More than 200 viruses can infect and cause disease in humans; most of us will be infected by several throughout our lives. Does an encounter with one virus influence how your immune system responds to a different one? If so, how? Does it weaken your defenses, increase them or have some other impact?
These are questions that scientists from Rockefeller University’s Laboratory of Virology and Infectious Diseases, led by Charles M. Rice, and Weill Cornell Medicine’s Epigenetics and Immunity Laboratory, led by Steven Z. Josefowicz, teamed up to answer in a new study published in journal Immunity. By analyzing mice that had been infected first with SARS-CoV-2 and then with the influenza A virus, scientists found that having recovered from COVID had a protective effect against the worst effects of the flu, and that this response from memory it came from an unexpected corner of the immune system.
It turned out that epigenetic changes in macrophages (innate immune cells that are among the first to respond to a threat) had developed a kind of “memory” after COVID that allowed these cells to mount a better defense against an unrelated virus. . Immune memory was long thought to be limited to adaptive immune cells, although recent work has challenged this dogma. Most intriguingly, what the macrophages remembered was not unique to any particular virus.
The findings advance our understanding of innate immune memory and may allow researchers to exploit the phenomenon in new ways to create therapies that confer widespread protection against multiple viruses.
“Immune memory is essential to defend against recurrent diseases caused by pathogens. What is interesting about our study is that we have discovered a broadly effective antiviral immune memory in macrophages after SARS-CoV-2 infection that can reduce disease caused by a completely different virus,” says first author Alexander Lercher, a postdoctoral fellow in the lab.
“A more detailed understanding of these mechanisms could help the development of new therapeutic strategies covering a variety of respiratory viruses,” says Rice.
“It was very exciting to team up with Alex and Charlie and delve deeper into the epigenetic mechanisms that encode this general antiviral memory,” adds Josefowicz. “The implications are profound. If we can walk around with boosted immunity for months after a season of respiratory infections, what are the implications for seasonal trends in these infections? How much human variation, genetic and epigenetic, is there in these pathways?”
cascade effect
When a virus invades the body, signaling molecules called cytokines instruct innate immune cells, such as macrophages, to hunt down and consume anything that raises their alarm. This unique approach is followed by a targeted attack by adaptive immune cells, such as T cells, which identify a specific antigen of the virus, adapt their offensive towards it and remember it in the long term to fight against future invasions of the virus. same virus.
However, discoveries over the past two decades show that innate immune responses can lead to cellular memory. In multiple studies, for example, researchers found that people who had received the live attenuated Bacillus Calmette-Guérin vaccine, which is intended to protect against tuberculosis, elicited innate immune memory responses that last for months and provide protection against unrelated infections. .
But little is known how this widely effective immune memory develops. In 2020, Lercher began investigating the phenomenon using widely circulating viruses: SARS-CoV-2, then the most dominant global pathogen, and the influenza A virus, a recurring scourge that has plagued humanity since the 1918 pandemic. , when it passed from birds to humans, spreading. globally and killing millions.
Flip the gene switch
Lercher and his colleagues set out to investigate the long-term consequences of past SARS-CoV-2 infections on the respiratory system. They focused their analysis on cells in the lungs and discovered that alveolar macrophages, located in the airways, acquired a new epigenetic program after infection. More specifically, they found that the chromatin that packages genes was more accessible around the antiviral genes, leaving them “ready to go” after COVID recovery.
These results were not limited to mice. Analyzing samples from people who had recovered from mild COVID, the researchers found similar epigenetic changes in blood monocytes, the progenitor cells of macrophages.
The result of this epigenetic reprogramming is the memory of previous infections and an altered immune response to future ones.
Acute memory
Because macrophages in the lungs of mice recovered from COVID had acquired an innate antiviral immune memory imprinted in their chromatin, they could more successfully combat disease caused by a new viral invader. Compared to naïve mice, they had fewer symptoms of influenza A disease, such as significant weight loss or dysregulated inflammatory responses, and lower mortality rates.
“The fact that viral RNA alone seems to be able to trigger memory in macrophages lays the groundwork for this memory to be antigen-independent,” says Lercher. “They are recognizing a pattern that many viruses share, as opposed to a virus-specific antigen.”
The researchers confirmed this by exposing mice to a synthetic imitation of an RNA virus and found memory responses similar to those they had observed after SARS-CoV-2 infection.
Interestingly, when it came to fighting secondary flu infection, memory-tuned macrophages outperformed adaptive T cells. “Macrophages are really what drive this response,” Lercher says.
Finally, to test how sharp the macrophage memory was, the researchers removed them from recovered mice, transferred them to naïve mice, and then infected them with the influenza A virus. So, if the recovered macrophages were up to task, recipient mice should develop less severe disease following influenza A infection.
They were. “Naïve mice implanted with recovered macrophages fared better against influenza than mice implanted with naïve macrophages,” Lercher says.
Preparedness for a pandemic
In the future, researchers want to identify what are the critical factors for establishing innate immune memory. “In an ideal world, we would find one or several factors that lead to the formation of this memory in macrophages and other innate cells, and then exploit it to develop therapies that offer broad protection against many viruses,” Rice says.
This approach could be especially useful in the face of a possible pandemic. “If there was a new emerging pathogen on the horizon, for example, it would be nice to have a therapy that boosts overall antiviral immunity over the next month,” Lercher says. “That’s still a long way off and a lot more research needs to be done, but I think it might be possible one day.”