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Mini-Lungs in a Lab Dish Mimic Early COVID-19 Infection

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Credit: Arvind Konkimalla, Tata Lab, Duke University, Durham, NC

Researchers have become skilled at growing an array of miniature human organs in the lab. Such lab-grown “organoids” have been put to work to better understand diabetes, fatty liver disease, color vision, and much more. Now, NIH-funded researchers have applied this remarkable lab tool to produce mini-lungs to study SARS-CoV-2, the coronavirus that causes COVID-19.

The intriguing bubble-like structures (red/clear) in the mini-lung pictured above represent developing alveoli, the tiny air sacs in our lungs, where COVID-19 infections often begin. In this organoid, the air sacs consist of many thousands of cells, all of which arose from a single adult stem cell isolated from tissues found deep within healthy human lungs. When carefully nurtured in lab dishes, those so-called alveolar epithelial type-2 cells (AT2s) begin to multiply. As they grow, they spontaneously assemble into structures that closely resemble alveoli.

A team led by Purushothama Rao Tata, Duke University School of Medicine, Durham, NC, developed these mini-lungs in a quest to understand how adult stem cells help to regenerate damaged tissue in the deepest recesses of the lungs, where SARS-CoV-2 attacks. In earlier studies, the researchers had shown it was possible for these cells to produce miniature alveoli. But there was a problem: the “soup” they used to nurture the growing cells included ingredients that weren’t well defined, making it hard to characterize the experiments fully.

In the study, now reported in Cell Stem Cell, the researchers found a way to simplify and define that brew. For the first time, they could produce mini-lungs consisting only of human lung cells. By growing them in large numbers in the lab, they can now learn more about SARS-CoV-2 infection and look for new ways to prevent or treat it.

Tata and his collaborators at the University of North Carolina, Chapel Hill, have already confirmed that SARS-CoV-2 infects the mini-lungs via the critical ACE2 receptor, just as the virus is known to do in the lungs of an infected person.

Interestingly, the cells also produce cytokines, inflammatory molecules that have been tied to tissue damage. The findings suggest the cytokine signals may come from the lungs themselves, even before immune cells arrive on the scene.

The heavily infected lung cells eventually self-destruct and die. In an unexpected turn of events, they even induce cell death in some neighboring healthy cells that are not infected. The relevance of the studies to the clinic was boosted by the finding that the gene activity patterns in the mini-lungs are a close match to those found in samples taken from six patients with severe COVID-19.

Now that he’s got the recipe down, Tata is busy making organoids and helping to model COVID-19 infections, with the hope of identifying and testing promising new treatments. It’s clear these mini-lungs are breathing some added life into the basic study of COVID-19.

Reference:

[1] Human lung stem cell-based alveolospheres provide insights into SARS-CoV-2-mediated interferon responses and pneumocyte dysfunction. Katsura H, Sontake V, Tata A, Kobayashi Y, Edwards CE, Heaton BE, Konkimalla A, Asakura T, Mikami Y, Fritch EJ, Lee PJ, Heaton NS, Boucher RC, Randell SH, Baric RS, Tata PR. Cell Stem Cell. 2020 Oct 21:S1934-5909(20)30499-9.

Links:

Coronavirus (COVID-19) (NIH)

Tata Lab (Duke University School of Medicine, Durham, NC)

NIH Support: National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences; National Institute of Diabetes and Digestive and Kidney Diseases


Planning Your Holidays During the COVID-19 Pandemic

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Thanksgiving 2020
Credit: Getty Images

With the holiday season fast approaching and coronavirus disease 2019 (COVID-19) surging in most parts of the country, millions of Americans—including me and my family—will break with tradition this year to celebrate in ways that we hope will help to keep us all safe and healthy. Granted, this may present some difficult emotional and logistical challenges, but I’m confident that the American can-do spirit will rise to meet those challenges.

I also recognize that this will be hard for many of us. Celebrating holidays alone or with your immediate household members can sound rather dreary. After all, who wants to roast and carve a turkey for just a few people? But, if you look at it another way, the pandemic does offer opportunities to make this holiday a season to remember in new and different ways. Here are a couple of ideas that you may want to consider:

Send Gifts. Although COVID-19 has changed our lives in many ways, sending cards or gifts remains a relatively easy way to let loved ones know that you’re thinking of them. Who wouldn’t want to receive some home-baked goodies, a basket of fresh fruit, or a festive wreath? If you enjoy knitting, candle making, or other ways of crafting gifts for the holidays, now’s the time to start planning for Thanksgiving through the New Year.

Make Videos. When I’m visiting family, there is often music involved—with guitar, piano, and maybe some singing. But, this year, I’ll have to be content with video recording a few songs and sending them to others by text or email. Come to think of it, the kids and the grandkids might enjoy these songs just as much—or even more—if they can watch them at a time and place that works best for them. (On the other hand, some of them might roll their eyes and decide not to open that video file!) If you don’t play a guitar or like to sing, you can still make your own holiday-themed videos. Maybe share a dance routine, a demonstration of athletic skill, or even some stand-up comedy. The key is to have fun and let your imagination run free.

