FDA
Nanoparticle Technology Holds Promise for Protecting Against Many Coronavirus Strains at Once
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 [1].
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 [1]. 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.
References:
[1] 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.
Links:
COVID-19 Research (NIH)
Bjorkman Lab (California Institute of Technology, Pasadena)
NIH Support: National Institute of Allergy and Infectious Diseases
The People’s Picks for Best Posts
Posted on by Dr. Francis Collins
It’s 2021—Happy New Year! Time sure flies in the blogosphere. It seems like just yesterday that I started the NIH Director’s Blog to highlight recent advances in biology and medicine, many supported by NIH. Yet it turns out that more than eight years have passed since this blog got rolling and we are fast approaching my 1,000th post!
I’m pleased that millions of you have clicked on these posts to check out some very cool science and learn more about NIH and its mission. Thanks to the wonders of social media software, we’ve been able to tally up those views to determine each year’s most-popular post. So, I thought it would be fun to ring in the New Year by looking back at a few of your favorites, sort of a geeky version of a top 10 countdown or the People’s Choice Awards. It was interesting to see what topics generated the greatest interest. Spoiler alert: diet and exercise seemed to matter a lot! So, without further ado, I present the winners:
2013: Fighting Obesity: New Hopes from Brown Fat. Brown fat, one of several types of fat made by our bodies, was long thought to produce body heat rather than store energy. But Shingo Kajimura and his team at the University of California, San Francisco, showed in a study published in the journal Nature, that brown fat does more than that. They discovered a gene that acts as a molecular switch to produce brown fat, then linked mutations in this gene to obesity in humans.
What was also nice about this blog post is that it appeared just after Kajimura had started his own lab. In fact, this was one of the lab’s first publications. One of my goals when starting the blog was to feature young researchers, and this work certainly deserved the attention it got from blog readers. Since highlighting this work, research on brown fat has continued to progress, with new evidence in humans suggesting that brown fat is an effective target to improve glucose homeostasis.
2014: In Memory of Sam Berns. I wrote this blog post as a tribute to someone who will always be very near and dear to me. Sam Berns was born with Hutchinson-Gilford progeria syndrome, one of the rarest of rare diseases. After receiving the sad news that this brave young man had passed away, I wrote: “Sam may have only lived 17 years, but in his short life he taught the rest of us a lot about how to live.”
Affecting approximately 400 people worldwide, progeria causes premature aging. Without treatment, children with progeria, who have completely normal intellectual development, die of atherosclerotic cardiovascular disease, on average in their early teens.
From interactions with Sam and his parents in the early 2000s, I started to study progeria in my NIH lab, eventually identifying the gene responsible for the disorder. My group and others have learned a lot since then. So, it was heartening last November when the Food and Drug Administration approved the first treatment for progeria. It’s an oral medication called Zokinvy (lonafarnib) that helps prevent the buildup of defective protein that has deadly consequences. In clinical trials, the drug increased the average survival time of those with progeria by more than two years. It’s a good beginning, but we have much more work to do in the memory of Sam and to help others with progeria. Watch for more about new developments in applying gene editing to progeria in the next few days.
2015: Cytotoxic T Cells on Patrol. Readers absolutely loved this post. When the American Society of Cell Biology held its first annual video competition, called CellDance, my blog featured some of the winners. Among them was this captivating video from Alex Ritter, then working with cell biologist Jennifer Lippincott-Schwartz of NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development. The video stars a roving, specialized component of our immune system called cytotoxic T cells. Their job is to seek out and destroy any foreign or detrimental cells. Here, these T cells literally convince a problem cell to commit suicide, a process that takes about 10 minutes from detection to death.
These cytotoxic T cells are critical players in cancer immunotherapy, in which a patient’s own immune system is enlisted to control and, in some cases, even cure the cancer. Cancer immunotherapy remains a promising area of research that continues to progress, with a lot of attention now being focused on developing immunotherapies for common, solid tumors like breast cancer. Ritter is currently completing a postdoctoral fellowship in the laboratory of Ira Mellman, Genentech, South San Francisco. His focus has shifted to how cancer cells protect themselves from T cells. And video buffs—get this—Ritter says he’s now created even cooler videos that than the one in this post.
