Posted on by Lawrence Tabak, D.D.S., Ph.D.
With the summer holiday season now in full swing, the blog will also swing into its annual August series. For most of the month, I will share with you just a small sampling of the colorful videos and snapshots of life captured in a select few of the hundreds of NIH-supported research labs around the country.
To get us started, let’s turn to the study of viruses. Researchers now can generate vast amounts of data relatively quickly on a virus of interest. But data are often displayed as numbers or two-dimensional digital images on a computer screen. For most virologists, it’s extremely helpful to see a virus and its data streaming in three dimensions. To do so, they turn to a technological tool that we all know so well: animation.
This research animation features the chikungunya virus, a sometimes debilitating, mosquito-borne pathogen transmitted mainly in developing countries in Africa, Asia and the Americas. The animation illustrates large amounts of research data to show how the chikungunya virus infects our cells and uses its specialized machinery to release its genetic material into the cell and seed future infections. Let’s take a look.
In the opening seconds, you see how receptor binding glycoproteins (light blue), which are proteins with a carbohydrate attached on the viral surface, dock with protein receptors (yellow) on a host cell. At five seconds, the virus is drawn inside the cell. The change in the color of the chikungunya particle shows that it’s coated in a vesicle, which helps the virus make its way unhindered through the cytoplasm.
At 10 seconds, the virus then enters an endosome, ubiquitous bubble-like compartments that transport material from outside the cell into the cytosol, the fluid part of the cytoplasm. Once inside the endosome, the acidic environment makes other glycoproteins (red, blue, yellow) on the viral surface change shape and become more flexible and dynamic. These glycoproteins serve as machinery that enables them to reach out and grab onto the surrounding endosome membrane, which ultimately will be fused with the virus’s own membrane.
As more of those fusion glycoproteins grab on, fold back on themselves, and form into hairpin-like shapes, they pull the membranes together. The animation illustrates not only the changes in protein organization, but the resulting effects on the integrity of the membrane structures as this dynamic process proceeds. At 53 seconds, the viral protein shell, or capsid (green), which contains the virus’ genetic instructions, is released back out into the cell where it will ultimately go on to make more virus.
This remarkable animation comes from Margot Riggi and Janet Iwasa, experts in visualizing biology at the University of Utah’s Animation Lab, Salt Lake City. Their data source was researcher Kelly Lee, University of Washington, Seattle, who collaborated closely with Riggi and Iwasa on this project. The final product was considered so outstanding that it took the top prize for short videos in the 2022 BioArt Awards competition, sponsored by the Federation of American Societies for Experimental Biology (FASEB).
The Lee lab uses various research methods to understand the specific shape-shifting changes that chikungunya and other viruses perform as they invade and infect cells. One of the lab’s key visual tools is cryo-electron microscopy (Cryo-EM), specifically cryo-electron tomography (cryo-ET). Cryto-ET enables complex 3D structures, including the intermediate state of biological reactions, to be captured and imaged in remarkably fine detail.
In a study in the journal Nature Communications  last year, Lee’s team used cryo-ET to reveal how the chikungunya virus invades and delivers its genetic cargo into human cells to initiate a new infection. While Lee’s cryo-ET data revealed stages of the virus entry process and fine structural details of changes to the virus as it enters a cell and starts an infection, it still represented a series of snapshots with missing steps in between. So, Lee’s lab teamed up with The Animation Lab to help beautifully fill in the gaps.
Visualizing chikungunya and similar viruses in action not only makes for informative animations, it helps researchers discover better potential targets to intervene in this process. This basic research continues to make progress, and so do ongoing efforts to develop a chikungunya vaccine  and specific treatments that would help give millions of people relief from the aches, pains, and rashes associated with this still-untreatable infection.
 Visualization of conformational changes and membrane remodeling leading to genome delivery by viral class-II fusion machinery. Mangala Prasad V, Blijleven JS, Smit JM, Lee KK. Nat Commun. 2022 Aug 15;13(1):4772. doi: 10.1038/s41467-022-32431-9. PMID: 35970990; PMCID: PMC9378758.
 Experimental chikungunya vaccine is safe and well-tolerated in early trial, National Institute of Allergy and Infectious Diseases news release, April 27, 2020.