Share a Meal Remotely. Most of our end-of-the-year holidays involve the family sitting around a table overflowing with delicious food. With all of the videoconferencing platforms now available, it is easy to set aside a block of time to share a meal and good conversation remotely with friends and family members, whether they live nearby or across the country. Rather than one cook slaving over a hot stove or a certain person monopolizing the dinner table conversation, everyone gets a chance to cook and share their stories via their smartphone, tablet, or laptop. You can compare your culinary creations, swap recipes, and try to remember to leave room for dessert. If you have a tradition of playing games or giving thanks for your many blessings, you can still do many of these activities remotely.

Take an After-Dinner Walk. Due to the physical demands and psychological impacts of the COVID-19 pandemic, it’s been difficult for many of us to stay physically active. The key is making exercise a daily priority, and the holidays are no different. After your holiday meal, go on a virtual group walk through your respective neighborhoods to work off the food. Thanks to your smartphone’s camera, you can share your time outdoors and all of the interesting sights along the way. (Yes, the new playground in the local park looks fantastic, and the neighbors really did just paint their house purple!)

Stay Safe. If you plan to go ahead and join a holiday gathering in person, it’s important to remain vigilant, even when interacting with dear friends and loved ones. The greatest risk for spread of COVID-19 right now is these family gatherings. Remember there are risks associated with travel and with interacting with people who’ve not been tested for the coronavirus prior to the event, especially if they reside in a COVID hot spot—which is almost everywhere these days. Try to keep any family gatherings brief and relatively small, about five people or less. If the weather permits, hold the get-together outdoors.

To protect yourself and your loved ones, both now and over the holidays, please follow these 3 W’s:

Wear a mask when you are out in public and when you are indoors with people who are not part of your immediate household. The only exception is while eating or drinking!
Watch your distance, staying at least 6 feet away from people who are not part of your immediate household.
Wash your hands thoroughly and frequently.

Making all of these adjustments is a lot to consider when you’re trying to have a good time and there are children and older adults in the mix. That’s why I and my wife Diane decided the best plan for us this holiday season is to stay home in Maryland and forgo our traditional trips to family in Michigan and North Carolina. Not only did we want to reduce the risk of possibly contracting COVID-19 from—or transmitting it to—our faraway loved ones, we want to do everything we can to protect our local friends and co-workers from the coronavirus.

While this holiday season is likely to be memorable in ways that we never could have imagined, I’m confident that, thanks to the rapid advances being made by medical research, we ultimately will get the COVID-19 pandemic under control so we can once again give everyone we love a big hug in person. Until then, please stay safe. Wishing each of you a wonderful and healthful holiday season, starting with a Happy Thanksgiving!

Links:

Coronavirus (COVID) (NIH)

Your Health: Holiday Celebrations and Small Gatherings (Centers for Disease Control and Prevention, Atlanta)

Your Health: Personal and Social Activities (CDC)


Speeding COVID-19 Drug Discovery with Quantum Dots

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Viruses with nanoparticles attached
Credit: Ethan Tyler and Alan Hoofring/NIH Medical Arts

These round, multi-colored orbs in the illustration above may resemble SARS-CoV-2, the coronavirus responsible for COVID-19. But they’re actually lab-made nanocrystals called quantum dots. They have been specially engineered to look and, in some ways, act like the coronavirus while helping to solve a real challenge for many labs that would like to study SARS-CoV-2.

Quantum dots, which have been around since the mid-1980s, are designed with special optical properties that allow them to fluoresce when exposed to ultraviolet light. The two pictured here are about 10 nanometers in diameter, about 3,000 times smaller than the width of a human hair. The quantum dot consists of a semi-conductive cadmium selenide inner core (orange) surrounded by a zinc sulfide outer shell (teal). Molecules on its surface (yellow) allow researchers to attach the viral spike protein (purple), which SARS-CoV-2 depends on to infect human cells.

To the left is a human cell (gray) studded with the ACE2 receptors (blue) that those viral spike proteins bind to before SARS-CoV-2 enters and infects our cells. In the background, you see another spike protein-studded quantum dot. But human neutralizing antibodies (pink) are preventing that one from reaching the human cell.

Because SARS-CoV-2 is so highly infectious, basic researchers without access to specially designed biosafety facilities may be limited in their ability to study the virus. But these harmless quantum dots offer a safe workaround. While the quantum dots may bind and enter human cells just like the virus, they can’t cause an infection. They offer a quick, informative way to assess the potential of antibodies or other compounds to prevent the coronavirus from binding to our cells.

In work published in the journal ACS Nano, a team that included Kirill Gorshkov, NIH’s National Center for Advancing Translational Sciences (NCATS), Rockville, MD, along with Eunkeu Oh and Mason Wolak, Naval Research Laboratory, Washington, D.C., demonstrated how these quantum dots may serve as a useful new tool to speed the search for new COVID-19 treatments. The dots’ fluorescent glow enabled the researchers to use a microscope to observe how these viral mimics bind to ACE2 in real time, showing how SARS-CoV-2 might attach to and enter our cells, and suggesting ways to intervene.

