Differing immune responses discovered in asymptomatic cases versus those with severe COVID-19


The largest study of its type in the UK has identified differences in the immune response to COVID-19 between people with no symptoms and those suffering a more serious reaction to the virus.

Researchers from the Wellcome Sanger Institute, Newcastle University, University College London, University of Cambridge, EMBL’s European Bioinformatics Institute (EMBL-EBI) and their collaborators within the Human Cell Atlas initiative, found raised levels of specific immune cells in asymptomatic people. They also showed people with more serious symptoms had lost these protective cell types, but gained inflammatory cells. These differences in the immune response could help explain serious lung inflammation and blood clotting symptoms, and could be used to identify potential targets for developing therapies.

The research, published today (20th April 2021) in Nature Medicine, is one of the only studies to include people who were asymptomatic. This large-scale collaborative study is part of the Human Cell Atlas initiative to map every cell type in the human body, to transform our understanding of health, infection and disease.

So far, the COVID-19 global pandemic has caused millions of deaths and many more infections worldwide. Symptoms vary widely in severity and can range from a mild cough to severe respiratory distress, blood clots and organ failure. Several previous studies have highlighted a complex immune response in the blood, but until now the full coordinated immune response and how this differs between symptomatic and asymptotic patients had not been investigated in detail.

In a new study to understand how different immune cells responded to the infection, a large team of researchers came together to analyze blood from 130 people with COVID-19. These patients came from three different UK centers (Newcastle, Cambridge and London) and ranged from asymptomatic to critically severe.

The team performed single-cell sequencing from ~800,000 individual immune cells, along with detailed analysis of cell surface proteins and antigen receptors found on immune cells in the blood. They revealed differences in multiple types of immune cells that are involved in the body’s response to COVID-19.

In those with no symptoms, the team found increased levels of B cells that produce antibodies that are found in mucus passages, such as the nose. These antibodies may be one of our first line of defense in COVID-19. However, these protective B cells were missing in people with serious symptoms, indicating the importance of an effective antibody-associated immune response at the nose and other mucus passages.

The team discovered that whereas patients with mild to moderate symptoms, had high levels of B cells and helper T-cells, which help fight infection, those with serious symptoms had lost many of these immune cells, suggesting that this part of the immune system had failed in people with severe disease.

In contrast, people with more serious symptoms leading to hospitalization had an uncontrolled increase in monocytes and killer T-cells, high levels of which can lead to lung inflammation. Those with severe disease also had raised levels of platelet-producing cells, which help blood to clot.

Professor Muzlifah Haniffa, senior author from Newcastle University and Senior Clinical Fellow at the Wellcome Sanger Institute, said: “This is one of the only studies of its kind that looks at samples collected from asymptomatic people, which helps us start to understand why some people react differently to COVID-19 infection. It could also explain symptoms such as lung inflammation and blood clots. The immune system is made up of lots of different groups of cells, similar to the way an orchestra is made up of different groups of instruments, and in order to understand the coordinated immune response, you have to look at these immune cells together.”

While it is not yet understood how the infection stimulates these immune responses, the study gives a molecular explanation for how COVID-19 could cause an increased risk of blood clotting and inflammation in the lungs, which can lead to the patient needing a ventilator. This also uncovers potential new therapeutic targets to help protect patients against inflammation and severe disease. For example, it may be possible to develop treatments that decrease platelet production or reduce the number of killer T-cells produced, however more research is required.

Professor Menna Clatworthy, senior author and Professor of Translational Immunology at the University of Cambridge and Wellcome Sanger Institute Associate Faculty, said: “This is one of the most detailed studies of immune responses in COVID-19 to date, and begins to help us understand why some people get really sick while others fight off the virus without even knowing they have it. This new knowledge will help identify specific targets for therapy for patients that get sick with COVID-19.”

In the future, research may identify those who are more likely to experience moderate to severe disease by looking at levels of these immune cells in their blood.

This study used samples from three centers in the UK, and found that some antibody responses were similar in individuals in one geographic area compared with those at a different center, hinting that this part of the immune response may be tailored to different variants of the virus.

