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

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  • Aging Cell . Aging-related cell type-specific pathophysiologic immune responses that exacerbate disease severity in aged COVID-19 patients


    Aging Cell


    . 2022 Jan 12;e13544.
    doi: 10.1111/acel.13544. Online ahead of print.
    Aging-related cell type-specific pathophysiologic immune responses that exacerbate disease severity in aged COVID-19 patients


    Yuan Hou 1 , Yadi Zhou 1 , Lara Jehi 2 3 , Yuan Luo 4 , Michaela U Gack 5 , Timothy A Chan 6 , Haiyuan Yu 7 8 , Charis Eng 1 9 10 11 , Andrew A Pieper 12 13 14 15 16 17 , Feixiong Cheng 1 9 11



    Affiliations

    Abstract

    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.

    Keywords: COVID-19; SARS-CoV-2; aging; cellular immunology; molecular biology of aging.

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