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Finding New Ways to Fight Coronavirus … From Studying Bats

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David Veesler/Credit: University of Washington Medicine, Seattle
 

David Veesler has spent nearly 20 years imaging in near-atomic detail the parts of various viruses, including coronaviruses, that enable them to infect Homo sapiens. In fact, his lab at the University of Washington, Seattle, was the first to elucidate the 3D architecture of the now infamous spike protein, which coronaviruses use to gain entry into human cells [1]. He uses these fundamental insights to guide the design of vaccines and therapeutics, including promising monoclonal antibodies.

Now, Veesler and his lab are turning to another mammal in their search for new leads for the next generation of antiviral treatments, including ones aimed at the coronavirus that causes COVID-19, SARS-CoV-2. With support from a 2020 NIH Director’s Pioneer Award, Veesler will study members of the order Chiroptera. Or, more colloquially, bats.

Why bats? Veesler says bats are remarkable creatures. They are the only mammals capable of sustained flight. They rarely get cancer and live unusually long lives for such small creatures. More importantly for Veesler’s research, bats host a wide range of viruses—more than any other mammal species. Despite carrying all of these viruses, bats rarely show symptoms of being sick. Yet they are the source for many of the viruses that have spilled over into humans with devastating effect, including rabies, Ebola virus, Nipah and Hendra viruses, severe acute respiratory syndrome coronavirus (SARS-CoV), and, likely, SARS-CoV-2.

Beyond what is already known about bats’ intriguing qualities, Veesler says humans still have much to discover about these flying mammals, including how their immune systems cope with such an onslaught of viral invaders. For example, it turns out that a bat’s learned, or adaptive, immune system is, for the most part, uncharted territory. As such, it offers an untapped source of potentially promising viral inhibitors just waiting to be unearthed, fully characterized, and then used to guide the development of new kinds of anti-viral therapeutics.

In his studies, Veesler will work with collaborators studying bats around the world to characterize their antibody production. He wants to learn how these antibodies contribute to bats’ impressive ability to tolerate viruses and other pathogens. What is it about the structure of bat antibodies that make them different from human antibodies? And, how can those structural differences serve as blueprints for promising new treatments to combat many potentially deadly viruses?

Interestingly, Veesler’s original grant proposal makes no mention of SARS-CoV-2 or COVID-19. That’s because he submitted it just months before the first reports of the novel coronavirus in Wuhan, China. But Veesler doesn’t consider himself a visionary by expanding his research to bats. He and others had been working on closely related coronaviruses for years, inspired by earlier outbreaks, including SARS in 2002 and Middle East respiratory syndrome (MERS) in 2012 (although MERS apparently came from camels). The researcher didn’t see SARS-CoV-2 coming, but he recognized the potential for some kind of novel coronavirus outbreak in the future.

These days, the Veesler lab has been hard at work to understand SARS-CoV-2 and the human immune response to the virus. His team showed that SARS-CoV-2 uses the human receptor ACE2 to gain entry into our cells [2]. He’s also a member of the international research team that identified a human antibody, called S309, from a person who’d been infected with SARS in 2003. This antibody is showing promise for treating COVID-19 [3], now in a phase 3 clinical trial in the United States.

In another recent study, reported as a pre-print in bioRxiv, Veesler’s team mapped dozens of distinct human antibodies capable of neutralizing SARS-CoV-2 by their ability to hit viral targets outside of the well-known spike protein [4]. Such discoveries may form the basis for new and promising combinations of antibodies to treat COVID-19 that won’t be disabled by concerning new variations in the SARS-CoV-2 spike protein. Perhaps, in the future, such therapeutic cocktails may include modified bat-inspired antibodies too.

References:

[1] Cryo-electron microscopy structure of a coronavirus spike glycoprotein trimer. Walls AC, Tortorici MA, Bosch BJ, Frenz B, Rottier PJM, DiMaio F, Rey FA, Veesler D. Nature. 2016 Mar 3;531(7592):114-117.

