How the Corona Virus Hacks the Immune System: the New Yorker

This is such a terrific article.  Not only does it do a creditable job of explaining the basics of the immune system, but also how Covid 19 acts to disrupt cells and highjacks the immune system.  Since I’m unsure if the article will be accessible if you’re lacking a subscription, I’ll quote some pertinent parts here.

“We tend to associate “survival of the fittest” with lions hunting antelope. But disease—the predation of parasites upon hosts—is actually the most potent force in evolution…

This device is so finely tuned that we seldom notice it at work. Our guts burble with foreign microbes outnumbering human cells roughly ten to one, but the good are seamlessly sorted from the bad; every day, some of our cells grow into cancers, but the immune system dispatches them before they become dangerous…

Normally, as part of what is known as the “innate” immune response—so called because it is genetically hardwired, and not tailored to a specific pathogen—a cell sends out two kinds of signals. One signal, carried by molecules called interferons, travels to neighboring cells, telling them to build defenses that slow viral spread. Another signal, transmitted through molecules called cytokines, gets a message to the circulatory system’s epithelial lining. The white blood cells summoned by this second signal don’t just eat invaders and infected cells; they also gather up their dismembered protein parts. Elsewhere in the immune system, these fragments are used to create virus-specific antibodies, as part of a sophisticated “adaptive” response that can take six or seven days to develop.

Usually, the viruses that humans care about are successful because they shut down both of these signalling programs. The coronavirus is different. “It seems to block only one of those two arms,” tenOever told me. It inhibits the interferon response but does nothing about the cytokines; it evades the local defenses but allows the cells it infects to call for reinforcements. White blood cells are powerful weapons: they arrive on an inflammatory tide, destroying cells on every side, clogging up passages with the wreckage. They are meant to be used selectively, on invaders that have been contained in a small area. With the coronavirus, they are deployed too widely—a carpet bombing, rather than a surgical strike. As they do their work, inflammation distends the lungs, and debris fills them like a fog.

In late May, tenOever’s team shared its findings in the biweekly journal Cell. In their article, they argued that it’s this imbalanced immune response that gives severe COVID-19—which can sometimes cause blood clots, strange swelling in children, and ultra-inflammatory “cytokine storms”—the character of an autoimmune disorder. As the virus spreads unchecked through the body, it drags a destructive immune reaction behind it. Individuals with COVID-19 face the same challenge as nations during the pandemic: if they can’t contain small sites of infection early—so that a targeted response can root them out—they end up mounting interventions so large that the shock inflicts its own damage.

In a sense, there are several immune systems. In health, they coördinate with and balance each other. But a machine with so many moving parts is, inevitably, vulnerable.

Ilya Metchnikoff, a Russian zoologist who would later help popularize yogurt in Western Europe, had developed an obsession with digestion, and with the process by which one cell eats another.

In fact, specialized cells responded to intruders in a process he described as “phagocytosis,” or cell-eating. One kind of cell-eater, called a “neutrophil”—because it can be stained only by pH-neutral dyes—swarmed to the site of the infection first. Larger cells called “macrophages” followed, absorbing both the invaders and the neutrophils into their “amoeboid protoplasm.” Neutrophils and macrophages, Metchnikoff found, lived in tissues throughout the body—a standing army.

Metchnikoff’s findings were promising: he had uncovered what would become known as “cellular” immunity…

It wasn’t clear what these antitoxins, later called “antibodies,” were made of. Still, von Behring and Kitasato had discovered what came to be known as “humoral” immunity, and it had nothing to do with cells eating other cells…

It turned out that the cells that produce antibodies—called B cells, because they were first discovered in the bursa of Fabricius, an organ that does for birds what bone marrow does for humans—can produce only one kind each. Its structure is random, and nearly every B cell is discarded unused. If, however, an antibody created by a B cell happens to match some part of an antigen, that B cell will not just survive but clone itself. The clone incorporates many mutations, which offer the possibility of an even better match. After a few generations, an antibody with the best fit is “constructed” through a process of mini-evolution that occurs continuously in our lymph nodes and spleen.

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.

Phagocytes were often present at the moment of infection. Antibodies in the blood, which could take days to emerge, pursued invaders outside the body’s cells, while T cells used MHC to peer inside those cells, destroying the ones that had been infected by viruses or corrupted by cancer.

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 cells—the weapons of adaptive immunity—are built to spec. Everything plays a double or triple role. Antibodies, for instance, don’t just attach to invaders to block their entry into cells; they also tag them so that they’ll be easier for white blood cells to find and eat. The innate and adaptive arms ramp up each other’s destructive abilities.

When scientists learned that a second pair of young brothers—twenty-one and twenty-three years old, of African ancestry—had 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 tenOever’s 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 doesn’t, the alarm is silent, and the infection spreads. This genetic abnormality had made the virus’s work dramatically easier. The raiders had come to an unlocked house.

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 rare—far 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 you’ve inhaled, and on whether they reach your lungs when you breathe them in. If you’ve had a cold recently, it’s possible that the T cells you developed to fight it could partially fit the coronavirus. Vitamin D levels might matter, because Vitamin D 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.

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.

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 isn’t just that being older makes you weak, and that COVID-19 preys on this weakness; the disease’s mechanism of action is actually amplified in the aging body.

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.

As we age, our immune systems stiffen up. “If I had to respond to an insult—bacteria, a virus, a trauma, a lesion—the 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 one’s health. “Even in individuals that are extremely healthy, extremely well nourished, have no disease, and they’re taking no drugs, there are some inflammatory markers whose concentration increases with aging…

Your level of inflammation contributes to your “biological” age—which is not always in perfect lockstep with your chronological age—and increases your risk of developing cardiovascular disease, cancer, and dementia; it contributes to what geriatricians call “frailty.”

Certain viruses use up more T-cell memory than others. Around twenty per cent of an older adult’s T-cell repertoire is devoted to fighting a single virus: human cytomegalovirus (HCMV), a strain of herpes that usually has no symptoms. It would be ironic if, in some small way, HCMV makes it harder to survive COVID-19. Unlike SARS-CoV-2, which spreads without hiding and so causes extensive damage, HCMV is a master of disguise. When infecting a cell, the virus turns off that cell’s MHC system. No cellular raft delivers evidence of the infection to the surface. Still, this isn’t enough to avoid detection. Our immune system has invented a weapon, the “natural killer” cell, that looks specifically for cells without functioning MHC systems. And so HCMV evolved to create a decoy MHC raft, designed to fool the natural killers.

As a parasite, HCMV is almost perfectly adapted to its host; able to spread without attracting attention, it does nothing but consume resources.