Last Christmas, as the Omicron variant was ricocheting around the United States, Mary Carrington unknowingly found herself at a superspreader eventan indoor party, packed with more than 20 people, at least one of whom ended up transmitting the virus to most of the gatherings guests.

After two years of avoiding the coronavirus, Carrington felt sure that her time had come: Shed been holding her great-niece, who tested positive soon after, and she was giving me kisses, Carrington told me. But she never caught the bug. And I just thought, Wow, I might really be resistant here. She wasnt thinking about immunity, which she had thanks to multiple doses of a COVID vaccine. Rather, perhaps via some inborn genetic quirk, her cells had found a way to naturally repel the pathogens assaults instead.

Carrington, of all people, understood what that would mean. An expert in immunogenetics at the National Cancer Institute, she was one of several scientists who, beginning in the 1990s, helped uncover a mutation that makes it impossible for most strains of HIV to enter human cells, rendering certain people essentially impervious to the pathogens effects. Maybe something analogous could be safeguarding some rare individuals from SARS-CoV-2 as well.

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The idea of coronaviral resistance is beguiling enough that scientists around the world are now scouring peoples genomes for any hint that it exists. If it does, they could use that knowledge to understand whom the virus most affects, or leverage it to develop better COVID-taming drugs. For individuals who have yet to catch the contagiona fast-dwindling proportion of the populationresistance dangles like a superpower that people cant help but think they must have, says Paula Cannon, a geneticist and virologist at the University of Southern California.

As with any superpower, though, bona fide resistance to SARS-CoV-2 infection would likely be very rare, says Helen Su, an immunologist at the National Institutes of Allergy and Infectious Disease. Carringtons original hunch, for one, eventually proved wrong: She recently returned from a trip to Switzerland and found herself entwined with the virus at last. Like most people who remained unscathed until recently, Carrington had done so for two and a half years through a probable combination of vaccination, cautious behavior, socioeconomic privilege, and luck. Its entirely possible that inborn coronavirus resistance may not even existor that it may come with such enormous costs that its not worth the protection it theoretically affords.

Of the 1,400 or so viruses, bacteria, parasites, and fungi known to cause disease in humans, Jean-Laurent Casanova, a geneticist and an immunologist at Rockefeller University, is certain of only three that can be shut out by bodies with one-off genetic tweaks: HIV, norovirus, and a malaria parasite.

The HIV-blocking mutation is maybe the most famous. About three decades ago, researchers, Carrington among them, began looking into a small number of people who we felt almost certainly had been exposed to the virus multiple times, and almost certainly should have been infected, and yet had not, she told me. Their superpower was simple: They lacked functional copies of a gene called CCR5, which builds a cell-surface protein that HIV needs in order to hack its way into T cells, the viruss preferred human prey. Just 1 percent of people of European descent harbor this mutation, called CCR5-32, in two copies; in other populations, the trait is rarer still. Even so, researchers have leveraged its discovery to cook up a powerful class of antiretroviral drugs, and purged the virus from two people with the help of 32-based bone-marrow transplantsthe closest that medicine has come to developing a functional HIV cure.

The stories with those two other pathogens are similar. Genetic errors in a gene called FUT2, which pastes sugars onto the outsides of gut cells, can render people resistant to norovirus; a genomic tweak erases a protein called Duffy from the walls of red blood cells, stopping Plasmodium vivax, one of several parasites that causes malaria, from wresting its way inside. The Duffy mutation, which affects a gene called DARC/ACKR1, is so common in parts of sub-Saharan Africa that those regions have driven rates of P. vivax infection way down.

In recent years, as genetic technologies have advanced, researchers have begun to investigate a handful of other infection-resistance mutations against other pathogens, among them hepatitis B virus and rotavirus. But the links are tough to definitively nail down, thanks to the number of people these sorts of studies must enroll, and to the thorniness of defining and detecting infection at all; the case with SARS-CoV-2 will likely be the same. For months, Casanova and a global team of collaborators have been in contact with thousands of people from around the world who believe they harbor resistance to the coronavirus in their genes. The best candidates have had intense exposures to the virussay, via a symptomatic person in their homeand continuously tested negative for both the pathogen and immune responses to it. But respiratory transmission is often muddied by pure chance; the coronavirus can infiltrate people silently, and doesnt always leave antibodies behind. (The team will be testing for less fickle T-cell responses as well.) People without clear-cut symptoms may not test at all, or may not test properly. And all on its own, the immune system can guard people against infection, especially in the period shortly after vaccination or illness. With HIV, a virus that causes chronic infections, lacks a vaccine, and spreads through clear-cut routes in concentrated social networks, it was easier to identify those individuals whom the virus had visited but not put down permanent roots within, says Ravindra Gupta, a virologist at the University of Cambridge. SARS-CoV-2 wont afford science the same ease of study.

