Image credit: Laura Olivares Boldú, Wellcome Connecting Science

Categories: COVID-199 August 20219.1 min read

From Mild to Mortal

Why is it that some people infected with a virus don’t get any symptoms at all, while others tragically, may die? This fundamental question applies to all viruses and bacteria that infect humans, and hundreds of years of research have not given scientists a full answer. Part of the explanation lies in our genomes; small variations in our genetic make-up mean that some people are more predisposed to symptoms than others. Much of the explanation lies in our immune system; a complex, ever changing network of cells that constantly defends our bodies from attack.

To discuss some of the latest research into human genetics, immunology and COVID-19, Wellcome Connecting Science and COVID Genomics UK (COG-UK) brought together three experts at their latest virtual event: Dr Michael Morgan, University of Cambridge, Dr Kenneth Baillie, University of Edinburgh and Dr Kerstin Meyer, Wellcome Sanger Institute. Chaired by writer and broadcaster Angela Saini, they shared some of the findings that explain the multiple ways our bodies respond to the SARS-CoV-2 virus.

You can watch a full recording of the talk on YouTube, and find details of the next event on the Connecting Science website.

Risk factors

Kenneth, who is a consultant in critical care medicine and Senior Research Fellow in anaesthesia & critical care, discussed the risk factors for becoming ill with COVID-19. “By far the biggest effect on an individual’s chance of becoming critically ill or dying from COVID is age. The difference in risk of death between someone aged under 50 and someone over 88 is 11-fold.”1

“The other biggest factors are sex – men are more likely to become ill compared to women – and other illnesses. The more other illnesses you have, the more likely you are to become very sick if you catch COVID,” said Kenneth. Precisely how these factors affect our risk though, is still being untangled.

The panel also discussed the genetic risk factors for COVID-19. One of the largest studies to date on human genetic risk factors, GenOMICC2, is taking place in the UK. Thousands of critically ill patients have taken part, and their genetic make up has been compared to those who are infected but don’t need hospital treatment. Researchers have found several genetic variations in people’s genomes that do affect the risk of becoming seriously ill with COVID. However, the effects of these variants in the population are small. The genetic variant with the biggest effect results in a 2.3 times greater risk of being admitted to ICU, compared to someone without the variant. This increase in risk is relatively small - it is nowhere near as big as the effects of age, for example. Plus, the variant is relatively rare – so it can’t explain much of the difference in symptoms that we see. It’s likely that there are many, many variants in our genomes, each with an even smaller effect on our risk, that are yet to be uncovered.

Before going into further details of how our immune system fights the virus, the discussion turned to the scientific method. How can researchers be sure that one thing is directly causing another, and not just correlated with it? This essential question is at the heart of so much science, including studying risk factors for a disease.

Cause or correlation

To answer the questions of cause and effect, researchers use randomisation. Kenneth described the central role this method has played in modern science: “It's part of the driving force behind the enlightenment, and all of the progress we've made since then: an understanding that the natural world is always more complicated that we think it is.”

In terms of drug trials, people are randomly assigned to receive one drug, or another. This means that with enough people taking part, all the things that vary in the population are evenly spread out between the groups. Any characteristic that varies between people that hasn’t been measured, can’t be measured, or we don’t even know exists, is not going interfere with the results of the study.

With large numbers of people in a study, randomly put in groups for treatment, researchers can conclude that any difference between the two groups would be caused by the different drug they received. “That's really why we've made so much progress on treating COVID,” Kenneth said.

Kenneth also described an approach called ‘Mendelian randomisation’. This method allows researchers to test, or estimate, the effects of different factors on a disease outcome, when a trial isn’t possible. It uses knowledge of the role of our genes. For COVID, this method was used to determine that both smoking and obesity are risk factors for becoming severely ill with the disease.

But even age, sex, illnesses, obesity, smoking and genetic factors put together still can’t explain all of the differences in symptoms we see between different people with COVID. The discussion turned to our immune system and how it reacts to infection.