2016: Exercise Releases Brain-Healthy Protein. The research literature is pretty clear: exercise is good for the brain. In this very popular post, researchers led by Hyo Youl Moon and Henriette van Praag of NIH’s National Institute on Aging identified a protein secreted by skeletal muscle cells to help explore the muscle-brain connection. In a study in Cell Metabolism, Moon and his team showed that this protein called cathepsin B makes its way into the brain and after a good workout influences the development of new neural connections. This post is also memorable to me for the photo collage that accompanied the original post. Why? If you look closely at the bottom right, you’ll see me exercising—part of my regular morning routine!
2017: Muscle Enzyme Explains Weight Gain in Middle Age. The struggle to maintain a healthy weight is a lifelong challenge for many of us. While several risk factors for weight gain, such as counting calories, are within our control, there’s a major one that isn’t: age. Jay Chung, a researcher with NIH’s National Heart, Lung, and Blood Institute, and his team discovered that the normal aging process causes levels of an enzyme called DNA-PK to rise in animals as they approach middle age. While the enzyme is known for its role in DNA repair, their studies showed it also slows down metabolism, making it more difficult to burn fat.
Since publishing this paper in Cell Metabolism, Chung has been busy trying to understand how aging increases the activity of DNA-PK and its ability to suppress renewal of the cell’s energy-producing mitochondria. Without renewal of damaged mitochondria, excess oxidants accumulate in cells that then activate DNA-PK, which contributed to the damage in the first place. Chung calls it a “vicious cycle” of aging and one that we’ll be learning more about in the future.
2018: Has an Alternative to Table Sugar Contributed to the C. Diff. Epidemic? This impressive bit of microbial detective work had blog readers clicking and commenting for several weeks. So, it’s no surprise that it was the runaway People’s Choice of 2018.
Clostridium difficile (C. diff) is a common bacterium that lives harmlessly in the gut of most people. But taking antibiotics can upset the normal balance of healthy gut microbes, allowing C. diff. to multiply and produce toxins that cause inflammation and diarrhea.
In the 2000s, C. diff. infections became far more serious and common in American hospitals, and Robert Britton, a researcher at Baylor College of Medicine, Houston, wanted to know why. He and his team discovered that two subtypes of C. diff have adapted to feed on the sugar trehalose, which was approved as a food additive in the United States during the early 2000s. The team’s findings, published in the journal Nature, suggested that hospitals and nursing homes battling C. diff. outbreaks may want to take a closer look at the effect of trehalose in the diet of their patients.
2019: Study Finds No Benefit for Dietary Supplements. This post that was another one that sparked a firestorm of comments from readers. A team of NIH-supported researchers, led by Fang Fang Zhang, Tufts University, Boston, found that people who reported taking dietary supplements had about the same risk of dying as those who got their nutrients through food. What’s more, the mortality benefits associated with adequate intake of vitamin A, vitamin K, magnesium, zinc, and copper were limited to amounts that are available from food consumption. The researchers based their conclusion on an analysis of the well-known National Health and Nutrition Examination Survey (NHANES) between 1999-2000 and 2009-2010 survey data. The team, which reported its data in the Annals of Internal Medicine, also uncovered some evidence suggesting that certain supplements might even be harmful to health when taken in excess.
2020: Genes, Blood Type Tied to Risk of Severe COVID-19. Typically, my blog focuses on research involving many different diseases. That changed in 2020 due to the emergence of a formidable public health challenge: the coronavirus disease 2019 (COVID-19) pandemic. Since last March, the blog has featured 85 posts on COVID-19, covering all aspects of the research response and attracting more visitors than ever. And which post got the most views? It was one that highlighted a study, published last June in the New England Journal of Medicine, that suggested the clues to people’s variable responses to COVID-19 may be found in our genes and our blood types.
The researchers found that gene variants in two regions of the human genome are associated with severe COVID-19 and correspondingly carry a greater risk of COVID-19-related death. The two stretches of DNA implicated as harboring risks for severe COVID-19 are known to carry some intriguing genes, including one that determines blood type and others that play various roles in the immune system.
In fact, the findings suggest that people with blood type A face a 50 percent greater risk of needing oxygen support or a ventilator should they become infected with the novel coronavirus. In contrast, people with blood type O appear to have about a 50 percent reduced risk of severe COVID-19.