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A full analogue to the HIV, malaria, and norovirus stories may not be possible. Genuine resistance can manifest in only so many ways, and tends to be born out of mutations that block a pathogens ability to force its way into a cell, or xerox itself once its inside. CCR5, Duffy, and the sugars dropped by FUT2, for instance, all act as microbial landing pads; mutations rob the bugs of those perches. If an equivalent mutation exists to counteract SARS-CoV-2, it might logically be found in, say, ACE2, the receptor that the coronavirus needs in order to break into cells, or TMPRSS2, a scissors-like protein that, for at least some variants, speeds the invasive process along. Already, researchers have found that certain genetic variations can dial down ACE2s presence on cells, or pump out junkier versions of TMPRSS2hints that there could be tweaks that further strip away the molecules. But ACE2 is very important to blood-pressure regulation and the maintenance of lung-tissue health, said Su, of NIAID, whos one of many scientists collaborating with Casanova to find SARS-CoV-2 resistance genes. A mutation that keeps the coronavirus out might very well muck around with other aspects of a persons physiology. That could make the genetic tweak vanishingly rare, debilitating, or even, as Gupta put it, not compatible with life. People with the CCR5-32 mutation, which halts HIV, are basically completely normal, Cannon told me, which means HIV kind of messed up in choosing CCR5. The coronavirus, by contrast, has figured out how to exploit something vital to its hostan ingenious invasive move.

The superpowers of genetic resistance can have other forms of kryptonite. A few strains of HIV have figured out a way to skirt around CCR5, and glom on to another molecule, called CXCR4; against this version of the virus, even people with the 32 mutation are not safe. A similar situation has arisen with Plasmodium vivax, which we do see in some Duffy-negative individuals, suggesting that the parasite has found a back door, says Dyann Wirth, a malaria researcher at Harvards School of Public Health. Evolution is a powerful strategyand with SARS-CoV-2 spewing out variants at such a blistering clip, I wouldnt necessarily expect resistance to be a checkmate move, Cannon told me. BA.1, for instance, conjured mutations that made it less dependent on TMPRSS2 than Delta was.

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Still, protection doesnt have to be all or nothing to be a perk. Partial genetic resistance, too, can reshape someones course of disease. With HIV, researchers have pinpointed changes in groups of so-called HLA genes that, through their impact on assassin-like T cells, can ratchet down peoples risk of progressing to AIDS. And a whole menagerie of mutations that affect red-blood-cell function can mostly keep malaria-causing parasites at baythough many of these changes come with a huge human cost, Wirth told me, saddling people with serious clotting disorders that can sometimes turn lethal themselves.

With COVID-19, too, researchers have started to home in on some trends. Casanova, at Rockefeller, is one of several scientists who has led efforts unveiling the importance of an alarm-like immune molecule called interferon in early control of infection. People who rapidly pump out gobs of the protein in the hours after infection often fare just fine against the virus. But those whose interferon responses are weak or laggy are more prone to getting seriously sick; the same goes for people whose bodies manufacture maladaptive antibodies that attack interferon as it passes messages between cells. Other factors could toggle the risk of severe disease up or down as well: cells ability to sense the virus early on; the amount of coordination between different branches of defense; the brakes the immune system puts on itself, so it does not put the hosts own tissues at risk. Casanova and his colleagues are also on the hunt for mutations that might alter peoples risk of developing long COVID and other coronaviral consequences. None of these searches will be easy. But they should be at least simpler than the one for resistance to infection, Casanova told me, because the outcomes theyre measuringserious and chronic forms of diseaseare that much more straightforward to detect.

If resistance doesnt pan out, that doesnt have to be a letdown. People dont need total blockades to triumph over microbesjust a defense thats good enough. And the protection were born with isnt all the leverage weve got. Unlike genetics, immunity can be easily built, modified, and strengthened over time, particularly with the aid of vaccines. Those DIY defenses are probably what kept Carringtons case of COVID down to a mild course, she told me. Immune protection is also a far surer bet than putting a wager on what we may or may not inherit at birth. Better to count on the protections we know we can cook up ourselves, now that the coronavirus is clearly with us for good.

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Could Genetics Be the Key to Never Getting the Coronavirus? - The Atlantic