Difference between infectivity and cell fusion abillity of Virus. (COVID 19)

Difference between infectivity and cell fusion abillity of Virus. (COVID 19)

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I'm a computational chemist who have interest in COVID-19.

As a physical chemist, I'm lack of basic knowledge for biology.

What is the difference between 'infectivity' and 'membrane fusion activity'?

I thought that, for corona virus, infection is equal to membrane(cell) fusion, but it seems wrong idea.

Thank you for reading!

COVID-19 severity affected by proportion of antibodies targeting crucial viral protein, study finds

A comprehensive study of immune responses to SARS-CoV-2 associates mild disease with comparatively high levels of antibodies that target the viral spike protein. But all antibodies wane within months.

A study co-authored by Scott Boyd found that people with severe COVID-19 have a lower proportion of antibodies targeting the coronavirus's spike protein than of antibodies targeting proteins of the virus’s inner shell.
Steve Fisch

COVID-19 antibodies preferentially target a different part of the virus in mild cases of COVID-19 than they do in severe cases, and wane significantly within several months of infection, according to a new study by researchers at Stanford Medicine.

The findings identify new links between the course of the disease and a patient’s immune response. They also raise concerns about whether people can be re-infected, whether antibody tests to detect prior infection may underestimate the breadth of the pandemic and whether vaccinations may need to be repeated at regular intervals to maintain a protective immune response.

“This is one of the most comprehensive studies to date of the antibody immune response to SARS-CoV-2 in people across the entire spectrum of disease severity, from asymptomatic to fatal,” said Scott Boyd, MD, PhD, associate professor of pathology. “We assessed multiple time points and sample types, and also analyzed levels of viral RNA in patient nasopharyngeal swabs and blood samples. It’s one of the first big-picture looks at this illness.”

The study found that people with severe COVID-19 have a lower proportion of antibodies targeting the spike protein used by the virus to enter human cells than of antibodies targeting proteins of the virus’s inner shell.

Boyd is a senior author of the study, which was published Dec. 7 in Science Immunology. Other senior authors are Benjamin Pinsky, MD, PhD, associate professor of pathology, and Peter Kim, PhD, the Virginia and D. K. Ludwig Professor of Biochemistry. The lead authors are research scientist Katharina Röltgen, PhD postdoctoral scholars Abigail Powell, PhD, and Oliver Wirz, PhD and clinical instructor Bryan Stevens, MD.

Virus binds to ACE2 receptor

The researchers studied 254 people with asymptomatic, mild or severe COVID-19 who were identified either through routine testing or occupational health screening at Stanford Health Care or who came to a Stanford Health Care clinic with symptoms of COVID-19. Of the people with symptoms, 25 were treated as outpatients, 42 were hospitalized outside the intensive care unit and 37 were treated in the intensive care unit. Twenty-five people in the study died of the disease.

SARS-CoV-2 binds to human cells via a structure on its surface called the spike protein. This protein binds to a receptor on human cells called ACE2. The binding allows the virus to enter and infect the cell. Once inside, the virus sheds its outer coat to reveal an inner shell encasing its genetic material. Soon, the virus co-opts the cell’s protein-making machinery to churn out more viral particles, which are then released to infect other cells.

Antibodies that recognize and bind to the spike protein block its ability to bind to ACE2, preventing the virus from infecting the cells, whereas antibodies that recognize other viral components are unlikely to prevent viral spread. Current vaccine candidates use portions of the spike protein to stimulate an immune response.

Boyd and his colleagues analyzed the levels of three types of antibodies — IgG, IgM and IgA — and the proportions that targeted the viral spike protein or the virus’s inner shell as the disease progressed and patients either recovered or grew sicker. They also measured the levels of viral genetic material in nasopharyngeal samples and blood from the patients. Finally, they assessed the effectiveness of the antibodies in preventing the spike protein from binding to ACE2 in a laboratory dish.

“Although previous studies have assessed the overall antibody response to infection, we compared the viral proteins targeted by these antibodies,” Boyd said. “We found that the severity of the illness correlates with the ratio of antibodies recognizing domains of the spike protein compared with other nonprotective viral targets. Those people with mild illness tended to have a higher proportion of anti-spike antibodies, and those who died from their disease had more antibodies that recognized other parts of the virus.”

Substantial variability in immune response

The researchers caution, however, that although the study identified trends among a group of patients, there is still substantial variability in the immune response mounted by individual patients, particularly those with severe disease.

