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‘Deep virology’ shapes up to fight viruses

Following 70 years of expertise investigating some of the most widespread and harmful viruses such as HIV, influenza and Ebola, Kyoto University’s Institute for Life and Medical Sciences is developing a new field of research it calls ‘deep virology’.

The field examines viral infection in humans, from the population and individual levels, all the way down to the atomic level. Deep virology is characterized by two strategies: taking a closer look at viral configurations using atomic resolution visualization methods, and investigating viruses in new ways by continually adopting techniques and technologies from different scientific disciplines.

A cell infected by the Ebola virus.

To develop the field, the institute recruited 40 emerging researchers with a wide range of expertise in virology, immunology, stem cell science, mathematical science, and genomic medicine.

The labs of two of these researchers, Takeshi Noda and Takao Hashiguchi, are revealing the detailed shapes of viruses at the atomic level, with a focus on filoviruses, such as Ebola, as well as viruses affecting predominantly children, including measles and mumps. Recently, the researchers have leveraged their expertise to study SARS-CoV-2.

“A generation ago, individual scientists organized their own teams to study viruses,” says Hashiguchi. “Now we are in an era where multiple researchers form a large team to study comprehensively, rapidly, and with state-of-the-art technologies from different fields.”

‘Filming’ viruses at atomic resolution

Filoviruses, such as the Ebola virus and Marburg virus, can cause severe haemorrhagic fevers in humans, leading to acute, life-threatening illness. Noda, who leads the Lab of Ultrastructural Virology, is working to identify better antiviral treatments by understanding how filoviruses replicate within human cells.

His team is revealing the structural details of the filovirus ‘nucleocapsid’ – a long, helical scaffolding structure that packages genetic material (RNA) – to understand how viral molecules collaborate for RNA synthesis.

A 3D image of the influenza virus taken using electron tomography.

Having previously revealed snapshot structures of how RNA wraps around the nucleocapsids of the Ebola virus, he is now hoping to capture the full progression of how the virus structure moves and changes during RNA synthesis. “If we know the structure and interactions in the helical nucleocapsid, we can develop new drugs to inhibit specific protein-protein interactions. This work will help develop treatments for filovirus infections,” says Noda.

A combination of cryo-electron microscopy and high-speed atomic force microscopy allows him to step through the viral lifecycle by resolving ‘ultrastructural’ components. He recently used the method to reveal the sequential steps of RNA replication of the influenza virus.

“I believe that structural analysis including live-imaging of the structural changes, or ‘4D’ structural analysis, is a tool of deep virology,” says Noda.

A closer look at viruses affecting children

While vaccines against measles and mumps were developed more than 50 years ago, these viruses continue to spread. Measles outbreaks are on the rise globally and were estimated to cause 200,000 deaths in 2019. Further, outbreaks of mumps occur every four years in Japan as the vaccine is not included in the routine vaccination programme.

Hashiguchi, who heads the Lab of Medical Virology, aims to help develop new antiviral therapies against these and other viruses that commonly affect children, by focusing on the entry of a virus into a host cell, which is the first stage of virus infection.

“I am interested in how viruses interact with target cells, in how they reorganize the proteins and how their structure changes,” says Hashiguchi.

He uses X-ray crystallography to resolve glycoproteins found on the surface of viruses that interact with surface molecules of host cells. “Viral glycoproteins are important not only in viral pathogenicity but also in the development of vaccines and new drugs. We aim to elucidate the detailed mechanisms of viral entry and its inhibition by integrating virology with structural biology, pharmaceutical science, macromolecular design, organoid science, and animal studies,” he says. “I think that diversity is important for the biological community.”

Combining expertise

Perhaps the best realization of the Institute’s highly collaborative vision so far has been its coronavirus research. Noda and Hashiguchi began working together shortly before the COVID-19 pandemic began, and are now trying uncover the atomic structure of the SARS-CoV-2 virus to better understand its pathogenesis. Further, “we started collaborating with other experts, including clinicians, immunologists and biologists,” says Noda.

Researchers operating a cryogenic electron microscope at the Institute for Life and Medical Sciences.

Hashiguchi is working with industry to develop future coronavirus vaccines by constructing new antigens and visualizing them using cryo-electron microscopy. Meanwhile, Noda and his collaborators are carrying out SARS-CoV-2 infection experiments on human organoids – three-dimensional organ-like tissues derived from stem cells.

“Organoids provide excellent models to study SARS-CoV-2 replication, pathogenesis and host cell responses,” says Noda. “Currently, we are investigating how SARS-CoV-2 replicates in the nasal respiratory epithelium and how it causes damage to the nasal tissue.”

This unique integration of techniques at the Institute for Life and Medical Sciences was made possible by a 2016 merger of predecessor institutes, combining expertise in both virology and regenerative medicine.

“Tissue-engineering technology is relatively new for the virology field, but will help us understand correctly how viruses infect human tissues, how they replicate within them, how viruses damage human tissues and how the infected tissues respond to virus infection,” says Noda.

“I think that most virologists notice that what we see with cultured cell lines and animal models is different from what happens in our body after virus infection,” he says. “To narrow the gap, we need to develop more appropriate models for virology and collaborate with researchers in different fields. This will help realize the field of deep virology.”

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