[2] Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Cell. 2020 Apr 16;181(2):281-292.e6.

[3] Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody. Pinto D, Park YJ, Beltramello M, Veesler D, Cortil D, et al. Nature.18 May 2020 [Epub ahead of print]

[4] N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2. McCallum M, Marco A, Lempp F, Tortorici MA, Pinto D, Walls AC, Whelan SPJ, Virgin HW, Corti D, Pizzuto MS, Veesler D, et al. bioRxiv. 2021 Jan 14.

Links:

COVID-19 Research (NIH)

Veesler Lab (University of Washington, Seattle)

Veesler Project Information (NIH RePORTER)

NIH Director’s Pioneer Award Program (Common Fund)

NIH Support: Common Fund; National Institute of Allergy and Infectious Diseases


Capturing Viral Shedding in Action

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Credit: Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, MT

You’ve probably seen some amazing high-resolution images of SARS-CoV-2, the novel coronavirus that causes COVID-19, on television and the web. What you might not know is that many of these images, including the ones shown here, were produced at Rocky Mountain Laboratories (RML), a part of NIH’s National Institute of Allergy and Infectious Diseases (NIAID) that’s located in the small Montana town of Hamilton.

The head of RML’s Electron Microscopy Unit, Elizabeth Fischer, was the researcher who took this portrait of SARS-CoV-2. For more than 25 years, Fischer has snapped stunning images of dangerous viruses and microbes, including some remarkable shots of the deadly Ebola virus. She also took some of the first pictures of the coronavirus that causes Middle East respiratory syndrome (MERS), which arose from camels and continues to circulate at low levels in people.

The NIAID facility uses a variety of microscopy techniques, including state-of-the-art cryo-electron microscopy (cryo-EM). But the eye-catching image you see here was taken with a classic scanning electron microscope (SEM).

SEM enables visualization of particles, including viruses, that are too small to be seen with traditional light microscopy. It does so by focusing electrons, instead of light, into a beam that scans the surface of a sample that’s first been dehydrated, chemically preserved, and then coated with a thin layer of metal. As electrons bounce off the sample’s surface, microscopists such as Fischer are able to capture its precise topology. The result is a gray-scale micrograph like the one you see above on the left. To make the image easier to interpret, Fischer hands the originals off to RML’s Visual Medical Arts Department, which uses colorization to make key features pop like they do in the image on the right.

So, what exactly are you seeing in this image? The orange-brown folds and protrusions are part of the surface of a single cell that’s been infected with SARS-CoV-2. This particular cell comes from a commonly studied primate kidney epithelial cell line. The small, blue spheres emerging from the cell surface are SARS-CoV-2 particles.

This picture is quite literally a snapshot of viral shedding, a process in which viral particles are released from a dying cell. This image gives us a window into how devastatingly effective SARS-CoV-2 appears to be at co-opting a host’s cellular machinery: just one infected cell is capable of releasing thousands of new virus particles that can, in turn, be transmitted to others.

While capturing a fixed sample on the microscope is fairly straightforward for a pro like Fischer, developing a sample like this one involves plenty of behind-the-scenes trial and error by NIAID investigators. As you might imagine, to see the moment that viruses emerge from an infected cell, you have to get the timing just right.

By capturing many shots of the coronavirus using the arsenal of microscopes available at RML and elsewhere, researchers are learning more every day about how SARS-CoV-2 enters a cell, moves inside it, and then emerges to infect other cells. In addition to advancing scientific knowledge, Fischer notes that images like these also hold the remarkable power to make an invisible enemy visible to the world at large.

Making SARS-CoV-2 tangible helps to demystify the challenges that all of us now face as a result of the COVID-19 pandemic. The hope is it will encourage each and every one of us to do our part to fight it, whether that means digging into the research, working on the front lines, or staying at home to prevent transmission and flatten the curve. And, if you could use some additional inspiration, don’t miss the NIAID’s image gallery on Flickr, which includes some of Fischer’s finest work.

