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 to 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.
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 these people made it through infection relatively unscathed or were exposed to the virus but were never symptomatic. Focusing on this population, which 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.