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Caught on Camera: Neutralizing Antibodies Interacting with SARS-CoV-2

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Caption: Illustration showing the binding regions for the four classes of SARS-CoV-2 neutralizing antibodies. They bind to a part of the virus’s spike protein called the receptor binding domain (gray). Credit: Christopher Barnes, California Institute of Technology, Pasadena

As this long year enters its final month, there is good reason to look ahead to 2021 with optimism that the COVID-19 pandemic will finally be contained. The Food and Drug Administration is now reviewing the clinical trial data of the Pfizer and Moderna vaccines to ensure their safety and efficacy. If all goes well, emergency use authorization could come very soon, allowing immunizations to begin.

Work also continues on developing better therapeutics against SARS-CoV-2, the novel coronavirus that causes COVID-19. Though we’ve learned a great deal about this coronavirus in a short time, structural biologists continue to produce more detailed images that reveal more precisely where and how to target SARS-CoV-2. This research often involves neutralizing antibodies that circulate in the blood of most people who’ve recovered from COVID-19. The study of such antibodies and how they interact with SARS-CoV-2 offers critical biological clues into how to treat and prevent COVID-19.

A recent study in the journal Nature brings more progress, providing the most in-depth analysis yet of how human neutralizing antibodies physically grip SARS-CoV-2 to block it from binding to our cells [1]. To conduct this analysis, a team of NIH-supported structural biologists, led by postdoc Christopher Barnes and Pamela Björkman, California Institute of Technology, Pasadena, used the power of cryo-electron microscopy (cryo-EM) to capture complex molecular interactions at near-atomic scale.

People infected with SARS-CoV-2 (or any foreign substance, for that matter) generate thousands of different versions of attack antibodies. Some of these antibodies are very good at sticking to the coronavirus, while others attach only loosely. Barnes used cryo-EM to capture highly intricate pictures of eight different human neutralizing antibodies bound tightly to SARS-CoV-2. Each of these antibodies, which had been isolated from patients a few weeks after they developed symptoms of COVID-19, had been shown in lab tests to be highly effective at blocking infection.

The researchers mapped all physical interactions between several human neutralizing antibodies and SARS-CoV-2’s spike protein that stud its surface. The virus uses these spiky extensions to infect a human cell by grabbing on to the angiotensin-converting enzyme 2 (ACE2) receptor. The molecular encounter between the coronavirus and ACE2 takes place via one or more of a trio of three protein domains, called receptor-binding domains (RBDs), that jut out from its spikes. RBDs flap up and down in the fluid surrounding cells, “reaching up” to touch and enter, or “laying down” to hide from an infected person’s antibodies and immune cells. Only an “up” RBD can attach to ACE2 and get into a cell.

Taken together with other structural information known about SARS-CoV-2, Barnes’ cryo-EM snapshots revealed four different types of shapes, or classes, of antibody-spike combinations. These high-resolution molecular views show that human neutralizing antibodies interact in many different ways with SARS-CoV-2: blocking access to either one or more RBDs in their “up” or “down” positions.

These results tell us a number of things, including underscoring why strategies that combine multiple types of antibodies in an “antibody cocktail” might likely offer broader protection against infection than using just a single type of antibody. Indeed, that approach is currently being tested in patients with COVID-19.

The findings also provide a molecular guide for custom-designing synthetic antibodies in the lab to foil SARS-CoV-2. As one example, Barnes and his team observed that one antibody completely locked all three RBDs into closed (“down”) positions. As you might imagine, scientists might want to copy that antibody type when designing an antibody-based drug or vaccine.

It is tragic that hundreds of thousands of people have died from this terrible new disease. Yet the immune system helps most to recover. Learning as much as we possibly can from those individuals who’ve been infected and returned to health should help us understand how to heal others who develop COVID-19, as well as inform precision design of additional vaccines that are molecularly targeted to this new foe.

While we look forward to the arrival of COVID-19 vaccines and their broad distribution in 2021, each of us needs to remember to practice the three W’s: Wear a mask. Watch your distance (stay 6 feet apart). Wash your hands often. In parallel with everyone adopting these critical public health measures, the scientific community is working harder than ever to meet this moment, doing everything possible to develop safe and effective ways of treating and preventing COVID-19.

Reference:

[1] SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies. Barnes CO, Jette CA, Abernathy ME, et al. Nature. 2020 Oct 12. [Epub ahead of print].

Links:

Coronavirus (COVID-19) (NIH)

Combat COVID (U.S. Department of Health and Human Services, Washington, D.C.)

