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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


Antibody Response Affects COVID-19 Outcomes in Kids and Adults

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Sick child during COVID
Credit: SDI Productions

Doctors can’t reliably predict whether an adult newly diagnosed with COVID-19 will recover quickly or battle life-threatening complications. The same is true for children.

Thankfully, the vast majority of kids with COVID-19 don’t get sick or show only mild flu-like symptoms. But a small percentage develop a delayed, but extremely troubling, syndrome called multisystem inflammatory syndrome in children (MIS-C). This can cause severe inflammation of the heart, lungs, kidneys, brain, and other parts of the body, coming on weeks after recovering from COVID-19. Fortunately, most kids respond to treatment and make rapid recoveries.

COVID-19’s sometimes different effects on kids likely stem not from the severity of the infection itself, but from differences in the immune response or its aftermath. Additional support for this notion comes from a new study, published in the journal Nature Medicine, that compared immune responses among children and adults with COVID-19 [1]. The study shows that the antibody responses in kids and adults with mild COVID-19 are quite similar. However, the complications seen in kids with MIS-C and adults with severe COVID-19 appear to be driven by two distinctly different types of antibodies involved in different aspects of the immune response.

The new findings come from pediatric pulmonologist Lael Yonker, Massachusetts General Hospital (MGH) Cystic Fibrosis Center, Boston, and immunologist Galit Alter, the Ragon Institute of MGH, Massachusetts Institute of Technology, and Harvard, Cambridge. Yonker runs a biorepository that collects samples from kids with cystic fibrosis. When the pandemic began, she started collecting plasma samples from children with mild COVID-19. Then, when Yonker and others began to see children hospitalized with MIS-C, she collected some plasma samples from them, too.

Using these plasma samples as windows into a child’s immune response, the research teams of Yonker and Alter detailed antibodies generated in 17 kids with MIS-C and 25 kids with mild COVID-19. They also profiled antibody responses of 60 adults with COVID-19, including 26 with severe disease.

Comparing antibody profiles among the four different groups, the researchers had expected children’s antibody responses to look quite different from those in adults. But they were in for a surprise. Adults and kids with mild COVID-19 showed no notable differences in their antibody profiles. The differences only came into focus when they compared antibodies in kids with MIS-C to adults with severe COVID-19.

In kids who develop MIS-C after COVID-19, they saw high levels of long-lasting immunoglobulin G (IgG) antibodies, which normally help to control an acute infection. Those high levels of IgG antibodies weren’t seen in adults or in kids with mild COVID-19. The findings suggest that in kids with MIS-C, those antibodies may activate scavenging immune cells, called macrophages, to drive inflammation and more severe illness.

In adults with severe COVID-19, the pattern differed. Instead of high levels of IgG antibodies, adults showed increased levels of another type of antibody, called immunoglobulin A (IgA). These IgA antibodies apparently were interacting with immune cells called neutrophils, which in turn led to the release of cytokines. That’s notable because the release of too many cytokines can cause what’s known as a “cytokine storm,” a severe symptom of COVID-19 that’s associated with respiratory distress syndrome, multiple organ failure, and other life-threatening complications.

To understand how a single virus can cause such different outcomes, studies like this one help to tease out their underlying immune mechanisms. While more study is needed to understand the immune response over time in both kids and adults, the hope is that these findings and others will help put us on the right path to discover better ways to help protect people of all ages from the most severe complications of COVID-19.

Reference:

[1] Humoral signatures of protective and pathological SARS-CoV-2 infection in children. Bartsch YC, Wang C, Zohar T, Fischinger S, Atyeo C, Burke JS, Kang J, Edlow AG, Fasano A, Baden LR, Nilles EJ, Woolley AE, Karlson EW, Hopke AR, Irimia D, Fischer ES, Ryan ET, Charles RC, Julg BD, Lauffenburger DA, Yonker LM, Alter G. Nat Med. 2021 Feb 12.

Links:

COVID-19 Research (NIH)

NIH effort seeks to understand MIS-C, range of SARS-CoV-2 effects on children,” NIH news release, March 2, 2021.

Lael Yonker (Massachusetts General Hospital, Boston)

Alter Lab (Ragon Institute of Massachusetts General Hospital, MIT, and Harvard, Cambridge)

NIH Support: National Institute of Allergy and Infectious Diseases; National Cancer Institute


Rogue Antibodies and Gene Mutations Explain Some Cases of Severe COVID-19

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SARS-CoV-2
Caption: Colorized scanning electron micrograph of a dying cell (blue) heavily infected with SARS-CoV-2 virus particles (yellow), isolated from a patient sample. Credit: National Institute of Allergy and Infectious Diseases, NIH

One of the many perplexing issues with COVID-19 is that it affects people so differently. That has researchers trying to explain why some folks bounce right back from the virus, or don’t even know they have it—while others become critically ill. Now, two NIH-funded studies suggest that one reason some otherwise healthy people become gravely ill may be previously unknown trouble spots in their immune systems, which hamper their ability to fight the virus.

