Earlier, in mice, researchers had identified genes that affected the success of organ transplants: they called this collection of genes the major histocompatibility complex, or MHC, from the Greek histos, for tissue. In the sixties, a human version of the MHC was found. The genes turned out to be a blueprint for a remarkable system designed to distinguish self from non-self. Fragments of proteins built inside our cells are loaded onto tiny molecular rafts, which ferry them to the cell surface for inspection by T cells. Meanwhile, in the thymus, T cells are trained as inspectors: they are presented with rafts containing protein fragments, some of which are natural to the body. Any T cell that ignores its raft, or that goes on the attack in response to self-generated fragments, is destroyed. Competent inspectors are set loose to search for foreign material. They look for cells that display unfamiliar protein parts in their rafts and kill them.

This is how skin grafts are detected and rejected; how incipient cancers are disposed of; how cells that have been co-opted by viruses are rooted out. Together, B cells and T cells allow the human immune system to update itself as fast as our cells can replicate. But their power comes with risks. The immune systems adaptive weapons arent always precise. Allergies affect somewhere between ten and forty per cent of the global population; as many as four per cent of people suffer from debilitating autoimmune diseases. And parasites could find ways to hack the system. The invention of acquired immunity was like escalating a war with an omnipotent opponent, Hedrick, who is a T-cell expert, writes. Our new weapons could be turned against us.

By the late eighties, it no longer made sense to contrast cellularists and humoralists. They had both been right; it was just that they saw different parts of the immune system depending on where and when they looked. Phagocytes were often present at the moment of infection. Antibodies in the blood, which could take days to emerge, pursued invaders outside the bodys cells, while T cells used MHC to peer inside those cells, destroying the ones that had been infected by viruses or corrupted by cancer.

Still, mysteries remained. At a 1989 symposium, the immunologist Charles Janeway described what he called the fields dirty little secret: a vaccine containing an antigen designed to elicit antibodies wouldnt work unless an extra irritant, or adjuvantusually a harmless chemical or bacteriumhad been added. Why wasnt the antigen enough to jump-start the creation of antibodies? To be quite honest, the answer is not known, Janeway said. His suspicion, though, was that the process couldnt begin unless the innate immune systemwith its interferons, cytokines, and epithelial cellshad sounded its alarms first. Without marching orders, the standing army remained on call.

An innate system has to anticipate its enemiesa seemingly impossible task, given their stupendous variety. It wasnt until around 1997 that Janeway began to understand how such anticipation might be accomplished. About a decade earlier, a pair of biologists named Christiane Nsslein-Volhard and EricF.Wieschaus had found a gene that affected development in fruit flies. Nsslein-Volhard had called it Toll, using the German word for great. (Das ist ja toll! she exclaimed, upon making the discovery.) Another scientist, JulesA.Hoffmann, learned that the same gene was involved in the fruit-fly immune response; Janeway, with the help of Ruslan Medzhitov, showed that a version of it was also present in humans, and employed in some of the white blood cells that are the innate immune systems first responders. Through experiments with human cells, they showed that the gene coded for what came to be called a Toll-like receptor, which could recognize a particular molecular motifa building block of bacterial membranes. It was as if evolution had noticed that, while many cells built their houses out of oak or brick, dangerous bacteria always seemed to use pinewood. Why not make a pine detector?

Immunologists soon discovered a second Toll-like receptor, then a third; they started giving them names like TLR4 and TLR5. Whole new families of pattern-recognition receptors were found. Each receptor, ingenious in its design, recognized some characteristic microbial or viral signaturea kink in a viruss RNA, a crenellation in a microbial cell wall.

At long last, a picture of the whole system was coming into focus. It was all interconnected. Innate immunity kicks off the immune response, as cells at the site of infection use their receptors to recognize and combat invaders, and release interferons and cytokines to raise the alarm. Various types of white blood cells respond, having been routed to the infection via the bloodstream. They identify and eat foreign cells, returning the digested bits, via the lymph nodes, to the thymus and the bone marrow, as intel. In the days that follow, antibodies and killer T cellsthe weapons of adaptive immunityare built to spec. Everything plays a double or triple role. Antibodies, for instance, dont just attach to invaders to block their entry into cells; they also tag them so that theyll be easier for white blood cells to find and eat. The innate and adaptive arms ramp up each others destructive abilities.

Here, again, Hedrick sounds a cautious note. Such a scheme should worry any systems analyst, he writes. A potentially lethal mechanism controlled by positive feedback is a recipe for runaway destruction.

In late March, a thirty-two-year-old man of Dutch ancestry was admitted to a hospital in the Netherlands. He had difficulty breathing, and a CT scan showed an opaque haze spreading in his lungs. He was given a diagnosis of COVID-19, and spent sixteen days in intensive care; four days after he was moved out of the I.C.U., one of his lungs collapsed. He recovered enough to be sent home nine days later. His twenty-nine-year-old brother, who lived in a different house, got sick at roughly the same time, and died. Their parents had moderate symptoms.

When scientists learned that a second pair of young brotherstwenty-one and twenty-three years old, of African ancestryhad also had severe cases of COVID-19, they sought to study all four men. By sequencing the genomes of the men and their parents, the researchers hoped to find an anomaly that might explain why some young people, particularly men, had such bad outcomes.

The Dutch team found something that echoed tenOevers theory about the way in which SARS-CoV-2 rewires the cellular alarm system. The four men all had an ineffective variant of TLR7, a Toll-like receptor that recognizes viral RNA. When it works, TLR7 helps produce interferons, which tell nearby cells to increase their antiviral efforts. When it doesnt, the alarm is silent, and the infection spreads. This genetic abnormality had made the viruss work dramatically easier. The raiders had come to an unlocked house.

