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Why Do Some People Never Get Covid?

Researchers throughout the globe are asking, and attempting to answer, why one parent without identifiable risk factors becomes critically ill while their spouse and children never test positive or are able to manage their symptoms at home.

Coronavirus spike, National Institutes of Health

As an intensive care unit doctor, I often find myself thinking about the apparent randomness of infectious disease. Two people go out to dinner and have the same meal; one ends up in the emergency room with food poisoning, but the other does not. The seasonal flu runs through an entire family, except for one individual who remains healthy. A case of mono can be a bad memory for one person and turn into a death sentence for another. Doctors look for the vulnerabilities that we can see to explain these outcomes, like age, vaccination status and underlying conditions, but we are often left without answers.

The unpredictability of the coronavirus has made clear just how much we don’t know. Standing at the bedside in the Covid intensive care unit during the first wave, I wondered why young men without identifiable risk factors had become critically ill while their spouses and children were able to manage their symptoms at home. More recently, Omicron has swept through cities, infecting people at a far greater rate than before, and yet some continued to test negative — even if a roommate was positive.

Now physicians and researchers throughout the globe are asking, and attempting to answer, similar questions. Mayana Zatz was taking her usual stroll near her home in São Paulo, Brazil, when she realized she hadn’t seen one of her neighbors for several weeks. When she ran into his wife, Dr. Zatz learned that he had been sick at home with a high fever, a cough and flulike symptoms. Even then, in February 2020, these were telltale signs of Covid. The woman was caring for him by herself, without a mask, and though she had expected to fall ill, too, she was feeling just fine.

In the weeks that followed, Dr. Zatz, a geneticist at the University of São Paulo, could not stop thinking about her neighbors. Why had the woman not gotten sick? Could it be that she had avoided infection altogether? Or was she simply less severely affected by the coronavirus? Both her neighbors took coronavirus antibody tests and shared the results with Dr. Zatz; as expected, the man showed evidence of prior infection, but the woman did not.

Dr. Zatz spread the word that she wanted to study more discordant couples like her neighbors. She appeared on Brazilian television asking to hear from people who had shared a home and a bed with an infected partner but did not get sick. And to her great surprise, she was inundated with thousands of emails. Her neighbors’ story wasn’t so unusual, after all.

Since the World Health Organization declared Covid-19 a pandemic in March of 2020, almost exactly two years ago, scientists and health workers have learned a tremendous amount about the coronavirus. The uncertainty and fear of that first spring have given way to clear evidence for how best to treat those who fall ill. We understand routes of transmission, and in the United States we are lucky to have access to effective vaccines and testing. Many of us are fortunate to lead lives that are no longer so limited by this virus. But why some people do not become sick despite significant exposure remains a mystery — one of the most important of the pandemic. A global network of scientists, Dr. Zatz prominent among them, believes crucial clues may lie in our genes.

Dr. Zatz has long suspected that genetics might be at play in why people have dissimilar reactions to the same disease. Early on in her training, she found herself drawn to studying muscular dystrophy — asking how two boys with the same genetic mutation could have such different degrees of disease, one ending up in a wheelchair at a young age, the other remaining highly mobile. Before the pandemic, she was also focused on the divergent effects of the Zika virus on twins. After observing sets of fraternal twins who had been exposed to Zika in the womb (one born with severe birth defects and the other somehow unimpaired), her lab was able to show that this difference was also likely driven by genetics.

Now as the pandemic tore through Brazil, Dr. Zatz once again set out to discover whether there were genes that protect people from illness and its effects and whether there are individuals who are naturally resistant to this virus. Her lab got to work collecting blood samples from 100 of the couples that reached out to her after her television appearance. The researchers found that the infected and uninfected members of the couple were similar in terms of age and ancestry, though men were more likely to have fallen ill with the virus.

Dr. Zatz and her colleagues believe that no single gene mutation could affect the response to the coronavirus, and so they instead looked for combinations of genes that could be at play. They ultimately found variants in genes of infected people, as compared with those of their asymptomatic partners, that influence the activity of natural killer cells, a key component of the immune system. Partners who showed no sign of infection were more likely to have a robust natural killer cell response, which could result in a stronger defense against infection. This does not mean that all who avoided disease did so by virtue of these genes, and Dr. Zatz’s team chose to focus on this one aspect of the immune response when there are likely many others at play. But the findings offered one piece of a puzzle.