That’s it for the blog’s year-by-year Top Hits. But wait! I’d also like to give shout outs to the People’s Choice winners in two other important categories—history and cool science images.
Top History Post: HeLa Cells: A New Chapter in An Enduring Story. Published in August 2013, this post remains one of the blog’s greatest hits with readers. The post highlights science’s use of cancer cells taken in the 1950s from a young Black woman named Henrietta Lacks. These “HeLa” cells had an amazing property not seen before: they could be grown continuously in laboratory conditions. The “new chapter” featured in this post is an agreement with the Lacks family that gives researchers access to the HeLa genome data, while still protecting the family’s privacy and recognizing their enormous contribution to medical research. And the acknowledgments rightfully keep coming from those who know this remarkable story, which has been chronicled in both book and film. Recently, the U.S. Senate and House of Representatives passed the Henrietta Lacks Enhancing Cancer Research Act to honor her extraordinary life and examine access to government-funded cancer clinical trials for traditionally underrepresented groups.
Top Snapshots of Life: A Close-up of COVID-19 in Lung Cells. My blog posts come in several categories. One that you may have noticed is “Snapshots of Life,” which provides a showcase for cool images that appear in scientific journals and often dominate Science as Art contests. My blog has published dozens of these eye-catching images, representing a broad spectrum of the biomedical sciences. But the blog People’s Choice goes to a very recent addition that reveals exactly what happens to cells in the human airway when they are infected with the coronavirus responsible for COVID-19. This vivid image, published in the New England Journal of Medicine, comes from the lab of pediatric pulmonologist Camille Ehre, University of North Carolina at Chapel Hill. This image squeezed in just ahead of another highly popular post from Steve Ramirez, Boston University, in 2019 that showed “What a Memory Looks Like.”
As we look ahead to 2021, I want to thank each of my blog’s readers for your views and comments over the last eight years. I love to hear from you, so keep on clicking! I’m confident that 2021 will generate a lot more amazing and bloggable science, including even more progress toward ending the COVID-19 pandemic that made our past year so very challenging.
Celebrating the Gift of COVID-19 Vaccines
Posted on by Dr. Francis Collins
The winter holidays are traditionally a time of gift-giving. As fatiguing as 2020 and the COVID-19 pandemic have been, science has stepped up this year to provide humankind with a pair of truly hopeful gifts: the first two COVID-19 vaccines.
Two weeks ago, the U.S. Food and Drug Administration (FDA) granted emergency use authorization (EUA) to a COVID-19 vaccine from Pfizer/BioNTech, enabling distribution to begin to certain high-risk groups just three days later. More recently, the FDA granted an EUA to a COVID-19 vaccine from the biotechnology company Moderna, Cambridge, MA. This messenger RNA (mRNA) vaccine, which is part of a new approach to vaccination, was co-developed by NIH’s National Institute of Allergy and Infectious Diseases (NIAID). The EUA is based on data showing the vaccine is safe and 94.5 percent effective at protecting people from infection with SARS-CoV-2, the coronavirus that causes COVID-19.
Those data on the Moderna vaccine come from a clinical trial of 30,000 individuals, who generously participated to help others. We can’t thank those trial participants enough for this gift. The distribution of millions of Moderna vaccine doses is expected to begin this week.
It’s hard to put into words just how remarkable these accomplishments are in the history of science. A vaccine development process that used to take many years, often decades, has been condensed to about 11 months. Just last January, researchers started out with a previously unknown virus and we now have not just one, but two, vaccines that will be administered to millions of Americans before year’s end. And the accomplishments don’t end there—several other types of COVID-19 vaccines are also on the way.
It’s important to recognize that this couldn’t have happened without the efforts of many scientists working tirelessly behind the scenes for many years prior to the pandemic. Among those who deserve tremendous credit are Kizzmekia Corbett, Barney Graham, John Mascola, and other members of the amazing team at the Dale and Betty Bumpers Vaccine Research Center at NIH’s National Institute of Allergy and Infectious Diseases (NIAID).
When word of SARS-CoV-2 emerged, Corbett, Graham, and other NIAID researchers had already been studying other coronaviruses for years, including those responsible for earlier outbreaks of respiratory disease. So, when word came that this was a new coronavirus outbreak, they were ready to take action. It helped that they had paid special attention to the spike proteins on the surface of coronaviruses, which have turned out to be the main focus the COVID-19 vaccines now under development.