“Antibody responses are not likely to be the sole determinant of someone’s outcome,” Boyd said. “Among people with severe disease, some die and some recover. Some of these patients mount a vigorous immune response, and others have a more moderate response. So, there are a lot of other things going on. There are also other branches of the immune system involved. It’s important to note that our results identify correlations but don’t prove causation.”

As in other studies, the researchers found that people with asymptomatic and mild illness had lower levels of antibodies overall than did those with severe disease. After recovery, the levels of IgM and IgA decreased steadily to low or undetectable levels in most patients over a period of about one to four months after symptom onset or estimated infection date, and IgG levels dropped significantly.

“This is quite consistent with what has been seen with other coronaviruses that regularly circulate in our communities to cause the common cold,” Boyd said. “It’s not uncommon for someone to get re-infected within a year or sometimes sooner. It remains to be seen whether the immune response to SARS-CoV-2 vaccination is stronger, or persists longer, than that caused by natural infection. It’s quite possible it could be better. But there are a lot of questions that still need to be answered.”

Boyd is a co-chair of the National Cancer Institute’s SeroNet Serological Sciences Network, one of the nation’s largest coordinated research efforts to study the immune response to COVID-19. He is the principal investigator of Center of Excellence in SeroNet at Stanford, which is tackling critical questions about the mechanisms and duration of immunity to SARS-CoV-2.

“For example, if someone has already been infected, should they get the vaccine? If so, how should they be prioritized?” Boyd said. “How can we adapt seroprevalence studies in vaccinated populations? How will immunity from vaccination differ from that caused by natural infection? And how long might a vaccine be protective? These are all very interesting, important questions.”

Other Stanford co-authors of the study are visiting pathology instructor Catherine Hogan, MD postdoctoral scholars Javaria Najeeb, PhD, and Ana Otrelo-Cardoso, PhD medical resident Hannah Wang, MD research scientist Malaya Sahoo, PhD research professional ChunHong Huang, PhD research scientist Fumiko Yamamoto laboratory director Monali Manohar, PhD senior clinical laboratory scientist Justin Manalac Tho Pham, MD, clinical assistant professor of pathology medical fellow Arjun Rustagi, MD, PhD Angela Rogers, MD, assistant professor of medicine Nigam Shah, PhD, professor of medicine Catherine Blish, MD, PhD, associate professor of medicine Jennifer Cochran, PhD, chair and professor of bioengineering Theodore Jardetzky, PhD, professor of structural biology James Zehnder, MD, professor of pathology and of medicine Taia Wang, MD, PhD, assistant professor of medicine and of microbiology and immunology senior research scientist Balasubramanian Narasimhan, PhD pathology instructor Saurabh Gombar, MD, PhD Robert Tibshirani, PhD, professor of biomedical data science and of statistics and Kari Nadeau, MD, PhD, professor of medicine and of pediatrics.

The study was supported by the National Institutes of Health (grants RO1AI127877, RO1AI130398, 1U54CA260517, T32AI007502-23, U19AI111825 and UL1TR003142), the Crown Family Foundation, the Stanford Maternal and Child Health Research Institute, the Swiss National Science Foundation, and a Coulter COVID-19 Rapid Response award.

Boyd, Röltgen, Kim and Powell have filed provisional patent applications related to serological tests for SARS-CoV-2 antibodies.

What Are COVID-19's Infectivity and Viral Load?

Why are basic questions about the biology of SARS-CoV-2 so hard to answer?

As the COVID-19 pandemic spreads, it has become clear that people need to understand basic facts about SARS-CoV-2, the virus that causes COVID-19, to make informed health care and public policy decisions. Two basic virological concepts have gotten a lot of attention recently – the “infectious dose” and the “viral load” of SARS-CoV-2.

As influenza virologists, these are concepts that we often think about when studying respiratory virus infections and transmission.

What is an ‘infectious dose’?

The infectious dose is the amount of virus needed to establish an infection. Depending on the virus, people need to be exposed to as little as 10 virus particles – for example, for influenza viruses – or as many as thousands for other human viruses to get infected.

Scientists do not know how many virus particles of SARS-CoV-2 are needed to trigger infection. COVID-19 is clearly very contagious, but this may be because few particles are needed for infection (the infectious dose is low), or because infected people release a lot of virus in their environment.

What is the ‘viral load’?

The viral load is the amount of a specific virus in a test sample taken from a patient. For COVID-19, that means how many viral genomes are detected in a nasopharyngeal swab from the patient. The viral load reflects how well a virus is replicating in an infected person. A high viral load for SARS-CoV2 detected in a patient swab means a large number of coronavirus particles are present in the patient.