Freezing a Moment in Time: Snapshots of Cryo-EM Research (National Institute of General Medical Sciences/NIH)

Björkman Lab (California Institute of Technology, Pasadena)

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


Vast Majority of Pregnant Women with COVID-19 Won’t Have Complications, Study Finds

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Pregnant woman
Credit: Getty Images/Eva-Katalin

It’s natural and highly appropriate for women to be concerned about their health and the wellbeing of their unborn babies during pregnancy. With the outbreak of the pandemic, those concerns have only increased, especially after a study found last spring that about 30 percent of pregnant women who become infected with SARS-CoV-2, the coronavirus that causes COVID-19, needed to be hospitalized [1].

But that early study didn’t clearly divide out hospitalizations that were due to pregnancy from those owing to complications of COVID-19. Now, a large, observational study has taken a more comprehensive look at the issue and published some reassuring news for parents-to-be: the vast majority of women who test positive for COVID-19 during their pregnancies won’t develop serious health complications [2]. What’s more, it’s also unlikely that their newborns will become infected with SARS-CoV-2.

The findings reported in JAMA Network Open come from a busy prenatal clinic that serves women who are medically indigent at Parkland Health and Hospital System, affiliated with the University of Texas Southwestern, Dallas. Researchers there, led by obstetrician Emily Adhikari, followed more than 3,300 pregnant women, most of whom were Hispanic (75 percent) or African American (14 percent). From March through August of this year, 252 women tested positive for COVID-19 during their pregnancies.

At diagnosis, 95 percent were asymptomatic or had only mild symptoms. Only 13 of the 252 COVID-19-positive women (5 percent) in the study developed severe or critical pneumonia, including just six with no or mild symptoms initially. Only 14 women (6 percent) were admitted to the hospital for management of their COVID-19 pneumonia, and all survived.

By comparing mothers with and without COVID-19 during pregnancy, the researchers found there was no increase in adverse pregnancy-related outcomes. Overall, women with COVID-19 during pregnancy were not more likely to give birth early on average. They weren’t at increased risk of dangerous preeclampsia, a pregnancy complication characterized by high blood pressure and organ damage, or an emergency C-section to protect the baby.

The researchers found no evidence that the placenta was compromised in any way by the SARS-CoV-2 infection. In most cases, newborns didn’t get sick. Only 6 of 188 infants (3 percent) tested positive for COVID-19. Most of those infected were born to mothers who were asymptomatic or had only mild illness.

This is all encouraging news. However, it is worth noting that mothers who developed severe COVID-19 before reaching 37 weeks, or well into the third trimester of pregnancy, were more likely to give birth prematurely. More research is needed, but the study also suggests that diabetes may increase the risk for severe COVID-19 in pregnancy.

This study’s bottom line is that most women who become infected with SARS-CoV-2 during pregnancy will do just fine. That doesn’t mean, however, that anyone should take this situation casually. The finding that 5 percent of pregnant women may become severely ill is still cause for concern. Plus not all researchers come to the same conclusion—an update to the first study cited in this post recently found a greater risk for pregnant women becoming severely ill from COVID-19 and giving birth prematurely.

Taken together, while there’s no need to panic about COVID-19 infection during pregnancy, it’s still a good idea for pregnant women and their loved ones to take extra precautions to protect their health. And, of course, follow the three W’s: Wear a mask, Watch your distance, and Wash your hands.

References:

[1] Characteristics of women of reproductive age with laboratory-confirmed SARS-CoV-2 infection by pregnancy status—United States, January 22–June 7, 2020. CDC COVID-19 Response Team. MMWR Morb Mortal Wkly Rep. 2020 Mar 27;69(12):343-346.

[2] Pregnancy outcomes among women with and without severe acute respiratory syndrome coronavirus 2 infection. Adhikari EH, Moreno W, Zofkie AC, MacDonald L, McIntire DD, Collins RRJ, Spong CY. JAMA Netw Open. 2020 Nov 2;3(11):e2029256.

Links:

Coronavirus (COVID) (NIH)

Combat COVID (U.S. Department of Health and Human Services, Washington, D.C.)

Data on COVID-19 during Pregnancy: Severity of Maternal Illness (Centers for Disease Control and Prevent, Atlanta)

COVID-19 Treatment Guidelines: Special Considerations in Pregnancy (NIH)

Emily Adhikari (University of Texas Southwestern Medical Center, Dallas)


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


Can Autoimmune Antibodies Explain Blood Clots in COVID-19?