Dr. John Marioni, senior author and head of research at EMBL’s European Bioinformatics Institute (EMBL-EBI) and Senior Group Leader at the Cancer Research UK Cambridge Institute, said: “Using data from three different centers has allowed us to look at how people react to COVID-19 throughout the UK. The amount of data collected in this study has given us crucial insight into the immune reaction in various different severities of COVID-19 infection.”

Professor Berthold Göttgens, senior author and professor of molecular hematology at the University of Cambridge, said: “Along with the findings, the way this study was conducted is noteworthy, as it was a new way of doing biomedical science. By bringing different experts together, we were able to employ a divide and conquer approach, which allowed us to complete the work in extra quick time. This study required a large teamwork effort, in the middle of the pandemic when labs were being shut down. This was an incredibly rewarding study to work on, with everyone understanding the importance of the work and willing to go the extra mile.”

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New defense against viral lung infections discovered

New defense against viral lung infections discovered

Researchers have uncovered a previously unknown arm of the immune defense system that protects the lung from lethal viral infections.

Respiratory diseases caused by viruses such as influenza A and SARS-CoV-2 cause damage not just through their own actions, but also from collateral damage as the immune system reacts to fight the infection.

A timely and proportionate response identifies viruses, isolating them in tiny vesicles called phagosomes that are then targeted for breakdown. This processalso triggers production of cytokines to alert the immune system.

Cytokine responses represent a fine balancing act that can sometimes tip over to an excessive state known as the cytokine storm. This has serious consequences for viral lung infections, as it leads to inflammation, fluid building up in the lungs and eventually death.

Given the impact of respiratory conditions, brought into sharp focus by the COVID-19 pandemic, there’s a clear need to fully understand the complexities of this immune response to develop better treatments or targets for drugs that can protect against infections taking hold.

To address this teams from the Quadram Institute and universities of Liverpool, East Anglia (UEA), and Bristol have worked together to studythe immune response to influenza A virus infection in the lungs of mice. Animal models provide a way of understanding how the immune system works, and as with SARS-CoV-2, animals may be a significant reservoir for viruses that, if transferred to humans, can trigger pandemics.

Funded by the Biotechnology and Biological Sciences Research Council, they focussed on a recently characterized form of non-canonical autophagy called LC3-associated phagocytosis (LAP) that recognizes pathogens as they enter cells.

Professor Tom Wileman at the Quadram Institute has worked with Dr. Penny Powell and Professor Ulrike Mayer at UEA to develop a LAP-deficient mouse to study viral infection. Unique to this study, the mice were designed to retain the normal autophagy machinery, and target LAP within immune cells, so are the best available option for understanding the precise role of this newly uncovered immune defense.

Prof James Stewart at the University of Liverpool characterized the function of LAP by infecting the transgenic mice with influenza virus and studying the response to infection.

The mice were found to be much more susceptible to the virus, with it triggering a cytokine storm leading to pneumonia. The researchers showed that LAP prevented a lethal cytokine storm by supressing lung inflammation.

So where does this protection come from? Dr. Yohei Yamauchi and colleagues from the University of Bristol provided the answer by looking at the cells lining the surface of the lung. There was no difference in how the virus initially binds to these cells, but they did see that non-canonical autophagy/LAP did slow the way the virus enters the cell. It may work by preventing the virus fusing with endosomes, which are the cell’s way of importing materials from outside.

Non-canonical autophagy/LAP is likely to be important as a first defense against infection, where there is no immunity from previous infections, especially in the specific case of influenza and SARS-CoV-2.

“Being able to describe this novel part of the immune defense system against respiratory infections in very exciting, especially given the current pandemic,” commented Professor Tom Wileman from the University of East Anglia and Quadram Institute.

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Newly discovered brain pattern has implications for treating paralyzed, Parkinson’s patients

Researchers discover hidden brain pattern

When reaching for a cup of coffee or catching or throwing a ball, our brain manages to coordinate the movement of no less than 27 joint angles in our arms and fingers. Exactly how the brain is able to do this is a topic of much debate among researchers.

