The body can “remember” its battle against infections by forming innate immune memory. Unlike adaptive immune memory, which develops in response to specific pathogens, innate immune memory provides broader protection against various diseases, including those the body has not yet encountered. For example, the BCG vaccine for tuberculosis has been shown to reduce mortality from other infections by activating innate immunity.
American researchers explored how a past SARS-CoV-2 infection affects the immune response during subsequent infection with the flu virus. They found that alveolar macrophages — essential immune cells in the respiratory system — retain innate memory and influence the outcome of secondary infections. This discovery opens possibilities for utilizing innate immune memory to develop new strategies for treating respiratory viruses.
Coronavirus Causes Long-Term Changes in Alveolar Macrophages, Which Retain Viral Exposure Memory and Alter Their Genetic Activity
After a SARS-CoV-2 infection, long-term changes occur in the alveolar macrophages of mice. These macrophages maintain an epigenetic memory — they alter their gene-level behavior without changing the DNA itself but by modifying the accessibility of certain genetic regions.
Researchers used sequencing technology to study this process, which allows them to simultaneously analyze the activity of thousands of genes in a cell. They found that alveolar macrophages responded more strongly to viral stimuli after a coronavirus infection. Genes involved in antiviral defense and type I interferon (IFN-I) signaling became more active in these macrophages.
COVID-19 Alters Genetic Activity in Circulating Monocytes in Humans
Scientists also investigated whether a protective antiviral response persists in humans after recovering from COVID-19. They collected blood samples from patients who had recovered from mild COVID-19 2-4 months prior and compared them to samples from healthy individuals. The study focused on monocytes — immune cells responsible for attacking pathogens.
In recovered patients, the activity of genes associated with antiviral defense was elevated. This finding mirrored results observed in mice that had recovered from coronavirus infection, where alveolar macrophages exhibited heightened antiviral activity.
Both in humans and mice, the immune system showed increased activity of proteins linked to antiviral defense and decreased activity of genes involved in inflammatory responses.
Past Infection Enhances Secondary Antiviral Immune Response in Mice’s Alveolar Macrophages
Researchers stimulated the macrophages of recovered and healthy mice with synthetic viral RNA. The macrophages of recovered mice responded much more vigorously, with higher levels of interferon-stimulated genes (ISG) responsible for viral defense. Additionally, these macrophages were 17 times less susceptible to infection with the vesicular stomatitis virus, confirming enhanced immune protection.
These findings demonstrate that a past coronavirus infection alters the genetic activity of respiratory macrophages, fostering the development of innate immune memory that strengthens future antiviral immune responses. Type I interferon signaling and the IRF9 protein were necessary to form immune memory.
Previous Coronavirus Infection May Protect Against Severe Influenza
Mice that had recovered from SARS-CoV-2 and were subsequently infected with influenza A lost less weight and had lower mortality rates than the control group due to the immune system’s memory of the virus, as alveolar macrophages and CD8 T cells in the recovered mice exhibited heightened antiviral activity. Additionally, inflammatory responses were reduced in these mice — the levels of pro-inflammatory cytokines IL-1β and IL-17 were significantly lower.
Conclusion
Past viral infections can provide long-term protection against other viruses, improving the body’s resilience to new pathogens.
A previous COVID-19 infection may lead to long-term changes in the genetic activity of respiratory macrophages, fostering the development of innate immune memory and enabling faster and more effective protection against viruses. The formation of innate immune memory depends on IFN-I signaling.
Mice that recovered from SARS-CoV-2 showed an enhanced immune response to the flu due to the activation of interferon-stimulated genes, which helped avoid excessive inflammation and reduced the risk of complications from subsequent flu infections.
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