Is a high viral load linked to higher risk of severe pneumonia or death?

Intuitively it might make sense to say the more virus, the worse the disease. But in reality the situation is more complicated.

In the case of the original SARS or influenza, whether a person develops mild symptoms or pneumonia depends not only on how much virus is in their lungs, but also on their immune response and their overall health.

Right now it is unclear whether the SARS-CoV-2 viral load can tell us who will get severe pneumonia. Two studies in The Lancet reported people who develop more severe pneumonia tend to have, on average, higher viral loads when they are first admitted to the hospital.

These studies also reported that the viral loads remain higher for more days in patients with more severe disease. However, the difference was not dramatic, and people with similar viral loads went on to develop both mild and severe disease.

Complicating the picture further, other studies found that some asymptomatic patients had similar viral loads to patients with COVID-19 symptoms. This means that the viral load alone is not a clear predictor of disease outcome.

Another common question is whether getting a higher virus dose upon infection – for example, through prolonged exposure to an infected person, like health care workers’ experience – will result in more severe disease. Right now, we simply do not know whether this is the case.

Does high viral load increase ability to pass the virus to others?

In general, the more virus you have in your airways, the more you will release when you exhale or cough, although there is a lot of person-to-person variation. Multiple studies have reported that patients have the highest viral load of the coronavirus at the time they are diagnosed.

This means that patients transmit COVID-19 more effectively at the beginning of their illness, or even before they know they are sick. This is bad news. It means people who look and feel healthy can transmit the virus to others.

Why is it hard to answer basic questions about virus amounts for SARS-CoV-2?

Normally, researchers like us determine the characteristics of a virus from a combination of highly controlled experimental studies in animal models and epidemiological observations from patients.

But since SARS-CoV-2 is a new virus, the research community is only just beginning to do controlled experiments. Therefore, all the information we have comes from observing patients who were all infected in different ways, have different underlying health conditions, and are of different ages and both sexes. This diversity makes it difficult to make strong conclusions that will apply to everyone from only observational data.

Where does the uncertainty on viral loads and infectious dose leave us?

Studying viral loads and the infectious dose will likely be important to make better decisions for health care providers. For the rest of us, regardless of the viral load of patients or the SARS-CoV-2 infectious dose, it is best to reduce exposure to any amount of virus, since it is clear the virus is transmitted efficiently from person to person.

Current social distancing practices and limited contact with groups of people in enclosed spaces will reduce the transmission of SARS-CoV-2. In addition, the use of face masks will reduce the amount of virus released from presymptomatic and asymptomatic individuals. So stay home and stay safe.

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This article is republished from The Conversation under a Creative Commons license. Read the original article.

COVID-19 coronavirus spike holds infectivity details

Several new findings on how the virus’ cell entry tools operate could expedite the design of vaccines, antibodies, antivirals and other therapeutics.

The spikes crowning the new coronavirus that causes COVID-19 atypical pneumonia are divulging how they attach, fuse and gain entry to cells. Analysis of the spike architecture and its mechanics is locating the virus’ vulnerabilities, and revealing other information that could prompt the discovery of countermeasures against this virus.

A research team at the University of Washington School of Medicine and Fred Hutchinson Cancer Research Institute uses cryo-electron microscopy and other investigative methods in this effort. They are helping to determine the structure and function of the SARS-CoV-2 spike protein and its chemical binding affinities as these relate to both infection and immune responses, and thereby obtain ideas for blocking the virus’ ingress to cells.

Their multiple findings were published as a preliminary report Feb.20 in bioRxiv, a preprint server for biology. The lead authors are Alexandra C. “Lexi” Walls, a recent postdoctoral fellow, and Young-Jun Park, a research scientist. Both conduct coronavirus studies in the lab of David Veesler, senior author of the report and assistant professor of biochemistry at the UW School of Medicine.

“The spike is the business part as far as viral entry is concerned,” Veesler explained. “It is in charge not only of attachment at the host cell surface, but also of fusing the viral and host cell membranes to allow the infection to start. The spike is also the main target of neutralizing antibodies, so it’s very important for vaccine and therapeutic design.”

While the Seattle researchers have been tirelessly examining the spike structure and function of new coronavirus since shortly after the disease outbreak, over the past several years they have performed similar spike studies of other serious coronaviruses, including the types that cause the diseases SARS (Severe Acute Respiratory Syndrome) and MERS (Middle East Respiratory Syndrome). They also study attachment and fusion proteins in the bat-harbored Hendra and Nipah henipaviruses.

