A Purdue University-led research team has figured out how to disable a part of the SARS virus responsible for hiding it from the immune system; a critical step in developing a vaccine against the deadly disease.
The findings also have potential applications in the creation of vaccines against other coronaviruses, including MERS, said Andrew Mesecar, who led the research.
"This is a first step toward creating a weakened and safe virus for use in an attenuated live vaccine," said Mesecar, Purdue's Walther Professor of Cancer Structural Biology and professor of biological sciences and chemistry. "This also could serve as a molecular roadmap for performing similar studies on other coronaviruses, like MERS, because this enzyme appears to be common to all viruses within this family."
Mesecar also is a part of a research team studying and creating potential treatment compounds for the Middle East respiratory syndrome coronavirus, or MERS, that recently arrived in the United States. There is currently no treatment or vaccine for the virus, which has an estimated fatality rate of 30 percent, according to the Centers for Disease Control and Prevention.
Because MERS and SARS are related, insight into one could provide a shortcut to finding a treatment or developing a vaccine for the other.
Mesecar and his team captured the molecular structure of a key SARS enzyme, papain-like protease, and revealed how it strips a host cell of the proteins ubiquitin and ISG15, which are involved in triggering an immune response.
A paper detailing the National Institutes of Health and National Institue of Allergy and Infectious Diseases-funded work was published in PLOS Pathogens on May 22 and is available online.
"With most viruses, when a cell is infected it sends out an alarm triggering an immune response that fights the infection, but successful viruses are able to trick the immune system," Mesecar said. "By clipping off these two proteins, SARS short circuits the host cell's signaling pathways and prevents it from alerting the immune system to its presence. By removing these proteins, the enzyme serves as a biological cloaking system for the SARS virus that allows it to live and replicate undetected."
The disruption in its natural signaling pathways also causes an infected cell to miscommunicate with the cells around it, which leads to a response that eventually kills those cells, he said.
"Some treatments prevent a virus from replicating and stop further infection, but that doesn't necessarily prevent a harmful reaction to the virus," Mesecar said. "Sometimes it is the confusion in cellular communication that makes a virus lethal."
The outbreak of SARS, severe acute respiratory syndrome, in 2003 led to hundreds of deaths and thousands of illnesses, and there is currently no treatment. The virus can be transmitted through coughing or sneezing, and the infection can quickly spread from person to person, according to the CDC. SARS spread through two dozen countries over a period of a few months before it was contained. A total of 8,098 people worldwide became ill and 774 died. There have been no reported cases of SARS since 2004.
In 2012 the National Select Agent Registry Program declared SARS virus a select agent, meaning it is considered to have the potential to pose a severe threat to public health and safety.
In addition to hiding the virus from the immune system, the SARS papain-like protease, or PLpro, enzyme also is responsible for snipping the viral polyprotein into individual proteins that are essential for viral replication. While some treatments are designed to prevent viral replication, researchers working on a vaccine must retain this function, he said.
"The goal in engineering a SARS virus that could be used as a vaccine is to create one that replicates in cells but is unable to fend off the body's immune response," Mesecar said. "We want enough viral particles to be generated to properly prime the immune sytem to fight off a true infection, but without the virus being able to cause illness in the vaccinated individual."
Mesecar and his team focused on uncovering parts of the SARS PLpro enzyme that would be involved in thwarting the immune response, but which could be altered without affecting viral replication, he said.
The team used X-ray crystallography to solve the three-dimensional structure of the SARS PLpro enzyme in complex with ubiquitin. This enabled them to see how it interatced with the protein and which amino acids are involved in linking the two together. They then used computer models and simulations to determine which amino acids are likely involved in binding ISG15. The researchers mutated the amino acids identified so that the SARS PLpro enzyme could no longer interact with the host cell proteins. The team then tested the mutatant enzyme to confirm that it could still perform its role in viral replication.
In addition to Mesecar, co-authors include Purdue postdoctoral researcher Yahira M. Baez-Santos; Kiira Ratia from the University of Illinois, Chicago; and Andrew Kilianski and Susan C. Baker from the Loyola University Chicago Stritch School of Medicine.
Mesecar and his team are currently applying their findings to the MERS virus. They have shown that the MERS virus PLpro enzyme also removes ISG15 and ubiquitin from host cell proteins, and were able to crystallize the MERS Plpro enzyme in complex with ubiquitn and ISG15, he said.
Writer: Elizabeth K. Gardner, 765-494-2081, email@example.com
Source: Andrew Mesecar, 765-494-1924, firstname.lastname@example.org
Elizabeth K. Gardner | Eurek Alert!
Penn vet research identifies new target for taming Ebola
12.01.2017 | University of Pennsylvania
The strange double life of Dab2
10.01.2017 | University of Miami Miller School of Medicine
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...
UMD, NOAA collaboration demonstrates suitability of in-orbit datasets for weather satellite calibration
"Traffic and weather, together on the hour!" blasts your local radio station, while your smartphone knows the weather halfway across the world. A network of...
Fiber-reinforced plastics (FRP) are frequently used in the aeronautic and automobile industry. However, the repair of workpieces made of these composite materials is often less profitable than exchanging the part. In order to increase the lifetime of FRP parts and to make them more eco-efficient, the Laser Zentrum Hannover e.V. (LZH) and the Apodius GmbH want to combine a new measuring device for fiber layer orientation with an innovative laser-based repair process.
Defects in FRP pieces may be production or operation-related. Whether or not repair is cost-effective depends on the geometry of the defective area, the tools...
10.01.2017 | Event News
09.01.2017 | Event News
05.01.2017 | Event News
16.01.2017 | Power and Electrical Engineering
16.01.2017 | Information Technology
16.01.2017 | Power and Electrical Engineering