Links:

Coronavirus (COVID-19) (NIH)

Rocky Mountain Laboratories (National Institute of Allergy and Infectious Diseases/NIH)

Elizabeth Fischer (National Institute of Allergy and Infectious Diseases/NIH)

NIH Support: National Institute of Allergy and Infectious Diseases


Bringing Needed Structure to COVID-19 Drug Development

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SARS-Cov-2 Molecular Map
Caption: Molecular map showing interaction between the spike protein (gold) of the novel coronavirus and the peptidase domain (blue) of human angiotensin-converting enzyme 2 (ACE2). Credit: Adapted from Yan R., Science, 2020.

With so much information swirling around these days about the coronavirus disease 2019 (COVID-19) pandemic, it would be easy to miss one of the most interesting and significant basic science reports of the past few weeks. It’s a paper published in the journal Science [1] that presents an atomic-scale snapshot showing the 3D structure of the spike protein on the novel coronavirus attached to a human cell surface protein called ACE2, or angiotensin converting enzyme 2. ACE2 is the receptor that the virus uses to gain entry.

What makes this image such a big deal is that it shows—in exquisite detail—how the coronavirus attaches to human cells before infecting them and making people sick. The structural map of this interaction will help guide drug developers, atom by atom, in devising safe and effective ways to treat COVID-19.

This new work, conducted by a team led by Qiang Zhou, Westlake Institute for Advanced Study, Hangzhou, China, took advantage of a high-resolution imaging tool called cryo-electron microscopy (cryo-EM). This approach involves flash-freezing molecules in liquid nitrogen and bombarding them with electrons to capture their images with a special camera. When all goes well, cryo-EM can solve the structure of intricate macromolecular complexes in a matter of days, including this one showing the interaction between a viral protein and human protein.

Zhou’s team began by mapping the structure of human ACE2 in a complex with B0AT1, which is a membrane protein that it helps to fold. In the context of this complex, ACE2 is a dimer—a scientific term for a compound composed of two very similar units. Additional mapping revealed how the surface protein of the novel coronavirus interacts with ACE2, indicating how the virus’s two trimeric (3-unit) spike proteins might bind to an ACE2 dimer. After confirmation by further research, these maps may well provide a basis for the design and development of therapeutics that specifically target this critical interaction.

The ACE2 protein resides on the surface of cells in many parts of the human body, including the heart and lungs. The protein is known to play a prominent role in the body’s complex system of regulating blood pressure. In fact, a class of drugs that inhibit ACE and related proteins are frequently prescribed to help control high blood pressure, or hypertension. These ACE inhibitors lower blood pressure by causing blood vessels to relax.

Since the COVID-19 outbreak, many people have wondered whether taking ACE inhibitors would be helpful or detrimental against coronavirus infection. This is of particular concern to doctors whose patients are already taking the medications to control hypertension. Indeed, data from China and elsewhere indicate hypertension is one of several coexisting conditions that have consistently been reported to be more common among people with COVID-19 who develop life-threatening severe acute respiratory syndrome.

In a new report in this week’s New England Journal of Medicine, a team of U.K. and U.S. researchers, partly supported by NIH, examined the use of ACE inhibitors and other angiotensin-receptor blockers (ARBs) in people with COVID-19. The team, led by Scott D. Solomon of Brigham and Women’s Hospital and Harvard Medical School, Boston, found that current evidence in humans is insufficient to support or refute claims that ACE inhibitors or ARBs may be helpful or harmful to individuals with COVID-19.

The researchers concluded that these anti-hypertensive drugs should be continued in people who have or at-risk for COVID-19, stating: “Although additional data may further inform the treatment of high-risk patients … clinicians need to be cognizant of the unintended consequences of prematurely discontinuing proven therapies in response to hypothetical concerns.” [2]

Research is underway to generate needed data on the use of ACE inhibitors and similar drugs in the context of the COVID-19 pandemic, as well as to understand more about the basic mechanisms underlying this rapidly spreading viral disease. This kind of fundamental research isn’t necessarily the stuff that will make headlines, but it likely will prove vital to guiding the design of effective drugs that can help bring this serious global health crisis under control.