One finding in their recent research was the detection of cross-neutralizing antibodies that inhibit the cellular fusion by SARS-CoV and SARS-CoV-2, and that these antibodies might be elicited by vaccination.

“The fact that antibodies elicited by the spike proteins in related SARS coronaviruses also neutralized infection with this new one is an important step forward to find antibodies and design vaccines that could block this group of coronaviruses,” Veesler said. These could provide broad protection against several SARS-CoV-like pathogens.

His group also showed that the cell surface receptor, angiotensin converting enzyme 2 (ACE2), is recognized by the new coronavirus and serves as the access point into human cells. This is also the receptor for SARS-CoV. The research results are in agreement with some similar, recently reported findings by other scientific teams demonstrating human ACE2 is a functional receptor for the new virus.

Previous work suggested that spike protein adaptation that causes a high affinity for human ACE2 receptors may be related to the severity of SARS-like coronavirus disease. The team showed that SARS-CoV-2 binds at least as well as SARS-CoV to ACE2. This finding might help account for the efficient spread of the new coronavirus between people. As with several other coronaviruses, the new virus probably originated in an animal which remains its reservoir, most likely a species of bat. Then, possibly through a different intermediary animal species, the virus jumped to humans, and became able to be transmitted between people. The exact origin of the new coronavirus disease has not yet been firmly established.

By closely examining the structure of the new coronavirus spike protein, the researchers did uncover something that sets it apart from the other SARS-related coronaviruses. Walls said that the research team unexpectedly found a furin cleavage site at a boundary between two subunits of the spike protein in the newly emerged coronavirus. It is not yet known if this difference is expanding the kinds of cells the new coronavirus could infect or enhancing its transmissibility, in a way that might be similar to that of highly pathogenic avian flu viruses.

As a whole, details contained in the results reported in this week’s paper may help to explain the efficiency of the new coronavirus in delivering its viral code into human cells, and its rapid transmission among people.

Coronavirus structure researcher Lexi Walls in a biochemistry lab.

At present, there are no preventatives or approved, specific treatments (aside from experimental therapies) that can be directed at the new coronavirus.

“Our ultimate goal would be if our work could contribute as a step towards a vaccine, antiviral or any sort of therapy that currently does not yet exist,” Walls said, and added that it would be fantastic if her team’s scientific efforts could be a step towards being helpful to people in that way.

Veesler described Walls and Park and others on the team as “amazing scientists who have been working almost 24 hours a day in the lab over the past month to obtain these amazing results” to contribute to advancing the field of coronavirus research and to addressing the current public health emergency .

Parks acknowledged that the hours have been long, but that didn’t matter because he is motivated in the lab by what patients in the midst of the epidemic have had to face.

“This is what we and other labs are doing to combat this virus, and the emergence and spread of future coronaviruses that might happen, as might be the case for other viruses found in wildlife. We should just work to be prepared for it,” Veesler said.

This study was supported by the National Institutes of General Medical Sciences (R01GM120553), National Institutes of Allergy and Infectious Diseases (HHSN272201700059C), a Pew Biomedical Scholars Award, and Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund, the Open Philanthropic Foundation, and the Pasteur Institute.

The researchers declared that they have no competing financial interests.

Study identifies genetic changes likely to have enabled SARS-CoV-2 to jump from bats to humans

Horseshoe bats. Credit: orientalizing on Flickr

A new study, involving the University of Cambridge and led by the Pirbright Institute, has identified key genetic changes in SARS-CoV-2—the virus that causes COVID-19—that may be responsible for the jump from bats to humans, and established which animals have cellular receptors that allow the virus to enter their cells most effectively.

The genetic adaptions identified were similar to those made by SARS-CoV—which caused the 2002-2003 SARS epidemic—when it adapted from bats to infect humans. This suggests that there may be a common mechanism by which this family of viruses mutates in order to jump from animals to humans. This understanding can be used in future research to identify viruses circulating in animals that could adapt to infect humans (known as zoonoses) and which potentially pose a pandemic threat.

"This study used a non-infectious, safe platform to probe how spike protein changes affect virus entry into the cells of different wild, livestock and companion animals, something we will need to continue monitoring closely as additional SARS-CoV-2 variants arise in the coming months," said Dr. Stephen Graham in the University of Cambridge's Department of Pathology, who was involved in the study.