According to the new findings in hundreds of racially diverse people with life-threatening COVID-19, a small percentage of people who suffer the most severe symptoms carry rare mutations in genes that disrupt their antiviral defenses. Another 10 percent with severe COVID-19 produce rogue “auto-antibodies,” which misguidedly disable a part of the immune system instead of attacking the virus.

Either way, the outcome is the same: the body has trouble fending off SARS-CoV-2, the novel coronavirus that causes COVID-19. The biological reason is there’s not enough of an assortment of signaling proteins, called type I interferons, that are crucial to detecting dangerous viruses like SARS-CoV-2 and sounding the alarm to prevent serious illness.

The research was led by Jean-Laurent Casanova, Howard Hughes Medical Institute and The Rockefeller University, New York; and the Imagine Institute, Necker Hospital, Paris. Casanova and his team began enrolling people with COVID-19 last February, with a particular interest in young adults battling severe illness. They were curious whether inherent weaknesses in their immune systems might explain their surprising vulnerability to the virus despite being otherwise young and healthy. Based on earlier findings in other infectious illnesses, they were especially interested in a set of 13 genes involved in interferon-driven immunity.

In their first study, published in the journal Science, researchers compared this set of genes in 659 patients with life-threatening COVID-19 to the same genes in 534 people with mild or asymptomatic COVID-19 [1]. It turned out that 23, or 3.5 percent, of people with severe COVID-19 indeed carried rare mutations in genes involved in producing antiviral interferons. Those unusual aberrations never turned up in people with milder disease. The researchers went on to show in lab studies that those genetic errors leave human cells more vulnerable to SARS-CoV-2 infection.

The discovery was certainly intriguing, but given the rarity of those mutations, it doesn’t explain most instances of severe COVID-19. Still, it did give Casanova’s team another idea. Perhaps some other people who suffer from severe COVID-19 lack interferons too, but for different reasons. Perhaps their bodies were producing rogue antibodies that were crippling their own antiviral defenses.

In their second study, also in Science, that’s exactly what researchers found in 101 of 987 (over 10 percent) patients from around the world with life-threatening COVID-19 [2]. In the bloodstreams of such individuals, they detected auto-antibodies against an assortment of interferon proteins. Those antibodies, which blocked the interferons’ antiviral activity, weren’t found in people with more mild cases of COVID-19.

Interestingly, the vast majority of patients with those harmful antibodies were men. The findings might help to explain the observation that men are at greater risk than women for developing severe COVID-19. The patients with auto-antibodies also were slightly older, with about half over the age of 65.

Many questions remain. For instance, it’s not yet clear what drives the production of those debilitating auto-antibodies. Might there be more mutations in antiviral defense-related genes that researchers have yet to discover? Is it possible that interferon treatment may help some people with severe COVID-19? Such treatment may be difficult in patients with auto-antibodies, although some clinical trials to explore this possibility already are underway.

The findings, if confirmed, have some potentially immediate implications. It’s possible that screening patients for the presence of damaging auto-antibodies might help to identify those at greater risk for progressing to severe disease. Treatments to remove those antibodies from the bloodstream or to boost antiviral defenses in other ways also may help. Ideally, it would be a good idea to make sure donated convalescent plasma now being tested in clinical trials as a treatment for severe COVID-19 doesn’t contain such disruptive auto-antibodies.

These new findings come from an international effort involving hundreds of scientists called the COVID Human Genetic Effort. Besides its ongoing efforts to understand severe COVID-19, Casanova says his team is also taking a look at the other side of the coin: how some people who’ve been exposed to severe COVID-19 in their own households manage to not get sick. A related international group called the COVID-19 Host Genetics Initiative is pursuing similar goals. Such insights will be invaluable as we continue to manage and treat COVID-19 patients in the future.

References:

[1] Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Zhang Q, Bastard P, Liu Z, Le Pen J, Moncada-Velez M, Gorochov G, Béziat V, Jouanguy E, Sancho-Shimizu V, Rice CM, Abel L, Notarangelo LD, Cobat A, Su HC, Casanova JL et al. Science. 2020 Sep 24:eabd4570. [Published online ahead of print.]

