Structure of an Australian mosquito virus may hold key to the infectivity of global flavivirus pathogens

The cryo-electron microscopy reconstruction of Binjari virus provides the missing piece to correctly model the architecture of immature flaviviruses. The largest piece depicts the collapse of the spike required for the acquisition of infectivity. The smaller piece represents a previous model that does not fit with the new structure.

Latest research led by Australian scientists is a major step forward in the development of vaccines against flaviviruses, which infect more than 400 million people a year resulting in diseases such as dengue, yellow fever, West Nile, Zika and Japanese encephalitis.

In a study published today in Science Advances, a team led by Associate Professor Fasséli Coulibaly, from Monash University in Melbourne, Australia, and Associate Professor Daniel Watterson, from the University of Queensland, have generated for the first time a complete high-resolution structure of an immature flavivirus - revealing that previous assumptions about how these viruses form has been wrong and providing a key to future vaccine development.

The development of vaccines against flaviviruses is an issue of ever-growing importance, because these pathogens continue to be a considerable medical problem in large areas of the world and new threats continually arise from the spread of flaviviruses to new geographic regions, as happened with the rise of Zika virus just before the Rio Olympics.

Since the first structure of an immature flavivirus was generated over 18 years ago, some key details have remained elusive due to "blurred" views of the virus structure before its metamorphosis into infectious particles.

According to Associate Professor Coulibaly, technological advances and a focus on a unique insect-specific virus “have allowed us to study the structure of flavivirus with an unprecedented level of detail”.

This breakthrough originated from a structure of the Binjari flavivirus, isolated in Australia from infected mosquitos and engineered as a vaccine platform by the University of Queensland team.

Dr Joshua Hardy, joint first author from the Monash Biomedicine Discovery Institute, froze the Binjari virus in very thin ice, to preserve its delicate components, and collected thousands of images at the Monash University Ramaciotti Centre for Cryo-Electron Microscopy.

“Obtaining the right ice thickness is crucial in seeing the finer details of the virus or else it is like looking through frosted glass and everything is blurred,” Dr Hardy said.

These images were combined to produce a 3D image that revealed the structure of the immature virus just before it becomes infectious. Importantly the research showed an unexpected architecture of the immature virus.

Associate Professor Daniel Watterson, from the University of Queensland, said the discovery was a surprise.

“Imagine trying to build a house when your blueprints are wrong – that’s exactly what it’s like when you’re attempting to build effective vaccines and treatments and your molecular ‘map’ is not quite right,” he said.

Associate Professor Coulibaly added: “Based on this new structure, we now know that the mechanism of maturation of flavivirus can be described as a guided collapse of viral particles.  It will make the development of better vaccines against these relentless viruses more attainable.”

Joint first author Dr Natalee Newton in the Watterson lab at the University of Queensland, said the discovery highlights the importance of pursuing fundamental science questions. “By asking basic questions we reveal new pathways to solve pressing human diseases,” she said.

Read the full paper in Science Advances titled: The structure of an infectious immature flavivirus redefines viral architecture and maturation.DOI: 10.1126/sciadv.abe4507

The immature flavivirus and its collapse into infectious particles – A/Prof Coulibaly

About the Monash Biomedicine Discovery Institute at Monash University
Committed to making the discoveries that will relieve the future burden of disease, the newly established Monash Biomedicine Discovery Institute at Monash University brings together more than 120 internationally-renowned research teams. Spanning six discovery programs across Cancer, Cardiovascular Disease, Development and Stem Cells, Infection and Immunity, Metabolism, Diabetes and Obesity, and Neuroscience, Monash BDI is one of the largest biomedical research institutes in Australia.  Our researchers are supported by world-class technology and infrastructure, and partner with industry, clinicians and researchers internationally to enhance lives through discovery.

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