Journal Article

Aging‐related cell type‐specific pathophysiologic immune responses that exacerbate disease severity in aged COVID‐19 patients

Eng, Charis, Pieper, Andrew A., Luo, Yuan, Cheng, Feixiong, Hou, Yuan, Zhou, Yadi, Jehi, Lara, Yu, Haiyuan, Chan, Timothy A., Gack, Michaela U.

2022

Overview

Coronavirus disease 2019 (COVID‐19) is especially severe in aged patients, defined as 65 years or older, for reasons that are currently unknown. To investigate the underlying basis for this vulnerability, we performed multimodal data analyses on immunity, inflammation, and COVID‐19 incidence and severity as a function of age. Our analysis leveraged age‐specific COVID‐19 mortality and laboratory testing from a large COVID‐19 registry, along with epidemiological data of ~3.4 million individuals, large‐scale deep immune cell profiling data, and single‐cell RNA‐sequencing data from aged COVID‐19 patients across diverse populations. We found that decreased lymphocyte count and elevated inflammatory markers (C‐reactive protein, D‐dimer, and neutrophil–lymphocyte ratio) are significantly associated with age‐specific COVID‐19 severities. We identified the reduced abundance of naïve CD8 T cells with decreased expression of antiviral defense genes (i.e., IFITM3 and TRIM22) in aged severe COVID‐19 patients. Older individuals with severe COVID‐19 displayed type I and II interferon deficiencies, which is correlated with SARS‐CoV‐2 viral load. Elevated expression of SARS‐CoV‐2 entry factors and reduced expression of antiviral defense genes (LY6E and IFNAR1) in the secretory cells are associated with critical COVID‐19 in aged individuals. Mechanistically, we identified strong TGF‐beta‐mediated immune–epithelial cell interactions (i.e., secretory‐non‐resident macrophages) in aged individuals with critical COVID‐19. Taken together, our findings point to immuno‐inflammatory factors that could be targeted therapeutically to reduce morbidity and mortality in aged COVID‐19 patients. Our study identified that elevated inflammatory markers (C‐reactive protein, D‐dimer, and neutrophil–lymphocyte ratio) are significantly associated with age‐specific COVID‐19 severities. Mechanistically, we identified that reduced abundance of naïve CD8 T cells and type I and II interferon deficiencies are associated with severity of COVID‐19 in aged individuals. We identified strong TGF‐beta‐mediated immune–epithelial cell interactions in aged individuals with critical COVID‐19.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Adolescent / Adult / Age groups / Aged / Aging / Cardiovascular disease / CD8 antigen / CD8-Positive T-Lymphocytes - immunology / Cell Communication / Cell interactions / Cell number / cellular immunology / Chronic obstructive pulmonary disease / Coronaviruses / COVID-19 / COVID-19 - epidemiology / COVID-19 - immunology / COVID-19 - physiopathology / Cytokines / Datasets / Disease control / Epidemiology / Epithelial cells / Epithelial Cells - immunology / Fatalities / Female / Hospitalization / Humans / Immune System / Inflammation / Influenza / Interferon / Interferons - metabolism / Leukocytes (neutrophilic) / Leukocytes, Mononuclear - metabolism / Lymphocytes / Lymphocytes T / Macrophages / Male / Middle Aged / molecular biology of aging / Morbidity / Mortality / Nasal Mucosa - virology / Odds Ratio / Registries / RNA-Seq / SARS-CoV-2 / Severe acute respiratory syndrome coronavirus 2 / Severity of Illness Index / Viral Load / Young Adult