The two vaccines currently authorized for administration in the United States work in a unique way. Their centerpiece is a small, non-infectious snippet of mRNA. Our cells constantly produce thousands of mRNAs, which provide the instructions needed to make proteins. When someone receives an mRNA vaccine for COVID-19, it tells the person’s own cells to make the SARS-CoV-2 spike protein. The person’s immune system then recognizes the viral spike protein as foreign and produces antibodies to eliminate it.
This vaccine-spurred encounter trains the human immune system to remember the spike protein. So, if an actual SARS-CoV-2 virus tries to infect a vaccinated person weeks or months later, his or her immune system will be ready to fend it off. To produce the most vigorous and durable immunity against the virus, people will need to get two shots of mRNA vaccine, which are spaced several weeks to a month apart, depending on the vaccine.
Some have raised concerns on social media that mRNA vaccines might alter the DNA genome of someone being vaccinated. But that’s not possible, since this mRNA doesn’t enter the nucleus of the cell where DNA is located. Instead, the vaccine mRNAs stay in the outer part of the cell (the cytoplasm). What’s more, after being transcribed into protein just one time, the mRNA quickly degrades. Others have expressed concerns about whether the vaccine could cause COVID-19. That is not a risk because there’s no whole virus involved, just the coding instructions for the non-infectious spike protein.
An important advantage of mRNA is that it’s easy for researchers to synthesize once they know the nucleic acid sequence of a target viral protein. So, the gift of mRNA vaccines is one that will surely keep on giving. This new technology can now be used to speed the development of future vaccines. After the emergence of the disease-causing SARS, MERS, and now SARS-CoV-2 viruses, it would not be surprising if there are other coronavirus health threats in our future. Corbett and her colleagues are hoping to design a universal vaccine that can battle all of them. In addition, mRNA vaccines may prove effective for fighting future pandemics caused by other infectious agents and for preventing many other conditions, such as cancer and HIV.
Though vaccines are unquestionably our best hope for getting past the COVID-19 pandemic, public surveys indicate that some people are uneasy about accepting this disease-preventing gift. Some have even indicated they will refuse to take the vaccine. Healthy skepticism is a good thing, but decisions like this ought to be based on weighing the evidence of benefit versus risk. The results of the Pfizer and Moderna trials, all released for complete public scrutiny, indicate the potential benefits are high and the risks, low. Despite the impressive speed at which the new COVID-19 vaccines were developed, they have undergone and continue to undergo a rigorous process to generate all the data needed by the FDA to determine their long-term safety and effectiveness.
Unfortunately, the gift of COVID-19 vaccines comes too late for the more than 313,000 Americans who have died from complications of COVID-19, and many others who’ve had their lives disrupted and may have to contend with long-term health consequences related to COVID-19. The vaccines did arrive in record time, but all of us wish they could somehow have arrived even sooner to avert such widespread suffering and heartbreak.
It will be many months before all Americans who are willing to get a vaccine can be immunized. We need 75-80 percent of Americans to receive vaccines in order to attain the so-called “herd immunity” needed to drive SARS-CoV-2 away and allow us all to get back to a semblance of normal life.
Meanwhile, we all have a responsibility to do everything possible to block the ongoing transmission of this dangerous virus. Each of us needs to follow the three W’s: Wear a mask, Watch your distance, Wash your hands often.
When your chance for immunization comes, please roll up your sleeve and accept the potentially life-saving gift of a COVID-19 vaccine. In fact, I just got my first shot of the Moderna vaccine today along with NIAID Director Anthony Fauci, HHS Secretary Alex Azar, and some front-line healthcare workers at the NIH Clinical Center. Accepting this gift is our best chance to put this pandemic behind us, as we look forward to a better new year.
Links:
Coronavirus (COVID-19) (NIH)
Combat COVID (U.S. Department of Health and Human Services, Washington, D.C.)
Dale and Betty Bumpers Vaccine Research Center (National Institute of Allergy and Infectious Diseases/NIH)
Moderna (Cambridge, MA)
Pfizer (New York, NY)
BioNTech (Mainz, Germany)
Reasons for Gratitude Amid the COVID-19 Pandemic
Posted on by Dr. Francis Collins
For many of us, Thanksgiving will feel really different this year. Less will need to be more, as we celebrate alone or with our immediate household members to stay safe and help combat the surge in COVID-19 cases across most of the land. And yet, times of trouble can also help us to focus on what’s really important in our lives. So, even as we face these challenges and the range of emotions that arise with them, it’s worth remembering that this Thanksgiving, there remain many reasons to be grateful.
