Several science fiction movies, especially zombies or pandemic viruses, have already anticipated it. Imagine being born naturally resistant to SARS-CoV-2 and never having to worry about contracting COVID-19 or spreading the virus. If someone comes to have this “superpower”, a group of researchers wants to know it to enroll in their most recent scientific study.
According to an article published in Nature Immunology, an international team of scientists has launched a global search for people who are genetically resistant to infection with the pandemic virus. The team hopes that identifying the genes that protect these individuals can lead to the development of virus-blocking drugs that not only protect people from COVID-19 but also prevent them from transmitting the infection.
“It’s a great idea,” says Mary Carrington, an immunogeneticist at the Frederick National Cancer Research Laboratory in Bethesda, Maryland. But success is not guaranteed. If there is genetic resistance to the SARS-CoV-2 coronavirus, there may be “only a handful” of people with this trait, says Isabelle Meyts, a pediatric immunologist and physician at the Catholic University of Leuven in Belgium, who is part of the consortium behind the effort.
“The question is how to find those people. It is very challenging. This is not for the faint of heart,” says Sunil Ahuja, an infectious disease specialist at the University of Texas Health Sciences Center at San Antonio.
People to find
The first step in finding that person (s) is to limit your search to those who have been exposed, unprotected, to a sick person for a prolonged period and who have not tested positive or have not exhibited an immune response against the virus. Of particular interest are people who shared a house and bed with an infected partner.
The team of co-authors from 10 research centers around the world, from Brazil to Greece, has already recruited some 500 potential candidates, that could meet these criteria. And since the publication of your article less than 2 weeks ago, another 600 people, including some from Russia and India, have contacted them, nominating themselves as possible candidates. The response was a real surprise, according to Jean-Laurent Casanova, a geneticist and study co-author at Rockefeller University in New York City. “I did not think for a second that the people themselves, exposed and apparently uninfected, would contact us.”
The goal is to have at least 1000 recruits, said one of the study’s authors, Evangelos Andreakos, an immunologist with the Biomedical Research Foundation of the Academy of Athens. “Even if we identify one, it will be really important,” he said.
A great challenge ahead
The researchers could have a near-impossible task, given the difficulties in proving that the candidates were highly exposed to the virus, argues Ahuja. They will have to confirm that the ill couple was shedding high doses of live virus when the couple were interacting closely with each other. These so-called “discordant” pairs are not uncommon, but it is rare to find those that meet these criteria and have been regularly evaluated, according to the authors. “The fact that many people have been vaccinated, potentially masking any genetic resistance to the virus, further limits the group of people to study,” adds Ahuja.
Once they have identified potential candidates, the researchers will compare the genomes of individuals with those of people who have been infected, looking for genes associated with resistance. All contending genes will be studied in cell and animal models to confirm a causal link with resistance and establish the mechanism of action. Casanova’s team has previously identified rare mutations that make people more susceptible to severe COVID-19, but researchers are now turning the tide from susceptibility to resistance.
In genetic studies called genome-wide association studies (GWAS), other groups have screened the DNA of tens of thousands of people for single nucleotide changes, which generally only have a weak biological effect, and identified some potential associated candidates. with the reduction of susceptibility to infection. One of these is found in the gene responsible for type O blood, but its protective effect is small, Carrington says, and how it is conferred is unclear.
Mechanisms of resistance
The researchers behind the new project have hypothesized the kinds of resistance mechanisms they might encounter. The most obvious thing might be that some people don’t have a working ACE2 receptor, which SARS-CoV-2 uses to enter cells. In a GWAS, published as a preprint and therefore not peer-reviewed, the researchers identified a possible link between a rare mutation that likely reduces ACE2 gene expression and a lower risk of infection.
This type of mechanism has previously been observed with HIV, the virus behind AIDS. Beginning in the 1990s, Ahuja and Carrington participated in work that helped identify a rare mutation that deactivates the CCR5 receptor on white blood cells, preventing HIV from entering them. “That knowledge has been really helpful,” says Carrington. It led to a class of HIV-blocking drugs and apparently two people were also cleared of HIV after receiving bone marrow transplants from donors with two copies of the resistant genes.
Other people resistant to SARS-CoV-2 can have very powerful immune responses, especially in the cells that line the inside of the nose. Andreakos says that some people may have mutations that increase genes that prevent the virus from replicating and repackaging itself into new viral particles, or from breaking down viral RNA in the cell. Despite the challenges ahead, she is optimistic about discovering people who are naturally resilient. “We are sure that we will find them,” he concluded.