[2] Auto-antibodies against type I IFNs in patients with life-threatening COVID-19. Bastard P, Rosen LB, Zhang Q, Michailidis E, Hoffmann HH, Gorochov G, Jouanguy E, Rice CM, Cobat A, Notarangelo LD, Abel L, Su HC, Casanova JL et al. Science. 2020 Sep 24:eabd4585. [Published online ahead of print.]

Links:

Coronavirus (COVID-19) (NIH)

Interferons (Alpha, Beta) (NIH)

Interferons. Taylor MW. Viruses and Men: A History of Interactions. 2014 July 22. (Pubmed)

Video: Understanding the underlying genetics of COVID-19, Jean-Laurent Casanova (Youtube)

Jean-Laurent Casanova (The Rockefeller University, New York)

COVID Human Genetic Effort

NIH Support: National Institute of Allergy and Infectious Diseases


Immune T Cells May Offer Lasting Protection Against COVID-19

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Healthy human T Cell
Caption: Scanning electron micrograph of a human T lymphocyte (T cell) from a healthy donor’s immune system. Credit: National Institute of Allergy and Infectious Diseases/NIH

Much of the study on the immune response to SARS-CoV-2, the novel coronavirus that causes COVID-19, has focused on the production of antibodies. But, in fact, immune cells known as memory T cells also play an important role in the ability of our immune systems to protect us against many viral infections, including—it now appears—COVID-19.

An intriguing new study of these memory T cells suggests they might protect some people newly infected with SARS-CoV-2 by remembering past encounters with other human coronaviruses. This might potentially explain why some people seem to fend off the virus and may be less susceptible to becoming severely ill with COVID-19.

The findings, reported in the journal Nature, come from the lab of Antonio Bertoletti at the Duke-NUS Medical School in Singapore [1]. Bertoletti is an expert in viral infections, particularly hepatitis B. But, like so many researchers around the world, his team has shifted their focus recently to help fight the COVID-19 pandemic.

Bertoletti’s team recognized that many factors could help to explain how a single virus can cause respiratory, circulatory, and other symptoms that vary widely in their nature and severity—as we’ve witnessed in this pandemic. One of those potential factors is prior immunity to other, closely related viruses.

SARS-CoV-2 belongs to a large family of coronaviruses, six of which were previously known to infect humans. Four of them are responsible for the common cold. The other two are more dangerous: SARS-CoV-1, the virus responsible for the outbreak of Severe Acute Respiratory Syndrome (SARS), which ended in 2004; and MERS-CoV, the virus that causes Middle East Respiratory Syndrome (MERS), first identified in Saudi Arabia in 2012.

All six previously known coronaviruses spark production of both antibodies and memory T cells. In addition, studies of immunity to SARS-CoV-1 have shown that T cells stick around for many years longer than acquired antibodies. So, Bertoletti’s team set out to gain a better understanding of T cell immunity against the novel coronavirus.

The researchers gathered blood samples from 36 people who’d recently recovered from mild to severe COVID-19. They focused their attention on T cells (including CD4 helper and CD8 cytotoxic, both of which can function as memory T cells). They identified T cells that respond to the SARS-CoV-2 nucleocapsid, which is a structural protein inside the virus. They also detected T cell responses to two non-structural proteins that SARS-CoV-2 needs to make additional copies of its genome and spread. The team found that all those recently recovered from COVID-19 produced T cells that recognize multiple parts of SARS-CoV-2.

Next, they looked at blood samples from 23 people who’d survived SARS. Their studies showed that those individuals still had lasting memory T cells today, 17 years after the outbreak. Those memory T cells, acquired in response to SARS-CoV-1, also recognized parts of SARS-CoV-2.

Finally, Bertoletti’s team looked for such T cells in blood samples from 37 healthy individuals with no history of either COVID-19 or SARS. To their surprise, more than half had T cells that recognize one or more of the SARS-CoV-2 proteins under study here. It’s still not clear if this acquired immunity stems from previous infection with coronaviruses that cause the common cold or perhaps from exposure to other as-yet unknown coronaviruses.

What’s clear from this study is our past experiences with coronavirus infections may have something important to tell us about COVID-19. Bertoletti’s team and others are pursuing this intriguing lead to see where it will lead—not only in explaining our varied responses to the virus, but also in designing new treatments and optimized vaccines.

Reference:

[1] SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls. Le Bert N, Tan AT, Kunasegaran K, et al. Nature. 2020 July 15. [published online ahead of print]

Links:

Coronavirus (COVID-19) (NIH)

Overview of the Immune System (National Institute of Allergy and Infectious Diseases/NIAID)

Bertoletti Lab (Duke-NUS Medical School, Singapore)


Finding Antibodies that Neutralize SARS-CoV-2

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Neutralizing Antibodies
Caption: Model of three neutralizing antibodies (blue, purple and orange) bound to the spike protein, which allows SARS-CoV-2 attach to our cells. Credit: Christopher Barnes and Pamela Bjorkman, California Institute of Technology, Pasadena.

