Hidden autoimmunity may explain how the coronavirus wreaks such widespread and unpredictable harm.
One of the enduring mysteries of COVID-19 is why it makes some people deathly sick but gives others only mild symptoms or none at all. We know that age matters, as do race; gender; and pre-existing medical conditions like high blood pressure, heart problems, and obesity. We also know that most people who succumb to the disease die because they develop severe pneumonia, also known as acute respiratory distress syndrome, or ARDS.
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What we still don’t know, however, is what tips one COVID-19 victim toward ARDS but not another. Early in the pandemic, doctors noticed that, compared to forms of ARDS caused by other respiratory infections like flu, some features of COVID ARDS were peculiar. Patients were not only slower to develop the syndrome but also slower to recover, in some cases spending weeks on a ventilator. Often, their immune systems continued a ruinous battle against their own bodies – ravaging their lungs and choking them of oxygen – even after SARS-CoV-2, the virus that causes COVID-19, had been cleared from their systems.
“It was very strange,” says UC San Francisco’s Carolyn Calfee, MD, MAS ’09, a critical care physician and one of the world’s leading experts on ARDS. “I thought, ‘What kind of ARDS does this?’” she recalls. “‘This is not normal.’”
It turns out that a lot about COVID-19 is not normal. Experts have learned that in addition to infecting the respiratory tract, SARS-CoV-2 can infect the heart, gut, and blood vessels. As in the lungs, however, the damage that the virus inflicts on these tissues often appears to pale in comparison to the destruction caused by patients’ own immune response. Inflammation is rampant and widespread – turning up even in the brain and the toes – and causes myriad debilitating symptoms that sometimes persist for months. In rare cases, children (and some adults) who have recovered from COVID-19 develop a mysterious inflammatory syndrome, in which many organs throughout the body become inflamed.
All of this has piqued scientists’ curiosity: What is going wrong with people’s immune systems?
In searching for answers, Calfee and other researchers are finding that COVID-19 unhinges the immune system in ways no one expected, going so far as to turn the body against itself. Some people who get especially bad or unusual symptoms, for instance, harbor rogue antibodies – similar to those seen in autoimmune diseases – that disrupt the body’s normal immune response or attack its own tissues. These discoveries could explain how the virus wreaks such extensive and variable harm; they could also help predict who, if infected, will fall dangerously ill and identify effective treatments. More profoundly still, they could change scientists’ fundamental understanding of human immunity and how it can go awry.
A Broken Alarm
Alexis Combes, PhD, couldn’t sleep. An early-career scientist at UCSF, he had grown up in Marseille, France, where a childhood illness had sparked a reverence for medical science. He arrived in San Francisco in 2017 to train in clinical immunology and, less than two years later, was hired to direct a new, state-of-the-art laboratory for UCSF Bakar ImmunoX, an initiative that is exploring the immune system’s role in cancer and other diseases in hopes of inspiring treatments.
In April 2020, members of ImmunoX teamed up with Calfee and other clinical researchers to launch a study examining how people’s immune systems respond to the new coronavirus. The study, called COMET (COVID-19 Multi-Phenotyping for Effective Therapies), required collecting blood and other bodily substances from hospitalized patients and then processing the samples – extracting fragile immune cells, genes, and other molecules – so that researchers could analyze them. Combes, whose lab specializes in this kind of deep investigation, jumped at the chance to help.
Still, he felt anxious. He lay awake, picturing himself pipetting tiny drops of blood from people dying of COVID-19, and hoped that nothing would go horribly wrong. “Later on, we learned there is almost no virus in the blood because it stays in the lungs,” Combes says, “but back then, we didn’t really know how dangerous these samples were.”
Around 4 a.m., he rose and dressed. The light-rail train he normally took into the lab had stopped running, so he rented an electric Lyft bicycle and pedaled the 15-minute commute on dark, abandoned streets. He arrived early so that he could get samples from the hospital’s morning blood draw while the specimens were still fresh. He had to work fast. Within hours, many important but short-lived immune cells would already be dead.
Combes ran the blood through a series of assays designed to pluck out immune cells and decode the genetic material in each cell, one by one – a process called single-cell sequencing. He wore two pairs of gloves, two lab coats, and an N95 mask. He focused on sequencing RNA, a marker of which genes (DNA) a cell has turned on. Like a computer’s task manager, which shows the software programs currently in use, the decoded RNA would reveal which genetic programs a patient’s immune cells were running in response to the coronavirus infection.
