Researchers have analyzed the molecular framework and characteristics of a crucial component of the lethal Nipah virus. Experiments conducted in cellular environments demonstrated how alterations in the viral polymerase—a protein essential for viral replication—can impact the virus’s capacity to replicate and infect cells. In-depth examination unveiled segments of the Nipah virus polymerase that might make the virus vulnerable to medications.
A team from Harvard Medical School and the Boston University Chobanian & Avedisian School of Medicine has scrutinized a vital segment of the Nipah virus, a highly deadly pathogen transmitted by bats that has prompted human outbreaks nearly every year since its discovery in 1999.
The progress, highlighted on January 20 in Cell, brings researchers closer to creating essential therapies. At present, there are no vaccines for preventing or alleviating Nipah virus infections, and treatments are limited to providing support.
The virus, maintained by fruit bats, can spread to pigs and humans. It can infect individuals through contaminated food and can also be transmitted from one person to another through respiratory droplets. The World Health Organization classifies the Nipah virus as a priority pathogen, indicating a need for urgent research to guide prevention and treatment measures due to its potential to cause severe outbreaks.
Nipah virus could trigger a pandemic, researchers warn, as it can be spread through airborne droplets and respiratory fluids. Furthermore, they observed that some individuals showing mild, vague symptoms could still transmit the virus.
Severe infections may result in serious respiratory issues and encephalitis, a brain inflammation that can cause significant neurological damage and fatalities. According to estimates from the Centers for Disease Control and Prevention, the virus has a fatality rate between 40 and 75 percent. For context, the Ebola virus has a mortality rate varying from 25 to 90 percent in past outbreaks, averaging around 50 percent.
In this recent investigation, the research focused on the viral polymerase complex, a set of proteins the virus employs to replicate its genetic material, facilitate dissemination, and infect cells. This research provides a comprehensive three-dimensional representation of the polymerase’s architecture and essential attributes. Understanding this critical component of the virus is pivotal in unraveling how it proliferates within its hosts.
Before this study, the structure and operation of the Nipah virus polymerase were not well understood, prompting researchers to urge further investigation to fully grasp how it generates various types of genetic materials essential for the virus’s replication.
Despite this, the team emphasized that understanding this aspect of the viral system is a fundamental initial step toward demystifying the workings of a virus that poses a significant threat.
“Understanding how the polymerase is regulated to activate or deactivate the different enzymatic functions necessary for viral replication would be revolutionary, and this study marks a vital move toward that objective,” stated Rachel Fearns, the co-corresponding author and Chair and Ernest Barsamian Professor of Virology, Immunology & Microbiology at the Boston University Chobanian & Avedisian School of Medicine.
Dissecting the molecular framework of the viral polymerase complex forms a base that can direct the creation of treatments.
“This newfound knowledge enables us to pinpoint the functional characteristics of the polymerase structure, which could be targeted in drug development,” explained Jonathan Abraham, co-corresponding author and associate professor of microbiology at Harvard Medical School and an investigator at the Howard Hughes Medical Institute.
After determining the enzyme’s structure, the researchers investigated how various components of the enzyme influence its different functions. Gaining insight into these components and how they can shift to different positions provides critical information on halting the virus’s spread.
The researchers completed their experiments in two distinct methods. First, they purified the polymerase and elucidated its structure through cryo-electron microscopy, a technique that visualizes biological samples at the molecular level. Second, they created mutations in the polymerase and observed the function of these mutated enzymes in cells to see how the changes impacted their performance.
By comparing the unique and shared properties of the Nipah virus polymerases with those of other viral polymerases, this study has generated crucial insights that could aid in developing broad-spectrum antiviral drugs, noted Heesu Kim, co-first author and researcher at the Fearns Lab.
The team pointed out a promising oral drug candidate developed by scientists at Georgia State University that is effective against viruses similar to Nipah, but not against Nipah itself.
To determine why this drug candidate fails against Nipah virus, the researchers performed various simulations to evaluate if specific structural modifications to the viral polymerase could enhance the drug’s binding capability. They discovered a segment of the viral polymerase that could serve as a potential drug target, thereby informing the design of small-molecule inhibitors that could weaken the viral polymerase and make Nipah virus more treatable.
“We anticipate that our findings will ignite interest and encourage further research from others, leading to new discoveries about this deadly pathogen,” expressed Side Hu, co-first author and post-doctoral researcher in the Abraham Lab. “Indeed, we were pleased to observe other groups share their data openly, just as we did, to advance this field.”
