our data constitute the second identification of CoVs from different genera that use the same receptor, implying that CoV receptor selection is subjected to specific restrictions that are still poorly understood.
(Continue . . . )

​New pig virus found to be a potential threat to humans 

Study first to show possible cross-species transmission of recently discovered coronavirus

By: Misti Crane

Published on May 14, 2018

COLUMBUS, Ohio – A recently identified pig virus can readily find its way into laboratory-cultured cells of people and other species, a discovery that raises concerns about the potential for outbreaks that threaten human and animal health.

Researchers at The Ohio State University and Utrecht University in the Netherlands collaborated to better understand the new virus and its potential reach. Their study, the first to point to possible transmission of this virus between species, appears online in the journal PNAS.

Porcine deltacoronavirus was first identified in 2012 in pigs in China, but it was not associated with disease. It was first detected in the United States in 2014 during a diarrhea outbreak in Ohio pigs and has since been detected in various countries. Young, infected pigs experience acute diarrhea and vomiting. The disease can be fatal. As of yet, no human cases have been documented, but scientists are concerned about the possibility.

“Before it was found in pigs – including in the Ohio outbreak – it had only been found in various birds,” said study senior author Linda Saif, an investigator in Ohio State’s Food Animal Health Research Program at the Ohio Agricultural Research and Development Center (OARDC), in Wooster.

“We’re very concerned about emerging coronaviruses and worry about the harm they can do to animals and their potential to jump to humans,” said Saif, a distinguished university professor of veterinary preventive medicine.

Emergence of the new virus is especially worrisome to veterinary and public-health experts because of its similarity to the life-threating viruses responsible for SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome) outbreaks.

The potential for a virus to jump from one species to another is highly dependent on its ability to bind to receptors on the cells of the animal or human, said lead researcher Scott Kenney, an assistant professor of veterinary preventive medicine based in the Food Animal Health Research Program at OARDC.

“A receptor is like a lock in the door. If the virus can pick the lock, it can get into the cell and potentially infect the host,” he said.

This study looked at a particular cellular receptor called aminopeptidase N that the researchers suspected might be involved.

“We know from other coronaviruses that these receptors on the cells are used and that they’re found in the respiratory and digestive tracts of a number of different animals,” Kenney said. “Now we know that this new virus could go into cells of different species, including humans.”

Saif said it’s important to recognize that, for now, the only known infection in humans and other species is in the laboratory, using cultured cells.

Their investigation confirmed that the virus could bind to the receptor in pigs, which was not a big surprise.

But it also was able to bind to the receptor in human cells, and to cells from cats and chickens.

“From that point, it’s just a matter of whether it can replicate within the cells and cause disease in those animals and humans,” Kenney said.

Added Saif, “This doesn’t prove that this virus can infect and cause disease in these other species, but that’s something we obviously want to know.”
(Continue. . . )

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