Together with a couple dozen technicians and trainees, Combes repeated this process of extracting and sequencing immune cells every morning for nearly two months. Then he and other COMET scientists began to dig into the resulting data.
Immune cells deploy a variety of programs for fighting viruses. One of the most powerful is known as the interferon response. Some immune cells are stationed along the body’s borders, such as in the skin or a nasal membrane. When one of these sentinel cells detects a virus attack, the cell emits warning proteins called interferons – the biochemical equivalent of an air raid siren. Nearby cells respond to the interferons by turning on antiviral genes, which slow the reproduction of the virus and induce any cells that do become infected to commit suicide.
Parsing the sequencing data, Combes’s team noticed that the immune cells from patients with mild COVID-19 (those discharged from the hospital within a few days) were running this crucial virus-defense program without a hitch. But that was not the case in the immune cells from patients with severe COVID-19 (those admitted to the ICU, often with ARDS). Alarmingly, none of their cells had deployed the interferon response.
“What’s concerning is this is something we see across the entire immune system,” says Matthew “Max” Krummel, PhD, the chair of ImmunoX, UCSF’s Smith Professor of Experimental Pathology, and co-lead of the COMET study. Without an interferon response to keep a virus contained, he explains, an invader is free to spread rapidly and widely. Increasing numbers of ambushed cells would call for reinforcements by flooding the bloodstream with inflammatory proteins called cytokines, setting off what’s known as a cytokine storm. Fresh troops arriving from the blood, such as white cells and antibodies, would then attempt to flush out the virus through biological carpet-bombing, resulting in extensive inflammation and tissue damage – much like that seen in COVID ARDS.
By fall 2020, scientists around the world had amassed similar evidence pointing to the same conclusion: In the sickest COVID-19 patients, something was shutting down their interferon response. But what?
The Autoimmune Connection
One day in February 2020, a 32-year-old woman checked into a hospital in Lombardy, Italy. She was struggling to breathe and had a fever and a cough. Her symptoms, no surprise, were caused by COVID-19. Because she was young, her doctors thought she would recover quickly. But her condition worsened. She remained in the hospital for 37 days, including a week on a ventilator. By the time she was discharged, the burgeoning coronavirus outbreak had sickened more than 85,000 people in Italy. Her case might have been lost in the wave, save for one odd detail: She happened to have a rare autoimmune disease called autoimmune polyglandular syndrome type 1, or APS1.
APS1 is unusual in that it’s linked to heritable mutations in a single gene; these mutations cause an astonishing array of autoimmune conditions, including type 1 diabetes, endocrine dysfunction, and chronic fungal infections. Mark Anderson, MD, PhD, a co-founder of ImmunoX and UCSF’s Friend Professor of Diabetes Research, has studied APS1 for more than 20 years. The miscreant gene, he and others have learned, plays a role in teaching the immune system to ignore, or tolerate, the body’s own cells and molecules. In APS1, self-tolerance breaks down, permitting the immune system to generate renegade warrior cells and antibodies that make civilians and allies the targets of war. One of these ally targets is the immune system’s virus alarm protein, interferon.
Antibodies that target interferons capture these proteins the way a glove traps a baseball – stopping them from delivering their warning and tagging them for destruction by immune cells. These antibodies are so abundant in APS1 patients that their presence is often used to diagnose the disease. Weirdly, though, they had never seemed to do much harm, Anderson notes, since patients had tended not to get bad cases of the flu and other viral infections. “Then, lo and behold, COVID comes along, and word gets out on the street that a few APS1 patients who got the virus had a very poor clinical course,” he says. After the Italian case, two more popped up in Maryland.
Then, in early August, Anderson got a call from Jean-Laurent Casanova, MD, PhD, an immunologist at Rockefeller University in New York City. Upon examining blood from nearly 1,000 people hospitalized with life-threatening COVID-19, Casanova told Anderson, his team had been shocked to find that more than 100 of them (about 1 in 10 people) had antibodies against interferons, just like the APS1 patients. None of these COVID patients, however, had any known autoimmune diseases.
In laboratory experiments, Casanova’s team showed that these antibodies block the interferon response in cells exposed to SARS-CoV-2, thus preventing the cells from resisting the virus and controlling its spread. The team had found no such antibodies in people with mild or asymptomatic COVID-19. They appeared to be a feature – a cause, likely – of some of the worst outcomes.
Read more at: UCSF