Now, led by Maryam Shanechi, USC Viterbi assistant professor of electrical and computer engineering and Andrew and Erna Viterbi Early Career Chair, researchers discovered a signature dynamic brain pattern that predicts naturalistic reach and grasp movements. The discovery, which is now published in Nature Communications, could become a catalyst for the development of better brain-machine interfaces and improving treatment for paralyzed patients.

In this study, the goal was to compare both the small and large spatiotemporal scales of brain activity. Small-scale activity refers to the spiking of individual neurons or brain cells; large-scale activity refers to Local Field Potential (LFP) brain waves that instead measure the aggregate activity of thousands of interacting individual neurons. Both may contribute to performing reach and grasp movements, but how?

To answer this question, Shanechi and Hamidreza Abbaspourazad, a Ph.D. student in electrical engineering, created a new machine-learning algorithm to extract dynamic neural patterns that co-exist in spiking and LFP activity at the same time and to identify how these patterns relate to each other and to movements. The study was done in collaboration with Bijan Pesaran, professor of neural science at NYU, who performed experiments to collect spiking and LFP brain activity during naturalistic reach and grasp movements using neurophysiology techniques in the field.

By applying the new algorithm to the collected data, they identified commonalities and differences between spiking and LFP activities. From there, they were able to ultimately discover a common pattern between them that was highly predictive of movements.

“When looking closer, we discovered that this common multiscale pattern actually happened to dominantly predict movement compared to all other existing patterns,” Shanechi said. In other words, the team identified a previously undetected pattern of brain activity associated with reach and grasp movements which provides a possible neural signature for them.

Shanechi, who recently received the NIH Director’s New Innovator Award and the ASEE Curtis W. McGraw Research Award, focuses on neurotechnology research; she studies the brain through modeling, decoding, and control of neural dynamics. This publication is just one of many recent projects Shanechi has led to better understand complex neural patterns and neural dysfunctions to develop therapies relating to both physical and mental disabilities. In fact, she has been on a bit of a streak lately, with multiple major Nature publications in the last few months.

“Interestingly,” Shanechi explains, “we found that this neural signature pattern was not only shared between spiking and LFP signals, but also between our different subjects who were making movements.”

This means that the shared pattern can help researchers understand how an individual’s brain controls reach and grasp movements. More importantly, it also suggests that different people may have a similar neural signature when making reach and grasp movements.

Of course, understanding what the brain is doing is only half the battle. Translating brain activity into action is another thing altogether. But Shanechi’s model can do just that. She and her team are able to translate brain activity into movement.

Abbaspourazad adds, “Our model not only discovers the signature patterns in neural activity but also predicts arm and finger movements quite accurately from these patterns.” This is especially promising in the development of brain-machine interfaces to restore movement in paralyzed patients.

In addition to helping paralyzed patients, Shanechi hopes this research can also help better understand the neural mechanisms of movement disorders like Parkinson’s disease to guide future therapies.

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Developmental origins of eczema and psoriasis discovered


Scientists have created a highly detailed map of skin, which reveals that cellular processes from development are re-activated in cells from patients with inflammatory skin disease. The researchers from the Wellcome Sanger Institute, Newcastle University and Kings College London, discovered that skin from eczema and psoriasis patients share many of the same molecular pathways as developing skin cells. This offers potential new drug targets for treating these painful skin diseases.

Published on 22nd January in Science, the study also provides a completely new understanding of inflammatory disease, opening up new avenues for research on other inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease.

Part of the global Human Cell Atlas effort to map every cell type in the human body, the new comprehensive atlas of developing and adult skin is a valuable resource for scientists worldwide. It could also provide a template for regenerative medicine, helping researchers grow skin in the laboratory more effectively.

Our skin acts as a barrier, protecting us against invading bacteria or viruses, and is vital for health. Inflammatory skin diseases such as atopic eczema and psoriasis are chronic conditions, where the immune system becomes overactive, causing itchy or flaky skin that can be very painful and prone to infection. These conditions can have significant impact on people’s lives, but the trigger is unknown and there is no cure, with treatments only helping to relieve the symptoms, not the cause.

Skin is a complex tissue made up of many different types of cells. To learn how skin forms and how this relates to adult health and disease, the researchers studied cells from developing skin, comparing these with biopsies from healthy adults, and eczema and psoriasis patients. Using cutting-edge single cell technology and machine learning, the team analysed more than half a million individual skin cells, to see exactly which genes were switched on in each cell. This allowed them to find out what each individual cell does and how the cells talk to each other.