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Today Dr. Zatz’s lab, which has become well known for its research on Covid resistance, is also looking for answers from a population that would, on the face of it, seem the most vulnerable to the coronavirus: centenarians. Her team has collected blood samples from 100 individuals older than 90, including 15 centenarians, one of them a remarkably healthy 114-year-old. All of them made it through infection relatively unscathed or were exposed to the virus but were never symptomatic. Focusing on these people, who would normally be considered extremely high risk because of their advanced age, could help isolate a genetic factor that explains Covid-19 outcomes. Dr. Zatz’s team will infect some of their cells in a lab with the Delta and Omicron variants to see if they can identify which mechanisms — including perhaps the function of natural killer cells — might offer this powerful protection.

“If we really can find out what the resistant genes are and what they do, I think we can find new treatments,” Dr. Zatz told me. “But that will take some time.”

One of the other key figures studying why some people seem resistant to Covid is the pediatric immunologist and geneticist Dr. Jean-Laurent Casanova of Rockefeller University. He is also on the hunt for genetic markers for Covid resistance at his lab in New York and Paris. Along with an international team of scientists, he recently published a worldwide call for individuals with protracted coronavirus exposure who never tested positive. He has already fielded more than 10,000 emails from people around the globe, including from Siberia, Patagonia and Indonesia, all willing to have their genomes sequenced. “We’re sending saliva kits to the four corners of the world,” he told me.

Dr. Casanova is also working on the same question in reverse: How is it that otherwise healthy people can develop life-threatening disease? Since his pediatric residency in Paris, where he became fascinated by children who grew critically ill after what should have been a mild illness, he has studied genetic mutations — what he terms “inborn errors of immunity” — that are associated with severe versions of otherwise relatively harmless infections. In 2015 his lab demonstrated that some cases of severe influenza pneumonia might be due to mutations in a gene that controls the immune system’s production of interferons, which are proteins that work to keep viruses in check. This work, he said, was the “base camp” for his study of the coronavirus.

So far, Dr. Casanova and his colleagues have identified a small percentage of patients with severe Covid-19 who have mutations in genes involved in interferon, resulting in a hole in the body’s ability to defend itself against infection. These people were all healthy before becoming infected with the coronavirus. He went on to find that at least 15 percent have misguided antibodies that attack interferon and impair its function in the immune response.

While Dr. Casanova’s research team is used to findings like these, it is unusual that they account for such a large proportion of cases, he said. “It’s a surprise for everyone in my field,” he told me. It suggests that perhaps scientists could test for these antibodies among people with other vulnerabilities, such as the elderly, in order to understand who is particularly at risk of severe disease.

Drs. Zatz and Casanova approached this work with specific hypotheses, ideas about what steps of the immune system might explain susceptibility or resistance to the coronavirus. But that is not the only way to investigate the role of genetics in disease. Dr. Casanova, along with other scientists, also takes a different approach to the same question, using biobanks of genetic data from large swaths of the population to search entire genomes for links between genes and disease. This method is called genomewide association studies.

“We let the data teach us what they’re going to teach us,” said Benjamin Neale, a co-director of the program in medical and population genetics at the Broad Institute in Boston. In March 2020, he and colleagues established the Covid-19 Host Genetics Initiative, bringing together academics and direct-to-consumer companies with genetic databases like Ancestry.com and 23andMe.

Knowing that time was of the essence as the virus spread worldwide, the researchers were gratified to find “robust data,” said Mark Daly, who is the director of the Institute of Molecular Medicine Finland and one of the leaders of the initiative. They described associations between severe coronavirus infection and genetic variants related to how the immune system responds to infection, including genes involved in the function of interferon. They also found associations between severe illness and genetic variants that are associated with other lung diseases, like interstitial lung disease and lung cancer. Finding connections like these does not definitively prove that the variants play a role in a person’s response to the virus, but they suggest a possible connection for further exploration.