In the 2002-2003 SARS epidemic, scientists were able to identify closely related isolates in both bats and civets—in which the virus is thought to have adapted to infect humans. However, in the current COVID-19 outbreak scientists do not yet know the identity of the intermediate host or have similar samples to analyze. But they do have the sequence of a related bat coronavirus called RaTG13 which shares 96 percent similarity to the SARS-CoV-2 genome. The new study compared the spike proteins of both viruses and identified several important differences.

SARS-CoV-2 and other coronaviruses use their spike proteins to gain entry to cells by binding to their surface receptors, for example ACE2. Like a lock and key, the spike protein must be the right shape to fit the cell's receptors, but each animal's receptors have a slightly different shape, which means the spike protein binds to some better than others.

To examine whether these differences between SARS-CoV-2 and RaTG13 were involved in the adaptation of SARS-CoV-2 to humans, scientists swapped these regions and examined how well these resulting spike proteins bound human ACE2 receptors—using a method that does not involve using live virus.

The results, published in the journal PLOS Biology, showed SARS-CoV-2 spikes containing RaTG13 regions were unable to bind to human ACE2 receptors effectively, while the RaTG13 spikes containing SARS-CoV-2 regions could bind more efficiently to human receptors—although not to the same level as the unedited SARS-CoV-2 spike protein. This potentially indicates that similar changes in the SARS-CoV-2 spike protein occurred historically, which may have played a key role in allowing the virus to jump the species barrier.

Researchers also investigated whether the SARS-CoV-2 spike protein could bind to the ACE2 receptors from 22 different animals to ascertain which of these, if any, may be susceptible to infection. They demonstrated that bat and bird receptors made the weakest interactions with SARS-CoV-2. The lack of binding to bat receptors adds weight to the evidence that SARS-CoV-2 likely adapted its spike protein when it jumped from bats into people, possibly via an intermediate host.

Dog, cat, and cattle ACE2 receptors were identified as the strongest interactors with the SARS-CoV-2 spike protein. Efficient entry into cells could mean that infection may be more easily established in these animals, although receptor binding is only the first step in viral transmission between different animal species.

"As we saw with the outbreaks in Danish mink farms last year, it's essential to understand which animals can be infected by SARS-CoV-2 and how mutations in the viral spike protein change its ability to infect different species," said Graham.

An animal's susceptibility to infection and its subsequent ability to infect others is reliant on a range of factors—including whether SARS-CoV-2 is able to replicate once inside cells, and the animal's ability to fight off the virus. Further studies are needed to understand whether livestock and companion animals could be receptive to COVID-19 infection from humans and act as reservoirs for this disease.

Natural Selection

Nature selects among a variety of individuals based on their ability to survive and reproduce — whether that's prey that evade predators or viruses that escape an immune system. That selective pressure from the environment is what can force a population of organisms to adapt, driving evolution by natural selection.

Several studies have tracked the evolution of SARS-CoV-2 variants in chronically-infected people. In such cases, researchers took samples from each patient and read the sequences in the viral gene pool to detect the presence of new mutants as they emerged. Through repeated sampling and sequencing, the scientists have identified variants that would provide the raw material for natural selection.

One study, led by Adam Lauring from the University of Michigan in Ann Arbor, described the case of a 60-year-old man with a history of lymphoma — cancer of the lymph nodes, which prevents the immune system's B-cells making antibodies.

Over four months, the immunocompromized patient was in-and-out of hospital three times due to Coronavirus Disease, and that prolonged infection enabled a steady accumulation of mutations. Nine mutations became prevalent (or 'fixed') in the viral population between days 93 and 106.

The fact that the man was repeatedly readmitted put other patients at risk of Covid as he would have continued to shed virus particles. As the Michigan study concluded, "This case highlights challenges in managing immunocompromized hosts, who may act as persistent shedders and sources of transmission."

Another study, led by Ravindra Gupta at Cambridge University, tracked SARS-CoV-2 evolution during treatment of an immunosuppressed man in his 70s. The patient's viral gene pool was sequenced 23 times over 101 days, so the fate of mutations could be followed in detail. He was treated with remdesivir (not effective) and convalescent plasma containing antibodies from someone who recovered from Covid.

Convalescent therapy led to the emergence of a variant with the D796H mutation and a deletion of two amino acids — ΔH69/ΔV70 — in the spike protein, which is what coronaviruses use to break into a cell. According to the study, that mutant became the dominant variant following competition among the patient's variants — evolution by natural selection.

The Cambridge study also used artificial viruses to show that the D796H mutation made spike proteins less susceptible to being neutralized by a matching antibody but also less effective at invading cells, whereas the ΔH69/ΔV70 deletion seemed to compensate by restoring the virus' ability to bind a cell's surface.

