Influenza A virus (IAV) remains a serious health burden that disproportionately affects older individuals. Most young people who contract IAV only experience mild to moderate symptoms, but older individuals (≥65 years of age) experience higher rates of susceptibility, mortality, and complications such as secondary bacterial infections. For example, 86% of the deaths due to 2017–2018 seasonal IAV infections in the United States (US) occurred in individuals 65 years or older, even though this age group is only 13% of the total US population. Overall, the susceptibility of older individuals to IAV is of increasing concern as the average age of the world’s population continues to rise across the globe.
Alveolar macrophages (AMs) are airway and airspace resident macrophages that maintain lung homeostasis and respond rapidly to respiratory pathogens. The importance of AMs in controlling IAV infection is exhibited by the rapid weight loss, increased tissue damage, and poor survival in IAV-infected murine models of genetic AM deficiency or pharmacological AM depletion. Prostaglandin E2 (PGE2) is an immune-modulating lipid and prior studies, and is associated with various inflammatory conditions including rheumatoid arthritis and cancer, as well as infections including IAV infection.
Compounding this issue, the three classes of anti-IAV medications: adamantanes, neuraminidase inhibitors, and cap-dependent endonuclease inhibitors, exhibit limited effectiveness in older individuals.
An inflammatory lipid appears to reduce the number of macrophages inside the lungs with age
The study, led by first author Judy Chen, a Ph.D. candidate, senior author Daniel Goldstein, M.D., the Eliza Maria Mosher Collegiate Professor in Internal Medicine and Professor of Microbiology and Immunology, and their team investigates why cells called alveolar macrophages, the first line of defense in the lungs, appear to be compromised with age.
Previous research by another group showed that when macrophages from an old mouse were put into a young mouse, cells looked young again. Signs pointed to a lipid immune modulator known as prostaglandin E2 (PGE2) with wide ranging effects, from labor induction in pregnancy to inflammation with arthritis. The study team discovered there is more PGE2 in the lungs with age. This increase in PGE2 acts on the macrophages in the lung, limiting their overall health and ability to generate.
The team suspects that the buildup of PGE2 is yet another marker of a biological process called senescence, which is often seen with age. Senescence serves as insurance against the runaway division of damaged cells; cells that are senescent are no longer able to replicate.The study showed that with age, the cells lining the air sacs in the lungs become senescent, and these cells lead to increased production of PGE2 and suppression of the immune response.
To test the link between PGE2 and increased susceptibility to influenza, they treated older mice with a drug that blocks a PGE2 receptor. The old mice that got that drug actually ended up having more alveolar macrophages and had better survival from influenza infection than older mice that did not get the drug.
The findings in this study introduces new potential therapeutic targets to reduce the burden of IAV, and possibly other respiratory viruses such as coronaviruses, in older adults. Also, it is important to get the Influenza vaccine in the indicated seasons to prevent the severity of the symptoms , especially in children, pregnant and older people.
Judy Chen, Jane C. Deng, Rachel L. Zemans, Karim Bahmed, Beata Kosmider, Min Zhang, Marc Peters-Golden, Daniel R. Goldstein (November 9,2022). Age-induced prostaglandin E2 impairs mitochondrial fitness and increases mortality to influenza infection. Nature Communications. Retrieved from : https://www.nature.com/articles/s41467-022-34593-y