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

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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 Gƶttgens, 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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Reversing a genetic cause of poor stress responses in mice

Reversing a genetic cause of poor stress responses in mice

Everyone faces stress occasionally, whether in school, at work, or during a global pandemic. However, some cannot cope as well as others. In a few cases, the cause is genetic. In humans, mutations in the OPHN1 gene cause a rare X-linked disease that includes poor stress tolerance. Cold Spring Harbor Laboratory (CSHL) Professor Linda Van Aelst seeks to understand factors that cause specific individuals to respond poorly to stress. She and her lab studied the mouse gene Ophn1, an analog of the human gene, which plays a critical role in developing brain cell connections, memories, and stress tolerance. When Ophn1 was removed in a specific part of the brain, mice expressed depression-like helpless behaviors. The researchers found three ways to reverse this effect.

To test for stress, the researchers put mice into a two-room cage with a door in between. Normal mice escape from the room that gives them a light shock on their feet. But animals lacking Ophn1 sit helplessly in that room without trying to leave. Van Aelst wanted to figure out why.

Her lab developed a way to delete the Ophn1 gene in different brain regions. They found that removing Ophn1 from the prelimbic region of the medial prefrontal cortex (mPFC), an area known to influence behavioral responses and emotion, induced the helpless phenotype. Then the team figured out which brain circuit was disrupted by deleting Ophn1, creating overactivity in the brain region and ultimately the helpless phenotype.

Understanding the circuit

Pyramidal neurons are central to this brain circuit. If they fire too much, the mouse becomes helpless.

Another cell, an interneuron, regulates the pyramidal neuron activity, making sure it does not fire too much.

These two cells feedback to each other, creating a loop.

Ophn1 controls a particular protein, RhoA kinase, within this feedback loop which helps regulate and balances activity.

Van Aelst found three agents that reversed the helpless phenotype. Fasudil, an inhibitor specific for RhoA kinase, mimicked the effect of the missing Ophn1. A second drug dampens excess pyramidal neuron activity. A third drug wakes up the interneurons to inhibit pyramidal neurons. Van Aelst says:

“So bottom line, if you can restore the proper activity in the medial prefrontal cortex, then you could rescue the phenotype. So that was actually very exciting. You should be open to anything. You never know. Everything is surprising.”

Van Aelst hopes that understanding the complex feedback loop behind Ophn1-related stress responses will lead to better treatments for stress in humans.

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