I’m certainly grateful for a loving family and friends that provide depth and meaning to life, even though most of us can’t be physically together and hug each other right now. My faith is also a source of comfort and reassurance at this time. I also feel a deep sense of gratitude for everyone who has sacrificed for the common good over the last several months, especially those who’ve masked up and physically distanced to provide essential services in our communities to keep everything going. You will no doubt have your own list of heroes, but here are just a few of mine:
• Healthcare workers, thanks for all you do under such difficult and dangerous conditions.
• Essential workers, thanks for clocking in every day. That includes bus drivers, grocery store cashiers, waste collectors, tradespeople, firefighters, law enforcement officers, and all those who deliver packages to my door.
• Teachers, working remotely or in person. Thanks for your commitment to our students and continuing to bring out the best in them.
• Parents, including so many now working with kids at home. Thanks for juggling responsibilities and making everything work.
• Clinical trials participants. Your participation is critical for developing treatments and vaccines. Thanks to you all, including the fine examples of many public figures, including the trial participation of Senator Rob Portman and financial contribution of legendary performer Dolly Parton.
• Everyone following the 3 W’s: Wear a mask, Watch your distance, and Wash your hands. Thank you for doing your part every day to keep yourself, your loved ones, and your community safe. You are our front lines in the battle.
• Researchers, from both the public and private sectors, who are working in partnership all around the world. Our shared goal is to learn all we can about COVID-19 and to develop better tests, new treatments, and safe and effective vaccines.
On that note, you may have heard about the very promising interim clinical trial results of an investigational COVID-19 vaccine known as mRNA-1273, co-developed by the biotechnology company Moderna, Cambridge, MA, and NIH’s National Institute of Allergy and Infectious Diseases. That mRNA vaccine was found to be 94.5 percent effective in preventing symptomatic COVID-19. Another mRNA vaccine, developed by Pfizer and BioNTech, also recently was shown to be 95 percent effective and has now submitted an application for emergency use authorization (EUA) to the Food and Drug Administration (FDA). In addition, AstraZeneca announced that, in a late-stage clinical trial, the vaccine it developed in partnership with the University of Oxford reduced the risk of COVID-19 infection by an average of 70 percent, with up to 90 percent efficacy in one dosing regimen.
Other promising vaccine candidates continue to work their way through clinical trials, and we’ll no doubt be hearing more about those soon. It is truly remarkable to accomplish in 10 months what normally takes about 8 years. Therapeutic progress is also moving forward rapidly, with a second monoclonal antibody treatment for high-risk outpatients receiving emergency use authorization from the FDA just a few days ago.
For all of these advances, I am immensely grateful. Of course, it will take time and continued study to get a COVID-19 vaccine fully approved and distributed to all those who need it. The success of any vaccine also will hinge on people across the country—including you and all those whom I’ve recognized here—making the choice to protect themselves and others by getting vaccinated against COVID-19.
As we look ahead to that day when the COVID-19 pandemic is under control, I encourage you to take some time to jot down your own list of reasons to be grateful. Encourage family members to do the same and take some time to share them with one another, whether it’s around the table or by email, phone, or videoconferencing. The holidays are a time for making memories and—as different as it may look—this year is no different. So, while you’re enjoying your Thanksgiving meal around a smaller table, remember that you’re doing it from a place of love and gratitude. I wish for you a safe and happy Thanksgiving.
Links:
Coronavirus (COVID) (NIH)
Your Health: Holiday Celebrations and Small Gatherings (Centers for Disease Control and Prevention, Atlanta)
Protein Mapping Study Reveals Valuable Clues for COVID-19 Drug Development
Posted on by Dr. Francis Collins
One way to fight COVID-19 is with drugs that directly target SARS-CoV-2, the novel coronavirus that causes the disease. That’s the strategy employed by remdesivir, the only antiviral drug currently authorized by the U.S. Food and Drug Administration to treat COVID-19. Another promising strategy is drugs that target the proteins within human cells that the virus needs to infect, multiply, and spread.