Interestingly, ΔH69/ΔV70 has also been deleted in the B.1.1.7 variant, which seems to have 50-70% higher transmissibility compared to the wild-type virus. So, as in the immunosuppressed patient, the deletion might have been favored by natural selection because it made the variant become more infectious and spread.

Based on a study led by Tanya Golubchik of Oxford University, the good news is that mutations that might help Coronavirus appear very rarely. According to the research, which used sequencing to measure genetic diversity across 1313 British people, most people carried distinct variants — but only one or two per person.

The Oxford study also examined transmission between people who come into regular contact — in the same household — and found that most variants are lost before they spread. That result suggests the vast majority of potentially dangerous new mutations are evolutionary dead-ends that are destroyed by the immune system.

The environment inside you — the human body — can be too harsh for Coronavirus.

COVID-19 is Mutating and A Scripps Research Study Reveals the Coronavirus May Become Even More Infectious

While the COVID-19 pandemic continues to spread across the United States and throughout the world, new research suggests that a coming genetic mutation within the SARS-CoV-2 coronavirus may make it much more dangerous than it already is. This finding has significant implications for clinical laboratories that perform COVID-19 testing and the in vitro diagnostics (IVD) companies that develop and manufacture tests for COVID-19.

The mutation, called D614G, will provide the coronavirus with sturdier spikes that will increase its ability to latch onto and infect cells. That’s according to a study conducted at The Scripps Research Institute (Scripps) in Jupiter, Fla., which found that a mutated coronavirus may be up to 10 times more infectious than the original strain.

“Viruses with this mutation were much more infectious than those without the mutation in the cell culture system we used,” said Hyeryun Choe, PhD, Professor, Department of Immunology and Microbiology, Scripps Research, and senior author of the study, in a Scripps news release.

Choe and Michael Farzan, PhD, co-chair and professor in the Department of Immunology at Scripps Research, co-authored the study, titled, “The D614G Mutation in the SARS-Cov-2 Spike Protein Reduces S1 Shedding and Increases Infectivity.” Their work is currently under peer review and can be downloaded on bioRxiv.

A More Flexible and Potent Coronavirus May Be Coming

The researchers found that coronavirus particles containing the mutation tend to have four to five times more functional spikes than particles without the mutation. The spikes enable the virus to bind to cells more easily. The research suggests that the greater the number of functional spikes on the viral surface the greater the flexibility and potency of the coronavirus.

In the Scripps news release, Farzan said, “more flexible spikes allow newly made viral particles to navigate the journey from producer cell to target cell fully intact, with less tendency to fall apart prematurely.

“Over time, it has figured out how to hold on better and not fall apart until it needs to,” he added. “The virus has, under selection pressure, made itself more stable.”

The image above, taken from the Scripps Research news release, shows “a cryogenic electron microscope image of a SARS-CoV-2 spike protein side view, the S1 section of the spike is shown in green and the S2 portion is shown in purple. This unique two-piece system has shown itself to be relatively unstable. A new mutation has appeared in the viral variant most common in New York and Italy that makes this spike both more stable and better able to infect cells.” (Graphic and caption copyright: Andrew Ward lab, Scripps Research.)

Mutation Makes SARS-CoV-2 Coronavirus ‘Much More Stable’

The two Scripps scientists have studied coronaviruses for nearly 20 years and performed extensive research on the Severe Acute Respiratory Syndrome (SARS) outbreak that occurred in 2003. They noted that there is a difference between spike proteins of SARS, an earlier strain of coronavirus, and the new SARS-CoV-2 strain.

The protein spikes of both strains were originally tripod shaped. However, the spikes of the SARS-CoV-2 coronavirus are divided into two different segments: S1 and S2. According to the published study: “The S1domain mediates receptor binding, and the S2 mediates downstream membrane fusion.”

This feature originally produced unstable spikes, but with the D614G mutation, the tripod breaks less frequently, which makes more of the spikes fully functional and the virus more infectious.

“Our data are very clear, the virus becomes much more stable with the mutation,” Choe said in the news release.

Is COVID-19 Spread Due to ‘Founder Effect’

The scientists also examined whether the spread of COVID-19 could have been the result of the “Founder Effect,” which is seen when a small number of variants fan out into a wide population by chance. Could the founder effect explain why COVID-19 outbreaks in some areas of the world were more severe than others? The researchers believe their data definitively answered that question.