The work of this network of researchers has drawn attention to a field of study that has not often found itself in the spotlight. Though researchers have studied genetic susceptibility and resistance to H.I.V., tuberculosis and malaria, there has never been such a large-scale effort to understand the role genetics might play in the response to one specific infection, with multiple studies and results at one time. Of course, there has never been a novel virus that has so thoroughly shut down and reshaped society at a time when scientists have had gene sequencing tools at their disposal.

“The host response to infectious agents has not nearly gotten the attention from genetics that rare diseases, common chronic diseases and cancer have,” Dr. Daly noted. “The knowledge gained here, the understanding of both susceptibility and severity, has opened my eyes to how much more genetics can teach us about infectious disease biology.”

Genetics is complicated. Often there’s a lot of noise, especially as a pandemic evolves. For one, understanding why someone might not get Covid-19 becomes more difficult as factors like vaccinations, boosters and prior infections now play a role in how people fare against the virus. Even the question of whether something as simple as blood type is related to Covid-19 outcomes — a focus early on in the pandemic — has been fraught with conflicting science and is still not something that we doctors view as meaningful at the bedside. To make things more challenging, people’s behaviors and environment can affect the way their genes work.

“As geneticists, we’re exceptionally practiced at identifying areas of the genome that matter somehow, but we have a long way before we can turn that ‘somehow’ into an understanding of the consequence to a particular illness,” said Dr. Neale. “That is simply where we are with genetics. It’s amazing, but it’s also very frustrating.”

And even the deepest understanding of the genetics of a disease does not guarantee that scientists can develop a drug that works. To make matters more complicated, genetic mutations can have positive and negative effects simultaneously: The same genetic variant that can lead to H.I.V. resistance might also increase susceptibility to West Nile virus.

But if there was ever a time to move a field forward through worldwide collaboration and tens of thousands of people willing to offer their genetic information to help spur research, this is it. Just as a Covid vaccine was developed on a time scale many thought impossible, so, too, might genetic research into disease be advancing in huge bounds that in normal times might seem implausible.

“I think that this pandemic has bridged two communities that haven’t worked closely enough together,” Dr. Daly told me, referring to the fields of genetics and infectious disease. And this is just the beginning.

When I started to think about genetics playing a role in this disease, I worried that in telling a story about our genes, we would shift our attention away from the social failures that have exacerbated the virus’s toll. Any scientist will tell you that observable factors like underlying conditions and age and environmental contributions that determine exposure play a major part. People who don’t have access to health care or are living in crowded, underserved nursing homes are likely at far greater risk than those with certain genetic markers who have the luxury of being able to keep themselves safe.

But that is not the only way to tell this story. Instead, the power of genetics is about making sense of randomness and understanding biology and in doing so, removing blame from the individual.

I recently spoke with a former Covid-19 patient who had nearly died from the disease while her parents remained largely healthy despite living with her in the days before she became symptomatic and tending to her. She said that people who learn what happened to her are always searching for an explanation, for some clue as to why a young and healthy woman nearly died from this virus. There must have been something that she did that put her at risk. “I think people are so uncomfortable with randomness that they victim-blame. They remove themselves from the tragedy,” she said. “I have lost control of my life, essentially. And people do not want to believe there’s randomness in that, because it frightens the living hell out of them.”

It is unlikely that we will ever have a complete explanation for every individual who grew severely ill and everyone who did not. But perhaps what this work on genetics can offer us is a way to come to terms with the truth that any of us might be vulnerable. There are the vulnerabilities that we can see, like age and underlying medical conditions. And there is also vulnerability that is less visible, that is maybe even encoded in our genes.

But our genetic code is just where it all starts. Dr. Zatz’s neighbors both did well, ultimately. The man recovered while the woman still has not been infected, at least not symptomatically. Was this because of their genes? Scientists might never know. Ultimately, our genes are just one piece of the impossibly complex story of this virus, a story that we will tell and retell in the years to come.

Daniela J. Lamas (@danielalamasmd), a contributing Opinion writer for the New York Times, is a pulmonary and critical-care physician at Brigham and Women’s Hospital in Boston.

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