Chikungunya Virus (Centers for Disease Control and Prevention, Atlanta)
Global Arbovirus Initiative (World Health Organization, Geneva, Switzerland)
The Animation Lab (University of Utah, Salt Lake City)
Video: Janet Iwasa (TED Speaker)
Lee Lab (University of Washington, Seattle)
BioArt Awards (Federation of American Societies for Experimental Biology, Rockville, MD)
NIH Support: National Institute of General Medical Sciences; National Institute of Allergy and Infectious Diseases
Posted on by Dr. Francis Collins
It’s truly encouraging to witness people all across our nation rolling up their sleeves to get their COVID-19 vaccines. That is our best chance to end this pandemic. But this is the third coronavirus to emerge and cause serious human illness in the last 20 years, and it’s probably not the last. So, this is also an opportunity to step up our efforts to develop vaccines to combat future strains of disease-causing coronavirus. With this in mind, I’m heartened by a new NIH-funded study showing the potential of a remarkably adaptable, nanoparticle-based approach to coronavirus vaccine development .
Both COVID-19 vaccines currently authorized for human use by the Food and Drug Administration (FDA) work by using mRNA to instruct our cells to make an essential portion of the spike protein of SARS-CoV-2, which is the novel coronavirus that causes COVID-19. As our immune system learns to recognize this protein fragment as foreign, it produces antibodies to attack SARS-CoV-2 and prevent COVID-19. What makes the new vaccine technology so powerful is that it raises the possibility of training the immune system to recognize not just one strain of coronavirus—but up to eight—with a single shot.
This approach has not yet been tested in people, but when a research team, led by Pamela Bjorkman, California Institute of Technology, Pasadena, injected this new type of vaccine into mice, it spurred the production of antibodies that react to a variety of different coronaviruses. In fact, some of the mouse antibodies proved to be reactive to related strains of coronavirus that weren’t even represented in the vaccine. These findings suggest that if presented with multiple different fragments of the spike protein’s receptor binding domain (RBD), which is what SARS-like coronaviruses use to infect human cells, the immune system may learn to recognize common features that might protect against as-yet unknown, newly emerging coronaviruses.
This new work, published in the journal Science, utilizes a technology called a mosaic nanoparticle vaccine platform . Originally developed by collaborators at the University of Oxford, United Kingdom, the nanoparticle component of the platform is a “cage” made up of 60 identical proteins. Each of those proteins has a small protein tag that functions much like a piece of Velcro®. In their SARS-CoV-2 work, Bjorkman and her colleagues, including graduate student Alex A. Cohen, engineered multiple different fragments of the spike protein so each had its own Velcro-like tag. When mixed with the nanoparticle, the spike protein fragments stuck to the cage, resulting in a vaccine nanoparticle with spikes representing four to eight distinct coronavirus strains on its surface. In this instance, the researchers chose spike protein fragments from several different strains of SARS-CoV-2, as well as from other related bat coronaviruses thought to pose a threat to humans.
The researchers then injected the vaccine nanoparticles into mice and the results were encouraging. After inoculation, the mice began producing antibodies that could neutralize many different strains of coronavirus. In fact, while more study is needed to understand the mechanisms, the antibodies responded to coronavirus strains that weren’t even represented on the mosaic nanoparticle. Importantly, this broad antibody response came without apparent loss in the antibodies’ ability to respond to any one particular coronavirus strain.
The findings raise the exciting possibility that this new vaccine technology could provide protection against many coronavirus strains with a single shot. Of course, far more study is needed to explore how well such vaccines work to protect animals against infection, and whether they will prove to be safe and effective in people. There will also be significant challenges in scaling up manufacturing. Our goal is not to replace the mRNA COVID-19 vaccines that scientists developed at such a remarkable pace over the last year, but to provide much-needed vaccine strategies and tools to respond swiftly to the emerging coronavirus strains of the future.
As we double down on efforts to combat COVID-19, we must also come to grips with the fact that SARS-CoV-2 isn’t the first—and surely won’t be the last—novel coronavirus to cause disease in humans. With continued research and development of new technologies such as this one, the hope is that we will come out of this terrible pandemic better prepared for future infectious disease threats.
 Mosaic RBD nanoparticles elicit neutralizing antibodies against SARS-CoV-2 and zoonotic coronaviruses. Cohen AA, Gnanapragasam PNP, Lee YE, Hoffman PR, Ou S, Kakutani LM, Keeffe JR, Barnes CO, Nussenzweig MC, Bjorkman PJ. Science. 2021 Jan 12.
COVID-19 Research (NIH)
Bjorkman Lab (California Institute of Technology, Pasadena)
NIH Support: National Institute of Allergy and Infectious Diseases