This spring, a clinical trial in the U.K. gave interferon-beta, a synthetic version of the molecule, to a random selection of a hundred and one patients hospitalized with COVID-19. The trial found that those who received interferon early in their infection were seventy-nine per cent less likely to become seriously ill. Researchers agree that timing is crucial. In the early days of a coronavirus infection, an interferon boost might help your innate immune system contain the virus. Later, though, it might be harmful; at that point, your adaptive immune system could already be out of control, and you might need an immunosuppressant, such as the steroid dexamethasone. (Last month, President Trump received dexamethasone as part of his treatment for COVID-19; he was also given a drug that contained lab-engineered antibodies capable of fighting the virus alongside, or ahead of, his bodys own adaptive response.)

The genes for TLR7 are on the sex-linked X chromosome. That could be a partial explanation for why men suffer from severe COVID-19 more often than women. But a TLR7 deficiency is likely to be rarefar rarer than the incidence of severe COVID-19 among young people. There are almost certainly other genetic or environmental factors that weaken the interferon response. In mid-September, research published in Science showed that some COVID-19 patients with bad outcomes had autoantibodies that were attacking their own interferon; another article published in the same issue outlined a genetic flaw related to TLR3, which is also involved in the interferon response. (As many as fourteen per cent of severe COVID-19 cases may be attributable to one of these two conditions.) The more researchers study our immune response to the virus, the more complexity they find. According to some theories, how things go for you could depend on how many viral particles youve inhaled, and on whether they reach your lungs when you breathe them in. If youve had a cold recently, its possible that the T cells you developed to fight it could partially fit the coronavirus. VitaminD levels might matter, because VitaminD can help control inflammation. Harmful autoantibodies could be responsible for the persistent symptoms suffered by COVID-19 long-haulers. All of this is still being explored.

The immune system uses feedback to stay balanced, like a gymnast on a beam. If a light breeze blows, the gymnast might sway a bit; sensing this, shell shift her weight to return to center. But, given a strong enough push, shes prone to overshoot with her reaction and, from the other side, overshoot again until she falls. Many factors contribute to the slipa tight hip flexor, a strained calf, moisture in the aireach magnifying the force of the shove.

Older gymnasts tend to be less agile. The same goes for the immune system, which is why COVID-19 disproportionately affects the elderly. The already high case fatality rate for sixty-five- to seventy-four-year-olds more than triples in people seventy-five and older. This age distribution is unique to the coronavirus. Kids are more susceptible to the seasonal flu; children and young adults who had the swine flu in 2009 were hospitalized the most, while the pandemic flu of 1918 hit adults in their twenties and thirties the hardest. (Perhaps their immune systems overreacted, or older people had acquired immunity to similar strains.) The difference of risk and profile, young versus oldI dont think anyone has seen an infectious agent behave quite like this before, Richard Hodes, the director of the National Institute on Aging, part of the National Institutes of Health, said, of the coronavirus.

The lopsidedness of the virus means that vaccines might not be as effective in older patients, even with double the dose, or after repeated inoculations. The beauty of a vaccine is that it relieves us of the task of completely understanding the virus; its package of antigens simply presses the On button of the great machine. Helping older people may require a more fine-tuned approach, tailored to the particular way this virus destabilizes the immune system. What we have learned so far suggests that it isnt just that being older makes you weak, and that COVID-19 preys on this weakness; the diseases mechanism of action is actually amplified in the aging body.

For this reason, about a month after beginning their coronavirus investigations, the researchers in tenOevers lab switched from ferrets to hamsters. Ferret immune systems are highly responsive, and the animals were getting better too quickly. They look a lot more like kids, tenOever said. By contrast, some hamsters, when infected with the virus, actually develop respiratory distress. We see a lot more infiltration in their lungs. In older hamsters, as in older people, innate immunity is less likely to contain the virus and adaptive immunity is slower to turn on and off. The hamster ends up wildly dysregulated. The difference between these two outcomes really comes down to, as you get older TenOever paused. Getting older sucks. Everything breaks down, even at the simplest of levels.

As we age, our immune systems stiffen up. If I had to respond to an insultbacteria, a virus, a trauma, a lesionthe response is slower and is less strong, Luigi Ferrucci, who studies the aging process and the immune system at the National Institute on Aging, told me. But, at the same time, the system becomes chronically activated. Cytokines circulate at a constant, high level in the blood, as though the body were at all times responding to some attack. This is true no matter ones health. Even in individuals that are extremely healthy, extremely well nourished, have no disease, and theyre taking no drugs, there are some inflammatory markers whose concentration increases with aging, Ferrucci said. Think of the welt that rises with a bite, then imagine the same processswelling, redness, stiffness, the accumulation of pusslowly pervading the body. Your level of inflammation contributes to your biological agewhich is not always in perfect lockstep with your chronological ageand increases your risk of developing cardiovascular disease, cancer, and dementia; it contributes to what geriatricians call frailty.

A phenomenon known as cellular senescence is partly responsible for the bodys increasing inflammation through time. As cells age and divide, small errors accrete in their DNA. These errors could lead to cancer, among other maladies. And so cells police themselves. When they detect decay in their DNA, they stop replicating and begin emitting cytokines, as though asking the immune system to inspect and destroy them. The accumulation of senescent cells may contribute to severe COVID-19: according to the current theory, Ferrucci said, they could expand tremendously the cytokine storm, in which a runaway feedback loop leads to a sudden spike in inflammation throughout the body.

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How the Coronavirus Hacks the Immune System - The New Yorker