SARS – severe acute respiratory syndrome – alarmed the world five years ago as the first global pandemic of the 21st century. The coronavirus (SARS-CoV) that sickened more than 8,000 people – and killed nearly 800 of them – may have originated in bats, but the actual animal source is not known.
In an effort to understand how SARS-CoV may have jumped from bats to humans, a team of investigators from Vanderbilt University Medical Center and the University of North Carolina at Chapel Hill has now generated a synthetic SARS-like bat coronavirus. The virus – the largest replicating synthetic organism ever made – is infectious in cultured cells and mice, the researchers report in the Proceedings of the National Academy of Sciences.
The findings identify pathways by which a bat coronavirus may have adapted to infect humans. The studies also provide a model approach for rapid identification, analysis and public health responses to future natural or intentional virus epidemics.
Zoonotic viruses – animal pathogens that can cause disease in humans – pose a serious threat to public health, said Mark Denison, M.D., professor of Pediatrics at Vanderbilt and a co-leader of the research with Ralph Baric, Ph.D., professor of Epidemiology at UNC.
"It's becoming more and more clear that new human epidemics will continue to originate in animals," said Denison, who is also an associate professor of Microbiology & Immunology. "However, the mechanisms of trans-species movement and adaptation of viruses from animals to humans remain poorly understood."
At the time of the SARS epidemic, the culprit virus was rapidly identified as a coronavirus (SARS-CoV). But it didn't look like the two human coronaviruses that were known, which cause 20 percent to 30 percent of common colds, and the animal "reservoir" (the original animal host for the virus) remained elusive.
Investigators became convinced that bats were the likely source, but bat coronaviruses had never been successfully grown in culture or animals, which blocked studies of replication, evolution and prevention.
The Denison and Baric teams, with lead authors Michelle Becker, Ph.D., of Vanderbilt, and Rachel Graham Ph.D., of UNC, determined that not being able to grow the virus represented a critical gap in the ability to rapidly identify and respond to new pathogens.
To address this vulnerability, the team decided to use synthetic biology to recover a non-cultivatable virus.
"The idea is, here's the virus, or the virus group, that we think became SARS-CoV," Denison said. "Let's see if we can synthetically recover the bat virus and test it in cultured cells and in animal models – let the bat virus show us the pathways that it may have used to become a human pathogen.
"Then we would have a viable candidate virus to test for diagnostics, vaccines and treatment."
The investigators used published SARS-like bat coronavirus sequences to establish a "consensus" genome sequence – "the best bet for a virus genome that would be viable," Denison said. They then used commercial DNA synthesis and reverse genetics to "build" the consensus viral genome and several variations.
The consensus synthetic SARS-like bat CoV did not initially grow in culture. But substitution of a single small region from human SARS-CoV – the Spike protein receptor binding domain that is critical for viral entry into human cells – allowed the new chimeric SARS-like bat CoV to grow well in monkey cells (commonly used to study human SARS-CoV).
"It was a tremendous surprise that such a small region of SARS-CoV was sufficient to allow the bat virus to move from zero growth to very efficient growth in cells," Denison said.
The chimeric virus also grew well in mouse cells modified to express the receptor for SARS-CoV and in primary human airway epithelial cells. It grew poorly in mice, but a single additional change in the Spike region allowed efficient growth in mice, without causing a SARS-like disease.
The studies suggest that a very simple recombination event may have been enough to allow a coronavirus to move from one species to another, Denison said, adding that "after a virus gains the capacity to jump species, additional simple adaptations may be adequate to increase its ability to grow in the new animal host."
At all stages of design and implementation, the Vanderbilt and UNC teams acknowledged potential safety concerns and encouraged ongoing external safety reviews. Research with all bat viruses – even weakened mutants – was performed under the same stringent biosafety conditions used to study virulent SARS-CoV. The investigators found that human antibodies known to render SARS-CoV noninfectious also neutralized the bat SARS-like coronavirus, providing an additional safety measure.
"The approaches used here address fundamental questions in virus movement between species," Denison said, "and also could improve public health preparedness by allowing rapid responses to naturally emerging or intentionally introduced zoonotic pathogens."
John Howser | EurekAlert!
Further reports about: > Coronavirus > Denison > Pathogen > SARS > SARS-CoV > SARS-like > SARS-like bat coronavirus > Synthetic virus > Vanderbilt > Zoonotic viruses > emerging infections > epidemic > first global pandemic > human coronaviruses > non-cultivatable virus > respiratory syndrome > synthetic
Nanoparticle Exposure Can Awaken Dormant Viruses in the Lungs
16.01.2017 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
Cholera bacteria infect more effectively with a simple twist of shape
13.01.2017 | Princeton University
Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.
While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...
Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales
Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).
Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...
Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.
The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...
10.01.2017 | Event News
09.01.2017 | Event News
05.01.2017 | Event News
17.01.2017 | Earth Sciences
17.01.2017 | Materials Sciences
17.01.2017 | Architecture and Construction