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Blood Clots
Caption: Illustration showing a blood vessel with a platelet clot (yellow). Red blood cells (red), neutrophils (purple), and Y-shaped antibodies called aPL (white) circulate through the vessel. Credit: Stephanie King/Michigan Medicine

For people with severe COVID-19, one of the most troubling complications is abnormal blood clotting that puts them at risk of having a debilitating stroke or heart attack. A new study suggests that SARS-CoV-2, the coronavirus that causes COVID-19, doesn’t act alone in causing blood clots. The virus seems to unleash mysterious antibodies that mistakenly attack the body’s own cells to cause clots.

The NIH-supported study, published in Science Translational Medicine, uncovered at least one of these autoimmune antiphospholipid (aPL) antibodies in about half of blood samples taken from 172 patients hospitalized with COVID-19. Those with higher levels of the destructive autoantibodies also had other signs of trouble. They included greater numbers of sticky, clot-promoting platelets and NETs, webs of DNA and protein that immune cells called neutrophils spew to ensnare viruses during uncontrolled infections, but which can lead to inflammation and clotting. These observations, coupled with the results of lab and mouse studies, suggest that treatments to control those autoantibodies may hold promise for preventing the cascade of events that produce clots in people with COVID-19.

Our blood vessels normally strike a balance between producing clotting and anti-clotting factors. This balance keeps us ready to seal up vessels after injury, but otherwise to keep our blood flowing at just the right consistency so that neutrophils and platelets don’t stick and form clots at the wrong time. But previous studies have suggested that SARS-CoV-2 can tip the balance toward promoting clot formation, raising questions about which factors also get activated to further drive this dangerous imbalance.

To learn more, a team of physician-scientists, led by Yogendra Kanthi, a newly recruited Lasker Scholar at NIH’s National Heart, Lung, and Blood Institute and his University of Michigan colleague Jason S. Knight, looked to various types of aPL autoantibodies. These autoantibodies are a major focus in the Knight Lab’s studies of an acquired autoimmune clotting condition called antiphospholipid syndrome. In people with this syndrome, aPL autoantibodies attack phospholipids on the surface of cells including those that line blood vessels, leading to increased clotting. This syndrome is more common in people with other autoimmune or rheumatic conditions, such as lupus.

It’s also known that viral infections, including COVID-19, produce a transient increase in aPL antibodies. The researchers wondered whether those usually short-lived aPL antibodies in COVID-19 could trigger a condition similar to antiphospholipid syndrome.

The researchers showed that’s exactly the case. In lab studies, neutrophils from healthy people released twice as many NETs when cultured with autoantibodies from patients with COVID-19. That’s remarkably similar to what had been seen previously in such studies of the autoantibodies from patients with established antiphospholipid syndrome. Importantly, their studies in the lab further suggest that the drug dipyridamole, used for decades to prevent blood clots, may help to block that antibody-triggered release of NETs in COVID-19.

The researchers also used mouse models to confirm that autoantibodies from patients with COVID-19 actually led to blood clots. Again, those findings closely mirror what happens in mouse studies testing the effects of antibodies from patients with the most severe forms of antiphospholipid syndrome.

While more study is needed, the findings suggest that treatments directed at autoantibodies to limit the formation of NETs might improve outcomes for people severely ill with COVID-19. The researchers note that further study is needed to determine what triggers autoantibodies in the first place and how long they last in those who’ve recovered from COVID-19.

The researchers have already begun enrolling patients into a modest scale clinical trial to test the anti-clotting drug dipyridamole in patients who are hospitalized with COVID-19, to find out if it can protect against dangerous blood clots. These observations may also influence the design of the ACTIV-4 trial, which is testing various antithrombotic agents in outpatients, inpatients, and convalescent patients. Kanthi and Knight suggest it may also prove useful to test infected patients for aPL antibodies to help identify and improve treatment for those who may be at especially high risk for developing clots. The hope is this line of inquiry ultimately will lead to new approaches for avoiding this very troubling complication in patients with severe COVID-19.

Reference:

[1] Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19. Zuo Y, Estes SK, Ali RA, Gandhi AA, Yalavarthi S, Shi H, Sule G, Gockman K, Madison JA, Zuo M, Yadav V, Wang J, Woodard W, Lezak SP, Lugogo NL, Smith SA, Morrissey JH, Kanthi Y, Knight JS. Sci Transl Med. 2020 Nov 2:eabd3876.