With the aim of developing such protein-targeted antiviral drugs, a large, international team of researchers, funded in part by the NIH, has precisely and exhaustively mapped all of the interactions that take place between SARS-CoV-2 proteins and the human proteins found within infected host cells. They did the same for the related coronaviruses: SARS-CoV-1, the virus responsible for outbreaks of Severe Acute Respiratory Syndrome (SARS), which ended in 2004; and MERS-CoV, the virus that causes the now-rare Middle East Respiratory Syndrome (MERS).
The goal, as reported in the journal Science, was to use these protein “interactomes” to uncover vulnerabilities shared by all three coronaviruses. The hope is that the newfound knowledge about these shared proteins—and the pathways to which they belong—will inform efforts to develop new kinds of broad-spectrum antiviral therapeutics for use in the current and future coronavirus outbreaks.
Facilitated by the Quantitative Biosciences Institute Research Group, the team, which included David E. Gordon and Nevan Krogan, University of California, San Francisco, and hundreds of other scientists from around the world, successfully mapped nearly 400 protein-protein interactions between SARS-CoV-2 and human proteins.
You can see one of these interactions in the video above. The video starts out with an image of the Orf9b protein of SARS-CoV-2, which normally consists of two linked molecules (blue and orange). But researchers discovered that Orf9b dissociates into a single molecule (orange) when it interacts with the human protein TOM70 (teal). Through detailed structural analysis using cryo-electron microscopy (cryo-EM), the team went on to predict that this interaction may disrupt a key interaction between TOM70 and another human protein called HSP90.
While further study is needed to understand all the details and their implications, it suggests that this interaction may alter important aspects of the human immune response, including blocking interferon signals that are crucial for sounding the alarm to prevent serious illness. While there is no drug immediately available to target Orf9b or TOM70, the findings point to this interaction as a potentially valuable target for treating COVID-19 and other diseases caused by coronaviruses.
This is just one intriguing example out of 389 interactions between SARS-CoV-2 and human proteins uncovered in the new study. The researchers also identified 366 interactions between human and SARS-CoV-1 proteins and 296 for MERS-CoV. They were especially interested in shared interactions that take place between certain human proteins and the corresponding proteins in all three coronaviruses.
To learn more about the significance of these protein-protein interactions, the researchers conducted a series of studies to find out how disrupting each of the human proteins influences SARS-CoV-2’s ability to infect human cells. These studies narrowed the list to 73 human proteins that the virus depends on to replicate.
Among them were the receptor for an inflammatory signaling molecule called IL-17, which has been suggested as an indicator of COVID-19 severity. Two other human proteins—PGES-2 and SIGMAR1—were of particular interest because they are targets of existing drugs, including the anti-inflammatory indomethacin for PGES-2 and antipsychotics like haloperidol for SIGMAR1.
To connect the molecular-level data to existing clinical information for people with COVID-19, the researchers looked to medical billing data for nearly 740,000 Americans treated for COVID-19. They then zeroed in on those individuals who also happened to have been treated with drugs targeting PGES-2 or SIGMAR1. And the results were quite striking.
They found that COVID-19 patients taking indomethacin were less likely than those taking an anti-inflammatory that doesn’t target PGES-2 to require treatment at a hospital. Similarly, COVID-19 patients taking antipsychotic drugs like haloperidol that target SIGMAR1 were half as likely as those taking other types of antipsychotic drugs to require mechanical ventilation.
More research is needed before we can think of testing these or similar drugs against COVID-19 in human clinical trials. Yet these findings provide a remarkable demonstration of how basic molecular and structural biological findings can be combined with clinical data to yield valuable new clues for treating COVID-19 and other viral illnesses, perhaps by repurposing existing drugs. Not only is NIH-supported basic science essential for addressing the challenges of the current pandemic, it is building a strong foundation of fundamental knowledge that will make us better prepared to deal with infectious disease threats in the future.
Reference:
[1] Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms. Gordon DE et al. Science. 2020 Oct 15:eabe9403.
Links:
Coronavirus (COVID-19) (NIH)
Krogan Lab (University of California, San Francisco)
NIH Support: National Institute of Allergy and Infectious Diseases; National Institute of Neurological Disorders and Stroke; National Institute of General Medical Sciences
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