A bout of COVID could protect you from a severe case of flu

Scientists from The Rockefeller University and Weill Cornell Medicine have found that recovery from COVID appears to have a protective effect against the worst effects of the flu, with this memory response coming from an unexpected corner of the immune system. Their findings, published in the journal Immunity, may enable researchers to create therapies that confer widespread protection against multiple viruses.

When a virus invades the body, signalling molecules called cytokines instruct innate immune cells like macrophages to pursue and consume anything that sounds their alarm. This one-size-fits-all approach is followed by a targeted assault by adaptive immune cells such as T cells, which identify a virus-specific antigen, tailor their offence towards it, and remember it long-term to fight future invasions by the same virus.

However, discoveries of the past two decades show that innate immune responses can lead to cellular memory. In multiple studies, for example, researchers discovered that people who had received the Bacillus Calmette-Guérin live-attenuated vaccine, which aims to protect against tuberculosis, elicited innate immune memory responses that last for months, and provide protection against unrelated infections.

But how this broadly effective immune memory develops is little understood. In 2020, Rockefeller’s Alexander Lercher began investigating the phenomenon using two widely circulating viruses: SARS-CoV-2 and influenza A virus.

Lercher and colleagues set out to investigate long-term consequences of past SARS-CoV-2 infection in the respiratory systems of mice. They focused their analysis on cells in the lungs and found that alveolar macrophages, located in the airway, acquired a new epigenetic program after infection. More specifically, they found that the chromatin that packages genes was more accessible around antiviral genes, which rendered them ‘ready to go’ following recovery from COVID-19.

These results weren’t limited to mice. When analysing samples from people who’d recovered from mild COVID, the researchers found similar epigenetic changes in monocytes in the blood, the progenitor cells of macrophages. The result of this epigenetic reprogramming is memory of previous infections — and an altered immune response to future ones.

Because macrophages in the lungs of COVID-recovered mice had acquired antiviral innate immune memory imprinted on their chromatin, they could more successfully fight disease caused by a new viral invader. Compared to naïve mice, they had fewer disease symptoms from influenza A, such as significant weight loss or dysregulated inflammatory responses, and lower mortality rates.

Lercher explained, “The fact that viral RNA alone seems to be able to trigger memory in macrophages lays the foundation of this memory being antigen independent. They’re recognising a pattern that is shared by many viruses, unlike a virus-specific antigen.” The researchers confirmed this by exposing mice to a synthetic mimic of an RNA virus, and found similar memory responses as they had seen following SARS-CoV-2 infection.

Interestingly, when it came to battling the secondary flu infection, memory-attuned macrophages outperformed adaptive T cells. As noted by Lercher, “The macrophages are really the ones driving this response.”

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

“The naïve mice with the implanted recovered macrophages fared better against influenza than mice implanted with naive macrophages,” Lercher confirmed.

While the findings increase our understanding of innate immune memory, the researchers now want to identify what the critical factors for establishing innate immune memory actually are.

“In an ideal world, we would find one or a few factors that lead to this memory formation in macrophages and other innate cells, and then exploit it to develop therapies that offer broad protection against many viruses,” said Rockefeller’s Charles M Rice. This approach could be especially useful in the face of a potential pandemic.

“If there were a new emerging pathogen on the horizon, for example, it would be nice to have a therapy that boosted your general antiviral immunity for the next month or so,” Lercher said. “That’s still very far away, and a lot more research needs to be done, but I think it could be possible one day.”

Image credit: iStock.com/Design Cells