Links:

Coronavirus (COVID-19) (NIH)

Antiphospholipid Antibody Syndrome (National Heart Lung and Blood Institute/NIH)

Kanthi Lab (National Heart, Lung, and Blood Institute, Bethesda, MD)

Knight Lab (University of Michigan)

ACTIV (NIH)

NIH Support: National Heart, Lung, and Blood Institute


Genome Data from Africa Reveal Millions of New Variants

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H2Africa logo
Credit: Human Heredity and Health in Africa Initiative

The first Homo sapiens emerged in Africa hundreds of thousands of years ago. We are all descended from that common pool of ancestors. Put another way, we are all Africans. While it’s not possible to study the DNA of these vanished original human populations, it is possible to study the genetic material of today’s African peoples to learn more about the human genome and its evolution over time. The degree of genetic diversity in Africa is greater than anywhere else in the world.

Progress continues to be made in this important area of genomic research. The latest step forward is a study just published in the journal Nature that analyzes more than 400 complete human genomes, including 50 distinct groups of people from 13 African countries. This work has uncovered about 3.4 million unique gene variants that had never before been described, greatly expanding our knowledge of human genetic variation and its implications for health and disease.

This work is the latest from the Human Heredity and Health in Africa (H3Africa) Initiative , which I helped establish a decade ago. This partnership between NIH, the Wellcome Trust, and the Alliance for Accelerating Excellence in Science in Africa (AESA) seeks to train a new generation of African scientists in genomic science and other disciplines, while conducting state-of-the-art health research on the African continent. The hope is to help these scientists use their new knowledge to improve human health in Africa and to help fill significant gaps in our knowledge of the diversity within human genomes.

The new study was led by Zané Lombard, the University of the Witwatersrand, South Africa; Neil Hanchard, Baylor College of Medicine, Houston; and Adebowale Adeyemo, NIH’s National Human Genome Research Institute, Bethesda, MD. It also included more than 50 other H3Africa data providers and data analysts from across Africa and around the world.

These researchers sequenced and analyzed the genomes of 426 individuals, almost all from studies and countries within the H3Africa Consortium, the network of NIH and Wellcome Trust-funded research sites in Africa. These individuals were carefully selected to provide broad coverage of the diverse landscape of African genomic variation. They also included many populations that hadn’t been studied at the genetic level before. The team focused its attention on single-letter differences, also known as single nucleotide variants (SNVs), located across the 3 billion DNA letters of the human genome.

All told, the researchers observed more than 31 million confirmed SNVs. Of the 3.4 million newly discovered SNVs, most turned up in the genomes of individuals from previously unstudied African ethnic groups with their own distinct languages. Even among SNVs that had been previously reported, several were found much more often than in other populations. That’s important because medical geneticists often include information about frequency in deciding whether a gene variant is a likely cause of rare disease. So, this more complete picture of normal genetic variation will be valuable for diagnosing such genetic conditions around the globe.

The researchers also found more than 100 regions of the genome where the pattern of genetic variation was suggestive of underlying variants that were evolutionarily favored at some time in the past. Sixty-two of those chromosomal locations weren’t previously known to be under such strong natural selection in human populations. Interestingly, those selected regions were found to contain genes associated with viral immunity, DNA repair, reproduction, and metabolism, or occurred close to variants that have been associated with conditions such as uterine fibroids and chronic kidney disease.

The findings suggest that viral infections, such as outbreaks of Ebola, yellow fever, and Lassa fever, may have played an important role over centuries in driving genetic differences on the African continent. The data also point to the possibility of human adaptation to differences across the African continent in local environments and diets, and these adaptations could be relevant to common diseases and traits we see now.

The researchers used the data to help gain insight into past migrations of human populations. The genetic data revealed complex patterns of ancestral mixing within and between groups. It also uncovered how distinct groups likely moved large distances across Africa in the past, going back hundreds to thousands of years. The findings also offered a more complete picture of the timing and extent of the migration of speakers of Africa’s most common language group (Bantu) as they moved from West Africa to the southern and eastern reaches of the continent—a defining event in the genetic history of Africa.

There’s still much more to learn about the diversity of human genomes, and a need for continued studies, including many more individuals representing more distinct groups in Africa. Indeed, H3Africa now consists of 51 projects all across the continent, focused on population-based genomic studies of many common health conditions, from heart disease to tuberculosis. As the cradle of all humanity, Africa has much to offer genomic research in the years ahead that will undoubtedly have far-reaching implications for people living in all parts of our planet.

Reference:

[1] High-depth African genomes inform human migration and health. Choudhury A et al. 2020 Oct;586(7831):741-748.

Links:

Human Heredity and Health in Africa (H3Africa) (NIH)

H3Africa (University of Cape Town, South Africa)

NIH Support: National Human Genome Research Institute; National Institute of Allergy and Infectious Diseases


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