“There have been at least a dozen scientific papers talking about the predominance of this mutation,” Farzan said. “Are we just seeing a founder effect? Our data nails it. It is not the founder effect.”

Hyeryun Choe, PhD (left), and Michael Farzan, PhD (right), scientists at Scripps Research explained that their research was performed using engineered viruses and that their observations of the virus and its mutation may not translate to increased transmissibility when a virus attaches to a host outside the lab. COVID-19 and its mutation appear to be relatively stable and are mutating at a rate slower than that of the seasonal flu, which may be critical factors in the development of a vaccine. (Photos copyright: Scripps Research.)

Findings Raise ‘Interesting’ Questions about the COVID-19 Coronavirus

Nevertheless, the two scientists are curious about some of their findings. “Our data raise interesting questions about the natural history of SARS-CoV-2 as it moved presumably from horseshoe bats to humans. At some point in this process, the virus acquired a furin-cleavage site, allowing its S1/S2 boundary to be cleaved in virus-producing cells. In contrast, the S1/S2 boundary of SARS-CoV-1, and indeed all SARS-like viruses isolated from bats, lack this polybasic site and are cleaved by TMPRSS2 or endosomal cathepsins in the target cells.

“In summary, we show that an S protein mutation that results in more transmissible SARS-CoV-2 also limits shedding of the S1 domain and increases S-protein incorporation into the virion. Further studies will be necessary to determine the impact of this change on the nature and severity of COVID-19,” the Scripps researchers concluded.

However, not all Scripps researchers agreed with the conclusions of Choe and Farzan’s research.

The Times of Israel reported that Kristian Andersen, PhD, a professor in the Department of Immunology and Microbiology, Scripps California Campus, told the New York Times that “other analyses of virus variants in labs had not found significant differences in infection rates.”

“That’s the main reason that I’m so hesitant at the moment,” Andersen said. “Because if one really was able to spread significantly better than the other, then we would expect to see a difference here, and we don’t.”

Times of Israel also reported that “In late May researchers in University College London said their studies of the genomes of more than 15,000 samples had not shown one strain being more infectious than others.”

So, the jury’s out. Nonetheless, clinical laboratory leaders will want to remain vigilant. A sudden increase in COVID-19 infection rates will put severe strain on already strained laboratory supply chains.

Somatic hypermutation

A key difference between the mutation of antibodies and viruses is that mutations in antibodies are not entirely random. They are, in fact, directly caused by an enzyme that is only found in B cells, known as Aid (activation-induced deaminase). This enzyme deliberately causes mutations in the DNA responsible for making the part of the antibody that can recognise the virus. This mutation mechanism was solved by pioneering researchers at the MRC Laboratory of Molecular Biology in Cambridge, UK, almost 20 years ago.

AID activity leads to a much higher rate of mutation in B cells than in any other cell in the body. This phenomenon is called “somatic hypermutation”.

Some of the mutations that are induced in the antibody binding site will improve the binding of that antibody to the target virus. But some mutations will have no effect, and others will actually decrease the antibody’s ability to latch onto the target virus. This means there needs to be a system whereby B cells making the best antibodies will be selected.

B cells congregate in small glands called lymph nodes while they are developing. Lymph nodes are found all around the body and often get bigger if you are fighting an infection.

B cells gather in lymph nodes while they are developing. Sakurra/Shutterstock

Within the lymph nodes, the B cells that can make better antibodies after somatic hypermutation are given positive signals to make them replicate faster. Other B cells fall by the wayside and die. This “survival-of-the-fittest” process is called affinity maturation the strength or “affinity” with which antibodies bind to their target matures and improves over time. After this rigorous selection, the newly emerged B cell will now mass produce its improved antibody, leading to a more effective immune response.

The course of a typical COVID infection is ten to 14 days, so the first wave of antibodies driving out the virus doesn’t have long enough to evolve because affinity maturation normally takes place over weeks. But research from the US has shown that small non-infectious bits of SARS-CoV-2 remain in the body after an infection is cleared, so B cells can keep being reminded of what the virus looks like. This allows antibody evolution to continue for months after an infection has been resolved.

Overall, antibody evolution means that if a person is infected with coronavirus for a second time, antibodies with far superior binding ability will be ready and waiting. This has important implications for vaccination. Antibody evolution will begin after the first vaccination so that much-improved antibodies will be present if the virus is encountered at a later date. Hopefully, it is comforting to know that it is not just the virus that is mutating, our own antibodies are keeping pace.

