Macrophage memory after COVID infection provides protection against viruses

More than 200 viruses can infect humans and cause disease; Most of us will be infected with several of these in our lifetime. Does encountering one virus affect your immune system's response to another? If yes, how? Does it weaken your immune system, strengthen it or have any other effect at all?

These are questions that Rockefeller University scientists from the Laboratory of Virology and Infectious Diseases, led by Charles M. Rice, and Weill Cornell Medicine's Laboratory of Epigenetics and Immunity, led by Steven Z. Josefowicz, sought to answer together in a new study, which was published in the magazine immunity. By analyzing mice infected first with SARS-CoV-2 and then with the influenza A virus, scientists found that recovery from COVID had a protective effect against the worst effects of the flu and that this Memory reaction came from an unexpected corner of the immune system.

It turned out that epigenetic changes in macrophages – cells of the innate immune system 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 a threat to build a related virus. It was long thought that immunological memory was limited to adaptive immune cells, but recent work has challenged this dogma. What's even more interesting is that what macrophages remembered wasn't unique to a particular virus.

The findings improve our understanding of innate immune memory and may allow researchers to exploit the phenomenon in new ways to develop therapies that provide broad protection against multiple viruses.

“Immune memory is crucial for warding off recurrent illnesses caused by pathogens. The exciting thing about our study is that after a SARS-CoV-2 infection, we discovered a broadly effective antiviral immune memory in macrophages that can reduce diseases caused by a completely different virus,” says first author Alexander Lercher, a postdoctoral researcher in the laboratory .

“A more detailed understanding of these mechanisms could support the development of new therapeutic strategies for a range of respiratory viruses,” says Rice.

“It was so exciting to work with Alex and Charlie and delve into the epigenetic mechanisms that encode this general antiviral memory,” adds Josefowicz. “The impact is profound. If we can walk around with boosted immunity for months after a season full of respiratory infections, what impact does that have on the seasonal trends in these infections? How big is the human variation – genetic and epigenetic – in this? “Paths?”

Cascade effect

When a virus enters the body, signaling molecules called cytokines instruct innate immune cells like macrophages to track and consume anything that alerts them. This unified approach is followed by a targeted attack by adaptive immune cells such as T cells, which identify a virus-specific antigen, focus their attack power on it, and remember it long-term to combat future invasions of the same virus.

However, discoveries over the last two decades show that innate immune responses can lead to cellular memory. For example, in several studies, researchers found that people who received the live-attenuated Bacillus Calmette-Guérin vaccine, intended to protect against tuberculosis, triggered innate immune memory responses that last for months and provide protection against unrelated infections.

But how this broad immune memory is created is poorly understood. In 2020, Lercher began studying the phenomenon using widespread viruses: SARS-CoV-2, then the world's most widespread pathogen, and the influenza A virus, a recurring scourge that has plagued humanity since the 1918 pandemic , when it passed from birds to humans and spread worldwide, killing millions.

Flipping the switch on genes

Lercher and colleagues set out to investigate the long-term consequences of a previous SARS-CoV-2 infection in the respiratory system. They focused their analysis on cells in the lungs and found 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 near antiviral genes, making them “ready for action” after recovering from COVID.

These results were not limited to mice. Analyzing samples from people who had recovered from mild COVID illness, researchers found similar epigenetic changes in monocytes in the blood, the precursor cells of macrophages.

The result of this epigenetic reprogramming is memory of previous infections and an altered immune response to future ones.

Sharp memory

Because macrophages in the lungs of mice that recovered from COVID had acquired an antiviral innate immune memory imprinted into their chromatin, they were able to more successfully fight disease caused by a new viral invader. Compared to naive mice, they had fewer symptoms of illness caused by influenza A, such as: B. significant weight loss or dysregulated inflammatory responses, and lower mortality rates.

“The fact that viral RNA alone appears to be able to trigger memory in macrophages lays the foundation for the idea that this memory is antigen-independent,” says Lercher. “They recognize a pattern that is common to many viruses, as opposed to a virus-specific antigen.”

The researchers confirmed this by exposing mice to a synthetic mimic of an RNA virus and found memory responses similar to those seen after SARS-CoV-2 infection.

Interestingly, memory-controlled macrophages outperformed adaptive T cells in fighting secondary influenza infection. “In reality, it is the macrophages that drive this reaction,” says Lercher.

Finally, to test how sharp the macrophages' memory was, the researchers extracted them from recovered mice, transferred them into naive mice, and then infected these mice with the influenza A virus. So if the reconstituted macrophages were up to the task, the recipient mice should develop less severe disease when infected with influenza A.

They were. “The naive mice with the implanted reconstituted macrophages performed better against influenza than mice with the implanted naive macrophages,” says Lercher.

Pandemic preparedness

In the future, the researchers want to find out which crucial factors are responsible for the development of innate immune memory. “In an ideal world, we would find one or more factors that lead to this memory formation in macrophages and other innate cells, and then use them to develop therapies that provide broad protection against many viruses,” says Rice.

This approach could be particularly useful in the face of a possible pandemic. “For example, if there was an emerging pathogen on the horizon, it would be nice to have a therapy that would boost your overall antiviral immunity for the next month or so,” says Lercher. “It’s still very far away and a lot more research needs to be done, but I think it might be possible one day.”