References:

[1] Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2. Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Science. 27 March 2020. [Epub ahead of publication]

[2] Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19. Vaduganathan M, Vardeny O, Michel T, McMurray J, Pfeffer MA, Solomon SD. 30 NEJM. March 2020 [Epub ahead of Publication]

Links:

Coronavirus (COVID-19) (NIH)

COVID-19, MERS & SARS (National Institute of Allergy and Infectious Diseases/NIH)

Transformative High Resolution Cryo-Electron Microscopy (Common Fund/NIH)

Qiang Zhou (Westlake Institute for Advanced Study, Zhejiang Province)

Scott D. Solomon (Brigham and Women’s Hospital, Boston)

NIH Support: National Center for Advancing Translational Sciences; National Heart, Lung, and Blood Institute


To Beat COVID-19, Social Distancing is a Must

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Teleworking with family at home
gettyimages/SDI Productions

Even in less challenging times, many of us try to avoid close contact with someone who is sneezing, coughing, or running a fever to avoid getting sick ourselves. Our attention to such issues has now been dramatically heightened by the emergence of a novel coronavirus causing a pandemic of an illness known as COVID-19.

Many have wondered if we couldn’t simply protect ourselves by avoiding people with symptoms of respiratory illness. Unfortunately, the answer is no. A new study shows that simply avoiding symptomatic people will not go far enough to curb the COVID-19 pandemic. That’s because researchers have discovered that many individuals can carry the novel coronavirus without showing any of the typical symptoms of COVID-19: fever, dry cough, and shortness of breath. But these asymptomatic or only mildly ill individuals can still shed virus and infect others.

This conclusion adds further weight to the recent guidance from U.S. public health experts: what we need most right now to slow the stealthy spread of this new coronavirus is a full implementation of social distancing. What exactly does social distancing mean? Well, for starters, it is recommended that people stay at home as much as possible, going out only for critical needs like groceries and medicines, or to exercise and enjoy the outdoors in wide open spaces. Other recommendations include avoiding gatherings of more than 10 people, no handshakes, regular handwashing, and, when encountering someone outside of your immediate household, trying to remain at least 6 feet apart.

These may sound like extreme measures. But the new study by NIH-funded researchers, published in the journal Science, documents why social distancing may be our best hope to slow the spread of COVID-19 [1]. Here are a few highlights of the paper, which looks back to January 2020 and mathematically models the spread of the coronavirus within China:

• For every confirmed case of COVID-19, there are likely another five to 10 people with undetected infections.
• Although they are thought to be only about half as infectious as individuals with confirmed COVID-19, individuals with undetected infections were so prevalent in China that they apparently were the infection source for 86 percent of confirmed cases.
• After China established travel restrictions and social distancing, the spread of COVID-19 slowed considerably.

The findings come from a small international research team that included NIH grantee Jeffrey Shaman, Columbia University Mailman School of Public Health, New York. The team developed a computer model that enabled researchers to simulate the time and place of infections in a grid of 375 Chinese cities. The researchers did so by combining existing data on the spread of COVID-19 in China with mobility information collected by a location-based service during the country’s popular 40-day Spring Festival, when travel is widespread.

As these new findings clearly demonstrate, each of us must take social distancing seriously in our daily lives. Social distancing helped blunt the pandemic in China, and it will work in other nations, including the United States. While many Americans will likely spend weeks working and studying from home and practicing other social distancing measures, the stakes remain high. If this pandemic isn’t contained, this novel coronavirus could well circulate around the globe for years to come, at great peril to us and our loved ones.

As we commit ourselves to spending more time at home, progress continues to be made in using the power of biomedical research to combat this novel coronavirus. A notable step this week was the launch of an early-stage human clinical trial of an investigational vaccine, called mRNA-1273, to protect against COVID-19 [2]. The vaccine candidate was developed by researchers at NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and their collaborators at the biotechnology company Moderna, Inc., Cambridge, MA.