Sarah L Caddy, Clinical Research Fellow in Viral Immunology and Veterinary Surgeon, University of Cambridge and Meng Wang, Cancer Research UK Clinician Scientist Fellow, University of Cambridge

This article is republished from The Conversation under a Creative Commons license. Read the original article.

The importance of SARS-CoV-2 neutralizing antibodies

The presence of neutralizing antibodies in our bodies has been shown to correlate with protection from viral infection. Hence, these molecules play an important role in SARS-CoV-2 vaccine and treatment research and development.

Most of the SARS-CoV-2 vaccines in use or under investigation aim to produce neutralizing antibodies specific for the spike protein on the outside of the virus particles. The spike protein facilitates fusion between the virus and our cell membranes and allows viral material to enter the cell.

Neutralizing antibodies against the spike protein can prevent the interaction between the virus and our cells and help eliminate an infection during its early stages. Thus, measuring the abundance of these antibodies is one of the key parameters for evaluating potential SARS-CoV-2 vaccines.

“Scientists are racing to develop vaccines that induce neutralizing antibodies against the SARS-CoV-2 spike protein,” explained Xu. “This approach has been used with many successful viral vaccines, and there’s hope that it will provide long-lasting protection here, too.”

Specific neutralizing antibody-based therapies are also being used to treat people already infected with the virus, and so far, these are showing great promise in reducing hospitalizations and death.

Neutralizing antibodies are important to a variety of SARS-CoV-2 research applications as well. Their abundance can indicate the potential therapeutic quality of plasma donated by previously infected individuals, and they can reveal how many people in a population have already been infected.

Neutralizing antibodies can further our understanding of SARS-CoV-2 infection in pets, livestock, and other animals, allowing us to act smartly to protect both ourselves and the animals.

And neutralizing antibodies might also play an important role in determining an individual’s basal immunity following vaccination or infection.

We just don’t know yet how long the protective effect from a vaccine or infection lasts,” said Xu. “If the protection fades over time, or if we need to show immunity passports for travel, measuring basal immunity will become very important.”

Researchers reveal genetic predisposition to severe COVID-19

The risk score suggested by the researchers (vertical axis) is considerably higher in the group of patients suffering severe COVID-19 (sample of patients from Moscow) Credit: S.Nersisyan et al.

HSE University researchers have become the first in the world to discover genetic predisposition to severe COVID-19. The results of the study were published in the journal Frontiers in Immunology.

T-cell immunity is one of the key mechanisms used by the human body to fight virus infections. The staging ground for cell immunity development is the presentation of virus peptides on the surface of infected cells. This is followed by activation of T lymphocytes, which start to kill the infected cells. The ability to successfully present virus peptides is largely determined by genetics. In human cells, human leukocyte antigen class I (HLA-I) molecules are responsible for this presentation. The set of six such molecules is unique in every human and is inherited from an individual's parents. In simple terms, if the set of alleles detects the virus well, then the immune cells will detect and destroy the infected cells fast if a person has a set that is bad at such detection, a more severe case of disease is more likely to occur.

Researchers from the HSE Faculty of Biology and Biotechnology—Maxim Shkurnikov, Stepan Nersisyan, Alexei Galatenko and Alexander Tonevitsky—together with colleagues from Pirogov Russian National Research Medical University and Filatov City Clinical Hospital (Tatjana Jankevic, Ivan Gordeev, Valery Vechorko) studied the interconnection between HLA-I genotype and the severity of COVID-19.

Risk score in a sample of patients from Spain. Credit: S.Nersisyan et al.

Using machine learning, they built a model that provides an integral assessment of the possible power of T-cell immune response to COVID-19: if the set of HLA-I alleles allows for effective presentation of the SARS-CoV-2 virus peptides, those individuals received low risk score, while people with lower presentation capability received higher risk scores (in the range from 0 to 100). To validate the model, genotypes of over 100 patients who had suffered from COVID-19 and over 400 healthy people (the control group) were analyzed. It turned out that the modeled risk score is highly effective in predicting the severity of COVID-19.

In addition to analyzing the Moscow population, the researchers used their model on a sample of patients from Madrid, Spain. The high precision of prediction was confirmed on this independent sample as well: the risk score of patients suffering severe COVID-19 was significantly higher than in patients with moderate and mild cases of the disease.

"In addition to the discovered correlations between the genotype and COVID-19 severity, the suggested approach also helps to evaluate how a certain COVID-19 mutation can affect the development of T-cell immunity to the virus. For example, we will be able to detect groups of patients for whom infection with new strains of SARS-CoV-2 can lead to more severe forms of the disease," Alexander Tonevitsky said.