To their surprise, the researchers discovered that the diseased skin cells shared many of the same cellular mechanisms as developing cells.

Professor Muzlifah Haniffa, co-senior author from Newcastle University and Associate Faculty at the Wellcome Sanger Institute, said: “This Skin Cell Atlas reveals specific molecular signals sent by healthy developing skin to summon immune cells and form a protective layer. We were amazed to see that eczema and psoriasis skin cells were sending the same molecular signals, which could over activate immune cells and cause the disease. This had never been seen before. Discovering that developing cell pathways re-emerge is a huge leap in our understanding of inflammatory skin disease, and offers new routes for finding treatments.”

Dr. Gary Reynolds, a first author on the study from Newcastle University, said: “While our study focused on inflammatory skin disease, there is potential that other inflammatory diseases such as rheumatoid arthritis or inflammatory bowel disease could be triggered in the same way. This research shows the importance of studying development, and could open up entirely new avenues for inflammatory disease research.”

The study uncovered how healthy skin tissue develops, and revealed the cells that are present in adult skin. This has great implications for regenerative medicine, especially for burns victims.

Professor Fiona Watt, co-senior author from Kings College London, said: “There have been decades of research on skin cells grown in the laboratory. However, it is not always clear how the properties of the cells change in the laboratory setting. By revealing the detailed make-up of cells immediately on isolation from developing and adult human skin, this Skin Cell Atlas can act as a template for researchers trying to reconstruct healthy skin in regenerative medicine. Our data is openly available, and we hope this will aid research into creating skin tissue in the laboratory.”

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Onnit’s Chief Fitness Officer Discovered His ‘Non-Negotiables’ in 2020

This article originally appeared in the December 2020 issue of Men’s Health.

JOHN WOLF’S job is all about thinking in new ways to break away from conventions—but 2020 was still an unprecedented challenge for him.

The man tasked with leading the fitness curriculum at Onnit, the company behind some of the most unconventional, versatile workout gear on the market, had to adjust the ways he approaches both his work and family.

He wound up building stronger connections than ever before.

Now, in his own words, Wolf shares the lessons he’s learned through a period that was challenging and isolating—but which ultimately led to deeper connections and a renewed sense of focus.

I think fitness is taking on a little more of a mental-emotional aspect during this pandemic. It is a thing that people have doubled down on in a variety of different ways, but it looks and feels so much different than it did before.

The availability of the equipment is a big issue these days. It’s forced kind of a Spartan and minimalist mindset, like, ‘How creative do I have to be to get the job done?’

Some of the coaching I’ve gone through for personal improvement is what I lean on in this larger group environment because it’s not like everybody looks the same. Not everybody has the same interests—except for everybody feels that they’re alone, to some degree, that their circumstances are uniquely theirs … Then through breaking down the barriers in the group, and me also being vulnerable to my experiences live and being forthright with them about those things, hoping that we’re facilitating an environment where people realize okay, the circumstances might all be really different, but the subjective experience that we’re all having is very consistent as human beings.

In this day and age, right now, the sense of feeling seen and feeling heard—to feel validated on some platform in some way—takes on a greater meaning and grander meaning than it ever has before… That’s really the biggest message, you show up here and you are seen and you are heard, and that even just that the act of showing up is enough to participate.

If it’s a nice day, we create a space where we can go for an hour-long walk as a pack. Walking together creates either quiet time, being around each other, being okay being quiet, and/or the perfect storm, the perfect opportunity to be able to converse about things that matter and observe the world around us at a tempo where there’s actually time to see something. You drive down the same street, you don’t see the detail on that flower. You might not even notice that those flowers bloomed between yesterday and today.

If you’re on the path to bettering yourself, there’s time and space that you have to dedicate to sharing that improved version of yourself with people you love, your family, your community, whatever that looks like. There’s concentric circles out from you. That is our right and responsibility: to make a positive impact in those circles, the ripples in the pond. It’s about creating sacred space and sacred times, and the things you cherish are non-negotiables.

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