This Phase 1 NIAID-supported trial will look at the safety of the vaccine—which cannot cause infection because it is made of RNA, not the whole coronavirus—in 45 healthy adults. The first volunteer was injected this past Monday at Kaiser Permanente Washington Health Research Institute, Seattle. If all goes well and larger follow-up clinical studies establish the vaccine’s safety and efficacy, it will then be necessary to scale up production to make millions of doses. While initiating this trial in record time is reason for hope, it is important to be realistic about all of the steps that still remain. If the vaccine candidate proves safe and effective, it will likely take at least 12–18 months before it would be widely available.

In the meantime, social distancing remains one of the best weapons we have to slow the silent spread of this virus and flatten the curve of the COVID-19 pandemic. This will give our health-care professionals, hospitals, and other institutions more valuable time to prepare, protect themselves, and aid the many people whose lives may be on the line from this coronavirus.

Importantly, saving lives from COVID-19 requires all of us—young, old and in-between—to take part. Healthy young people, whose risk of dying from coronavirus is not zero but quite low, might argue that they shouldn’t be constrained by social distancing. However, the research highlighted here demonstrates that such individuals are often the unwitting vector for a dangerous virus that can do great harm—and even take the lives of older and more vulnerable people. Think about your grandparents. Then skip the big gathering. We are all in this together

References:

[1] Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV2). Li R, Pei S, Chen B, Song Y, Zhang T, Yang W, Shaman J. Science. 16 March 2020. [Preprint ahead of publication]

[2] NIH clinical trial of investigational vaccine for COVID-19 begins. NIH News Release, March 16, 2020.

Links:

Coronavirus (COVID-19) (NIH)

COVID-19, MERS & SARS (National Institute of Allergy and Infectious Diseases/NIH)

Coronavirus (COVID-19) (Centers for Disease Control and Prevention, Atlanta)

NIH Support: National Institute of Allergy and Infectious Diseases; National Institute of General Medical Sciences


Structural Biology Points Way to Coronavirus Vaccine

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Spike Protein on Novel Coronavirus
Caption: Atomic-level structure of the spike protein of the virus that causes COVID-19.
Credit: McLellan Lab, University of Texas at Austin

The recent COVID-19 outbreak of a novel type of coronavirus that began in China has prompted a massive global effort to contain and slow its spread. Despite those efforts, over the last month the virus has begun circulating outside of China in multiple countries and territories.

Cases have now appeared in the United States involving some affected individuals who haven’t traveled recently outside the country. They also have had no known contact with others who have recently arrived from China or other countries where the virus is spreading. The NIH and other U.S. public health agencies stand on high alert and have mobilized needed resources to help not only in its containment, but in the development of life-saving interventions.

On the treatment and prevention front, some encouraging news was recently reported. In record time, an NIH-funded team of researchers has created the first atomic-scale map of a promising protein target for vaccine development [1]. This is the so-called spike protein on the new coronavirus that causes COVID-19. As shown above, a portion of this spiky surface appendage (green) allows the virus to bind a receptor on human cells, causing other portions of the spike to fuse the viral and human cell membranes. This process is needed for the virus to gain entry into cells and infect them.

Preclinical studies in mice of a candidate vaccine based on this spike protein are already underway at NIH’s Vaccine Research Center (VRC), part of the National Institute of Allergy and Infectious Diseases (NIAID). An early-stage phase I clinical trial of this vaccine in people is expected to begin within weeks. But there will be many more steps after that to test safety and efficacy, and then to scale up to produce millions of doses. Even though this timetable will potentially break all previous speed records, a safe and effective vaccine will take at least another year to be ready for widespread deployment.

Coronaviruses are a large family of viruses, including some that cause “the common cold” in healthy humans. In fact, these viruses are found throughout the world and account for up to 30 percent of upper respiratory tract infections in adults.