It’s now clear that nearly everyone who recovers from coronavirus disease 2019 (COVID-19) produces antibodies that specifically target SARS-CoV-2, the novel coronavirus that causes the infection. Yet many critical questions remain. A major one is: just how well do those particular antibodies neutralize the virus to fight off the infection and help someone recover from COVID-19? Fortunately, most people get better—but should the typical antibody response take the credit?

A new NIH-funded study of nearly 150 people who recovered from COVID-19 offers some essential insight. The study, published in the journal Nature, shows that most people, in fact, do produce antibodies that can effectively neutralize SARS-CoV-2. But there is a catch: 99 percent of the study’s participants didn’t make enough neutralizing antibodies to mount an ideal immune response.

The good news is that when researchers looked at individuals who mounted a strong immune response, they were able to identify three antibodies (depicted above) that were extremely effective at neutralizing SARS-CoV-2. By mass-producing copies of these antibodies as so-called monoclonal antibodies, the researchers can now better evaluate their potential as treatments to help people who don’t make strongly neutralizing antibodies, or not enough of them.

These findings come from a team led by Michel Nussenzweig, Paul Bieniasz, and Charles Rice at The Rockefeller University, New York, and Pamela Bjorkman at the California Institute of Technology, Pasadena. In the Nussenzweig lab, the team has spent years searching for broadly neutralizing antibodies against the human immunodeficiency virus (HIV). In response to the COVID-19 pandemic and its great urgency, Nussenzweig and team shifted their focus recently to look for promising antibodies against SARS-CoV-2.

Antibodies are blood proteins that the immune system makes to neutralize viruses or other foreign invaders. The immune system doesn’t make just one antibody to thwart an invader; it makes a whole family of antibodies. But not all antibodies in that family are created equal. They can vary widely in where they latch onto a virus like SARS-CoV-2, and that determines how effective each will be at blocking it from infecting human cells. That’s one reason why people respond differently to infections such as COVID-19.

In early April, Nussenzweig’s team began analyzing samples from volunteer survivors who visited The Rockefeller Hospital to donate plasma, which contains the antibodies. The volunteers had all recovered from mild-to-severe cases of COVID-19, showing their first signs of illness about 40 days prior to their first plasma collection.

Not surprisingly, all volunteers had produced antibodies in response to the virus. To test the strength of the antibodies, the researchers used a special assay that shows how effective each one is at blocking the virus from infecting human cells in lab dishes.

Overall, most of the plasma samples—118 of 149—showed at best poor to modest neutralizing activity. In about one-third of individuals, their plasma samples had below detectable levels of neutralizing activity. It’s possible those individuals just resolved the infection quickly, before more potent antibodies were produced.

More intriguing to the researchers were the results from two individuals that showed an unusually strong ability to neutralize SARS-CoV-2. Among these two “elite responders” and four other individuals, the researchers identified 40 different antibodies that could neutralize SARS-CoV-2. But again, not all antibodies are created equal. Three neutralized the virus even when present at extremely low levels, and they now will be studied further as possible monoclonal antibodies.

The team determined that those strongly neutralizing antibodies bind three distinct sites on the receptor-binding domain (RBD) of the coronavirus spike protein. This portion of the virus is important because it allows SARS-CoV-2 to bind and infect human cells. Importantly, when the researchers looked more closely at plasma samples with poor neutralizing ability, they found that they also contained those RBD-binding antibodies, just not in very large numbers.

These findings help not only to understand the immune response to COVID-19, they are also critical for vaccine design, revealing what a strong neutralizing antibody for SARS-CoV-2 should look like to help the immune system win. If a candidate vaccine can generate such strongly neutralizing antibodies, researchers will know that they are on the right track.

While this research showed that there’s a lot of variability in immune responses to SARS-CoV-2, it appears that most of us are inherently capable of producing antibodies to neutralize this devastating virus. That brings more reason for hope that the many vaccines now under study to elicit such neutralizing antibodies in sufficient numbers may afford us with much-needed immune protection.

Reference:

[1] Convergent antibody responses to SARS-CoV-2 in convalescent individuals. Robbiani DF, Gaebler C, Muecksch F, et al. Nature. 2020 Jun 18. [Published online ahead of print].

Links:

Coronavirus (COVID-19) (NIH)

Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)

Nussenzweig Lab (The Rockefeller University, New York)

Bjorkman Lab (California Institute of Technology, Pasadena)

NIH Support: National Institute of Allergy and Infectious Diseases


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