Nature looks for people who have never been infected with the new coronavirus

Imagine someone who is born resistant to SARS-CoV-2 and never has to worry about contracting COVID-19 or spreading the virus
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If you have this kind of superpower, the researchers want to see you and ask you to join their research

In a paper published this month in Nature Immunology, an international team of scientists has begun to search the world for people who are genetically resistant to pandemic virus infection
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The team hopes that identifying genes that protect these individuals may help develop virus-blocking drugs that will not only protect people from COVID-19 infection, but also prevent them from passing the infection to others

Mary Carrington, an immunogeneticist at the National Cancer Research Laboratory, said: "This is a great idea
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" "Really, it's wise to do so

But there is no guarantee of success

"The question is how to find these people," said Sunil Ahuja, an infectious disease expert at the University of Texas in San Antonio
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"This is very challenging

Nonetheless, the authors of this study, including immunologist Evangelos Andreakos of the Biomedical Research Foundation of the Academy of Athens, said they are confident that they will find their target

The first step is to narrow the search to those who have been in contact with patients for a long time without protection and who have not tested positive or have no immune response to the virus
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Particularly interesting are those who share a home and a bed with an infected partner

Looking for the genes that cause severe COVID

This team of co-authors from 10 research centers around the world including Brazil and Greece has recruited about 500 candidates who may meet these criteria
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Since their paper was published less than two weeks ago, 600 people have contacted them, including some from Russia and India, to nominate themselves as possible candidates

Jean-Laurent Casanova, a geneticist and co-author of the study from Rockefeller University in New York, said that people's reaction is really surprising
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"I never thought that people who have been exposed to the virus and apparently have not been infected will contact us
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"

The goal is to recruit at least 1,000 people, and they have already begun to analyze the data
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Great challenges for the future

But Ahuja believes that considering the difficulty of proving that candidates are highly exposed to the virus, researchers may face an almost impossible task
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They must confirm that when the couple is in close contact with each other, the sick partner is releasing a high dose of live virus
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But it is rare to find couples who meet these standards and undergo regular testing, he said
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Ahuja added that many people are now vaccinated, which may mask any genetic resistance to the virus, which further limits the population available for research
.

Once they have identified possible candidates, the researchers will compare the genomes of these people with those of the infected person, looking for genes related to drug resistance
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Any competitor genes will be studied in cells and animal models to confirm the causal relationship with drug resistance and establish the mechanism of action
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Casanova’s team has previously discovered rare mutations that make people more susceptible to severe COVID-19, but they are now moving from susceptibility to drug resistance
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In a genetic survey called the genome-wide association study (GWAS), other research groups searched the DNA of tens of thousands of people looking for single nucleotide changes—which usually have only weak biological effects and identified some Candidate genes that may be related to reduced susceptibility to infection
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One of them is found in the gene of type O blood, but its protective effect is very small, Carrington said, and it is not clear how it is given
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Resistance mechanism

The researchers behind the new project hypothesized the resistance mechanism they might discover
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The most obvious possibility is that some people's ACE2 receptors are not fully functional, and SARS-CoV-2 uses ACE2 to enter cells
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In a pre-printed GWAS study that was not peer-reviewed, researchers discovered a link between rare mutations that may reduce ACE2 gene expression and reduce the risk of infection
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This mechanism has previously been observed in the HIV virus behind AIDS
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Beginning in the 1990s, Ahuja and Carrington have been involved in a work to help identify a rare mutation that disables the CCR5 receptor on white blood cells, thereby preventing HIV from entering white blood cells
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"This knowledge is really useful," Carrington said
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This led to the production of an HIV-blocking drug, and two people were apparently cleared of HIV after receiving bone marrow transplants from donors carrying two drug-resistant genes
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Other people who are resistant to SARS-CoV-2 may have a very strong immune response, especially in the cells inside their noses
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Some people may have mutations, adding genes that prevent the virus from replicating and repackaging into new virus particles, or destroying the viral RNA in the cell
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Despite the challenges, he is optimistic about discovering those who are inherently resistant
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"We are confident to find them," he said
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