By Roberta Attanasio
Back in March 2020, Jane Brody wrote in The New York Times “While most people focus, as they should, on social distancing, face coverings, hand washing and even self-isolation to protect against the deadly coronavirus now ravaging the country, too few are paying serious attention to two other factors critically important to the risk of developing a Covid-19 infection and its potential severity. Those factors are immunity, which should be boosted, and inflammation, which should be suppressed.” However, major efforts were already underway at that time not only to develop a SARS-CoV-2 vaccine, but also to understand how the virus triggers a blizzard of uncontrolled inflammatory immune responses. These uncontrolled inflammatory immune responses—usually called cytokine storms—eventually cause acute respiratory distress and multi-organ damage.
In the past two years, researchers have developed several COVID vaccines and, now, have discovered why SARS-CoV-2 sets off cytokine storms. A study published in the journal Nature at the beginning of April 2022 shows that SARS-CoV-2 can infect immune cells called monocytes and macrophages, causing their fiery death by a process dubbed pyroptosis. Judy Lieberman, one of the study authors, said: “We wanted to understand what distinguishes patients with mild versus severe COVID-19. We know that many inflammatory markers are elevated in people with severe disease, and that inflammation is at the root of disease severity, but we hadn’t known what triggers the inflammation.”
Monocytes and macrophages are immune cells that serve as “sentinels”, ready to detect invading microbes. Once SARS-CoV-2 infects them, both cells die by pyroptosis, which releases a barrage of powerful inflammatory alarm signals that cause fever and call more immune cells to the site of infection. The process is like a fire that, once started, cannot be stopped—there are no biological fire extinguishers that work against pyroptosis. “In the infected patients, about 6 percent of blood monocytes were dying an inflammatory death,” said Lieberman. “That’s a large number to find, because dying cells are rapidly eliminated from the body.” The researchers also found that about a quarter of the macrophages in the tissue were dying.
The investigators were surprised to find that monocytes and macrophages could be infected with SARS-CoV-2, as monocytes don’t carry the ACE2 receptor, the classic entry portal for the virus, and macrophages have low amounts of this receptor. However, they also found that although SARS-CoV-2 was able to infect monocytes and macrophages, it wasn’t able to produce new infectious viruses within them—likely because the cells die quickly from pyroptosis before new viruses could fully form. Lieberman said: “In some ways, uptake of the virus by these ‘sentinel’ cells is protective: it sops up the virus and recruits more immune cells. But the bad news is that all these inflammatory molecules get released. In people who are more prone to inflammation, such as the elderly, this can get out of control.”
The study also revealed that monocytes carrying a receptor called CD16 was especially likely to be infected. Interestingly, the number of these monocytes increased in patients with COVID-19 and were more likely to be infected with the virus. The CD16 receptor seems to bind antibodies that recognize the SARS-CoV-2 spike protein—these antibodies may actually facilitate infection of monocytes carrying the receptor. “The antibodies coat the virus, and cells with the CD16 receptor then take the virus up,” Lieberman said. Notably, healthy patients who had received mRNA vaccines against COVID-19 did not produce antibodies that facilitate infection. It is possible that vaccine-generated antibodies don’t bind as well to the CD16 receptor and, therefore, the cells don’t take the virus up.
The researchers believe that these findings may explain why COVID-19 treatments based on monoclonal antibodies work only when given early. Lieberman said: “It may be that later on, antibodies may help enhance inflammation. We may need to look at the properties of the antibodies.”
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