Nipah virus glycoprotein structure suggests therapeutic strategies
Posted by Jerry Carter on March 25th, 2022
Recent molecular discoveries have provided new details on how Nipah and Hendra viruses attack cells, and the immune responses that fight back against this attack. The findings point to a multi-pronged strategy for preventing and treating these deadly diseases. The study was published in Science recently.
Both Nipah virus and Hendra virus are carried by indigenous bats in some parts of the world. These henipaviruses span species and can infect many other mammals including humans. These viruses cause brain inflammation and respiratory symptoms. People infected with either of these diseases have a 50% to 100% chance of dying.
There is already a vaccine approved for use on horses and a modified vaccine has entered human clinical trials.
Horses can transmit Hendra virus to their breeders through saliva and nasal secretions, and Hendra virus may be infected by eating fruits contaminated with bats. An experimental cross-reactive antibody that has not been approved is expected to work against both Nipah virus and Hendra virus, and 15 people who have been exposed to high-risk viruses have been injected with this antibody which was conducted according to the Emergency Humane Use Guide. This antibody is undergoing clinical trials in Australia, and it has just completed its first phase of testing. In addition to supportive care, there are currently no approved vaccines or therapies for use in humans against these henipaviruses, and patients have limited hope of overcoming the virus.
After the discovery of a new Hendra virus strain a few months ago, new attempts to design life-saving preventive and therapeutic approaches became more urgent. Over the past 20 years, there have been outbreaks of Nipah virus in Bangladesh almost every year. This disease has also been found in India and the Philippines. In Africa, people and foxes have found antibodies to henipavirus. It is estimated that 200 million people in the world live in areas where the transmission of henipaviruses by bat or animal vectors may pose a threat.
The lead author of the latest Henipah virus paper in Science is David Weiler, an associate professor of biochemistry at Washington University School of Medicine and a Howard Hughes Medical Fellow. He studies the immunity of bats to many dangerous viruses and studies the molecular structure and function of the infection mechanism of coronaviruses, other related viruses, and henipaviruses. His laboratory also studies the interaction of antibodies and viruses, providing clues for the design of antiviral drugs and vaccines for these two virus families.
The researchers explain that Nipah virus and Hendra virus enter cells by binding and fusing glycoproteins that work together. These glycoproteins are key targets of the antibody defense system.
Through cryo-electron microscopy, scientists were able to determine the structure of key components in the mechanism of Nipa virus infection that interact with broadly neutralizing antibody fragments. They also observed that a mixture of antibodies or \"cocktails\" together better disarmed the Nipah virus. Similar synergistic effects were found in a panel of antibodies against Hendra virus. The combination of this force also helps prevent escape mutants from emerging, thereby avoiding antibody responses.
The antibody response of laboratory animals inoculated at key sites to study the mechanism of Nipah virus infection provides important information. The analysis indicates which region of the viral receptor-binding protein is dominant in eliciting immune responses.
Before this study, there was no data on the structure of the HNV G protein, a key part of the antibody response elicited by henipaviruses, the researchers said. This lack of information is a barrier to understanding immunization and improving vaccine candidate design.
Now that researchers have revealed the 3D tissue structure and some conformational dynamics of HNV G proteins, scientists may be closer to creating a template to make new and improved vaccines.
In the simplified description of the more complex findings, an important part of the accessory structure has a neck and four heads. Only one of the four heads points its receptor binding site to the potential host cell; the other three turn to the viral membrane. This allows the viral structure to freely relocate the head region to bind to the host receptor.
Scientists note that this structure \"adopts a unique two head-up and two head-down conformation, which is different from any other paramyxovirus-attached glycoprotein.\" Paramyxoviruses are a large family of single-stranded RNA viruses. They cause several different types of disease, most of which are transmitted by respiratory droplets. They include measles, mumps, canine distemper, parainfluenza, and recent transmission of henipavirus disease from animals to humans.
In studying the nature of the antibody response to the attachment protein G of p-Nipah virus and Hendra virus, scientists examined two animals immunized with this glycoprotein. A robust, diverse neutralizing antibody response ensues. The head region was found to be the major, if not the only target, for immune-inducing antibody neutralization, even when intact tetramers were used. This suggests that the antibody response narrows within the receptor binding region.
The researchers point out that these findings \"provide a blueprint for the design of next generation vaccine candidates with stability and immunogenicity.\" They anticipated a similar design approach for the newer in silico designed SARS-CoV-2 and respiratory syncytial virus candidates. Chimeras of head antigens will be presented on the human body as ordered arrays on a multivalent display. Using just the head region instead of the intact G protein could also make mass production of vaccines simpler.
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About the AuthorJerry Carter
Joined: November 1st, 2019
Articles Posted: 30
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