This outbreak of COVID-19 marks the third time in recent years that a coronavirus has emerged to cause severe disease and death in some people. Earlier coronavirus outbreaks included SARS (severe acute respiratory syndrome), which emerged in late 2002 and disappeared two years later, and MERS (Middle East respiratory syndrome), which emerged in 2012 and continues to affect people in small numbers.

Soon after COVID-19 emerged, the new coronavirus, which is closely related to SARS, was recognized as its cause. NIH-funded researchers including Jason McLellan, an alumnus of the VRC and now at The University of Texas at Austin, were ready. They’d been studying coronaviruses in collaboration with NIAID investigators for years, with special attention to the spike proteins.

Just two weeks after Chinese scientists reported the first genome sequence of the virus [2], McLellan and his colleagues designed and produced samples of its spike protein. Importantly, his team had earlier developed a method to lock coronavirus spike proteins into a shape that makes them both easier to analyze structurally via the high-resolution imaging tool cryo-electron microscopy and to use in vaccine development efforts.

After locking the spike protein in the shape it takes before fusing with a human cell to infect it, the researchers reconstructed its atomic-scale 3D structural map in just 12 days. Their results, published in Science, confirm that the spike protein on the virus that causes COVID-19 is quite similar to that of its close relative, the SARS virus. It also appears to bind human cells more tightly than the SARS virus, which may help to explain why the new coronavirus appears to spread more easily from person to person, mainly by respiratory transmission.

McLellan’s team and his NIAID VRC counterparts also plan to use the stabilized spike protein as a probe to isolate naturally produced antibodies from people who’ve recovered from COVID-19. Such antibodies might form the basis of a treatment for people who’ve been exposed to the virus, such as health care workers.

The NIAID is now working with the biotechnology company Moderna, Cambridge, MA, to use the latest findings to develop a vaccine candidate using messenger RNA (mRNA), molecules that serve as templates for making proteins. The goal is to direct the body to produce a spike protein in such a way to elicit an immune response and the production of antibodies. An early clinical trial of the vaccine in people is expected to begin in the coming weeks. Other vaccine candidates are also in preclinical development.

Meanwhile, the first clinical trial in the U.S. to evaluate an experimental treatment for COVID-19 is already underway at the University of Nebraska Medical Center’s biocontainment unit [3]. The NIH-sponsored trial will evaluate the safety and efficacy of the experimental antiviral drug remdesivir in hospitalized adults diagnosed with COVID-19. The first participant is an American who was repatriated after being quarantined on the Diamond Princess cruise ship in Japan.

As noted, the risk of contracting COVID-19 in the United States is currently low, but the situation is changing rapidly. One of the features that makes the virus so challenging to stay in front of is its long latency period before the characteristic flu-like fever, cough, and shortness of breath manifest. In fact, people infected with the virus may not show any symptoms for up to two weeks, allowing them to pass it on to others in the meantime. You can track the reported cases in the United States on the Centers for Disease Control and Prevention’s website.

As the outbreak continues over the coming weeks and months, you can be certain that NIH and other U.S. public health organizations are working at full speed to understand this virus and to develop better diagnostics, treatments, and vaccines.

References:

[1] Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh CL, Abiona O, Graham BS, McLellan JS. Science. 2020 Feb 19.

[2] A new coronavirus associated with human respiratory disease in China. Wu F, Zhao S, Yu B, Chen YM, Wang W, Song ZG, Hu Y, Tao ZW, Tian JH, Pei YY, Yuan ML, Zhang YL, Dai FH, Liu Y, Wang QM, Zheng JJ, Xu L, Holmes EC, Zhang YZ. Nature. 2020 Feb 3.

[3] NIH clinical trial of remdesivir to treat COVID-19 begins. NIH News Release. Feb 25, 2020.

Links:

Coronaviruses (National Institute of Allergy and Infectious Diseases/NIH)

Coronavirus (COVID-19) (NIAID)

Coronavirus Disease 2019 (Centers for Disease Control and Prevention, Atlanta)

NIH Support: National Institute of Allergy and Infectious Diseases


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