Indeed, imagine thousands of tiny wells in which human cells are growing. Imagine adding a different candidate drug to each well; then imagine adding the loaded quantum dots to each well and using machine vision to identify the wells where the dots could not enter the cell. That’s not science fiction. That’s now.

With slightly different versions of their quantum dots, the NCATS researchers and their colleagues at the Naval Research Laboratory will now explore how other viral proteins are important for the coronavirus to infect our cells. They also can test how slight variations in the spike protein may influence SARS-CoV-2’s behavior. This work provides yet another stunning example of how scientists with widely varying expertise have banded together—using all the tools at their disposal—to forge ahead to find solutions to COVID-19.

Reference:

[1] Quantum dot-conjugated SARS-CoV-2 spike pseudo-virions enable tracking of angiotensin converting enzyme 2 binding and endocytosis. Gorshkov K, Susumu K, Chen J, Xu M, Pradhan M, Zhu W, Hu X, Breger JC, Wolak M, Oh E. ACS Nano. 2020 Sep 22;14(9):12234-12247.

Links:

What are Quantum Dots? (National Institute of Biomedical Imaging and Bioengineering/NIH)

Coronavirus (COVID-19) (NIH)

I Am Translational Science: Kirill Gorshkov (National Center for Advancing Translational Sciences/NIH)

U. S. Naval Research Laboratory (Washington, D.C.)

NIH Support: National Center for Advancing Translational Sciences


Face Coverings Could Save 130,000 American Lives from COVID-19 by March

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Wearing a mask
Credit: Diane Baker

The coronavirus disease 2019 (COVID-19) pandemic has already claimed the lives of more than 230,000 Americans, the population of a mid-sized U.S. city. As we look ahead to winter and the coming flu season, the question weighing on the minds of most folks is: Can we pull together to contain the spread of this virus and limit its growing death toll?

I believe that we can, but only if each of us gets fully engaged with the public health recommendations. We need all Americans to do the right thing and wear a mask in public to protect themselves and their communities from spreading the virus. Driving home this point is a powerful new study that models just how critical this simple, low-cost step will be this winter and through the course of this pandemic [1].

Right now, it’s estimated that about half of Americans always wear a mask in public. According to the new study, published in Nature Medicine, if this incomplete rate of mask-wearing continues and social distancing guidelines are not adhered to, the total number of COVID-19 deaths in the United States could soar to more than 1 million by the end of February.

However, the model doesn’t accept that we’ll actually end up at this daunting number. It anticipates that once COVID mortality reaches a daily threshold of 8 deaths per 1 million citizens, U.S. states would re-instate limits on social and economic activity—as much of Europe is now doing. If so, the model predicts that by March, such state-sanctioned measures would cut the projected number of deaths in half to about 510,000—though that would still add another 280,000 lives lost to this devastating virus.

The authors, led by Christopher Murray, Institute of Health Metrics and Evaluations, University of Washington School of Medicine, Seattle, show that we can do better than that. But doing better will require action by all of us. If 95 percent of people in the U.S. began wearing masks in public right now, the death toll would drop by March from the projected 510,000 to about 380,000.

In other words, if most Americans pulled together to do the right thing and wore a mask in public, this simple, selfless act would save more than 130,000 lives in the next few months alone. If mask-wearers increased to just 85 percent, the model predicts it would save about 96,000 lives across the country.

What’s important here aren’t the precise numbers. It’s the realization that, under any scenario, this pandemic is far from over, and, together, we have it within our power to shape what happens next. If more people make the decision to wear masks in public today, it could help to delay—or possibly even prevent—the need for future shutdowns. As such, the widespread use of face coverings has the potential to protect lives while also minimizing further damage to the economy and American livelihoods. It’s a point that NIH’s Anthony Fauci and colleagues presented quite well in a recent commentary in JAMA [2].

As we anxiously await the approved vaccines for COVID-19 and other advances in its prevention and treatment, the life-saving potential of face coverings simply can’t be overstated. I know that many people are tired of this message, and, unfortunately, mask-wearing has been tangled up in political perspectives at this time of deep divisions in our country.

But think about it in the same way you think about putting on your seat belt—a minor inconvenience that can save lives. I’m careful to wear a mask outside my home every time I’m out and about. But, ultimately, saving lives and livelihoods as we head into these winter months will require a collective effort from all of us.

To do so, each of us needs to follow these three W’s: Wear a mask. Watch your distance (stay 6 feet apart). Wash your hands often.

References:

[1] Modeling COVID-19 scenarios for the United States. IHME COVID-19 Forecasting Team. Nat Med. 2020 Oct 23.

[2] Preventing the spread of SARS-CoV-2 with masks and other “low-tech” interventions. Lerner AM, Folkers, GK, Fauci AS. JAMA. 2020 October 26.

Links:

Coronavirus (COVID-19) (NIH)

Institute for Health Metrics and Evaluations (University of Washington School of Medicine, Seattle)


Protein Mapping Study Reveals Valuable Clues for COVID-19 Drug Development

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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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