Older adults are much more likely to become seriously ill from flu or COVID because aging lung cells can drive excessive immune responses, according to a new study led by researchers at UC San Francisco.
For the study, published in Immunity, the scientists engineered the lung’s structural cells—called fibroblasts—to turn on an age-related distress signal in young mice. The signal led the lungs to form clusters of inflamed cells, including some marked by the GZMK gene, which was first seen in severe COVID-19.
The signal is part of a pathway called NF-kB that is often seen in the diseases of aging. In the study, the fibroblasts prompted the lung’s macrophages to rally an immune response. Then, immune cells rushed into the lungs from the bloodstream. Although the GZMK cells were impotent against disease, they were still capable of damaging the lungs.
Once they had these immune clusters, the lungs of the young mice experienced severe symptoms from an infection—as if they were old. When the scientists used a genetic trick to eliminate the GZMK cells in these mice, their lungs were able to withstand the infection. This suggests the aging lung tissue itself is driving inflammation.
The team also examined lung tissue from older patients hospitalized with COVID-related ARDS (acute respiratory distress syndrome) and found it had clusters of cells that looked like what they had seen in mice. The sicker the patient, the more inflamed clusters they had. Lung tissue from healthy donors had none.
“We saw during COVID that our most vulnerable patients no longer had the infection but still had persistent and devastating lung inflammation,” Peng said. “This circuit of dysfunction between lung and immune cells makes for a promising new therapeutic target.”
Data from UCSF