The immune system

Our immune system is incredibly complex, with multiple types of cells interacting with each other, and with the pathogens they encounter in our bodies. Pathogens will activate the immune system, but can also  interfere with the way the immune system works. Our immunity is shaped by the pathogens we’ve come across before – our cells have a memory system, and are able to react quickly if we encounter a familiar pathogen.

Michael is a Senior Research Associate in computational biology. He described some of his recent work into the immune system and COVID. He has been looking at the types of white blood cells that you'd broadly expect to see during the course of a viral infection over time. They compared those cells to what happens when someone's infected with coronavirus.

“We found that particular types of white blood cells were elevated in patients without symptoms. These were cells that either made antibodies, or helped in the process. That suggests that those individuals are mounting a proper immune response to the virus. In contrast, in patients that were really poorly and in ICU, we saw delayed reactions in those types of white blood cells. That might indicate that prior to the infection there are differences between individuals that predispose them to that differential response to the viral infection itself,” Michael said.

The panel also noted the potential role of the immune system in long COVID, a condition where symptoms last for weeks or months after infection. “It isn’t yet understood, but one hypothesis is that long COVID is similar to autoimmune disorders, where the immune system mistakenly recognises the body’s cells,” Michael said. He also highlighted some of the ongoing research into long COVID both here in the UK and around the world, and his hopes for a better understanding and treatments for the condition soon.

The immune system in children

Kerstin, a Principal Staff Scientist working on the Human Cell Atlas, discussed some of her work on the immune system in children. Younger age groups are much, much less severely affected by COVID-19 and the difference is likely driven by the immune system. When we are born, we haven’t had any infections at all – our immune systems can be described as ‘naïve’. As adults, we have had a lifetime of exposure to different pathogens. This means that when a common cold virus comes along, for example, an adult is usually incredibly good at responding to it – we’re likely to have seen it before and we have cells that recognise it, and they quickly multiply to destroy it.

Kerstin explained how this relates to coronavirus: “In the case of COVID, this is a bit of a double edged sword. Some of our cells may recognise the virus partially – because perhaps it is similar to one they’ve seen before. So they will expand and multiply, but not necessarily actually neutralise the virus properly. The activation of the immune system continues, with more and more cells multiplying, and in some cases, this can cause a ‘cytokine storm’. This results in inflammation that is really dangerous for the body, and can lead to organ damage.”

“We’ve found that in children, you don’t see this expansion of these cell types, and you don’t see a cytokine storm. The cells that do multiply are not determined by what they’ve seen before, and so are probably pretty specific to the virus. We presume that this will help to clear it quickly.”

Kerstin discussed her related findings – studies into the ‘innate’ immune system. This part of our immune system doesn’t work in the same way as the cells with immunological memory. The innate immune system is a way our bodies respond to danger. “We’ve found that in the airway, cells that respond to danger signals do so much more strongly in children compared to adults. Those cells usually produce antiviral proteins, like interferons, which stop the virus replicating – helping children to clear the virus faster,” said Kerstin. “We don’t fully understand it yet, but one theory is that SARS-CoV-2 has a way of suppressing the interferon response. It appears that in children that suppression is less effective, and therefore kids can clear the virus better.”

The role of genetics

While genetic studies have only identified variants with small effects so far, there is still big potential. If any of the genetic variations in humans that affect risk are involved in the immune system, this could be important for drug development.

Kerstin highlighted the rapid advances in understanding how our genes work in different cells of the body, and the myriad of effects that has. “The pace of research, and huge progress we've seen over the last 18 months, really gives me hope,” she said.

Kenneth summarised what he see’s as the role of genetics. “Genetics can cut through all of the complexity of the immune system. It can take us straight to the components where a change in a gene means a change in the outcome for the patient. That's potentially very important therapeutic evidence – it can tell us what targets we need to aim for with drugs.”

Michael agreed, “We really need to understand the genomics of host susceptibility, as well as the genomics of the virus itself, and how they interact with each other, to stay one step ahead of COVID.”

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