Abstract
Advanced age is a key predictor of severe COVID-19. To gain insight into this relationship, we used the rhesus macaque model of SARS-CoV-2 infection. Eight older and eight younger macaques were inoculated with SARS-CoV-2. Animals were evaluated using viral RNA quantification, clinical observations, thoracic radiographs, single-cell transcriptomics, multiparameter flow cytometry, multiplex immunohistochemistry, cytokine detection, and lipidomics analysis at predefined time points in various tissues. Differences in clinical signs, pulmonary infiltrates, and virus replication were limited. Transcriptional signatures of inflammation-associated genes in bronchoalveolar lavage fluid at 3 dpi revealed efficient mounting of innate immune defenses in both cohorts. However, age-specific divergence of immune responses emerged during the post-acute phase. Older animals exhibited sustained local inflammatory innate responses, whereas local effector T-cell responses were induced earlier in the younger animals. Circulating lipid mediator and cytokine levels highlighted increased repair-associated signals in the younger animals, and persistent pro-inflammatory responses in the older animals. In summary, despite similar disease outcomes, multi-omics profiling suggests that age may delay or impair antiviral cellular immune responses and delay efficient return to immune homeostasis.
Highlights
Increased rates of severe and fatal coronavirus disease 2019 (COVID-19) have been reported in individuals >65 yr of age, males, and those with comorbidities, including hypertension, type II diabetes, cardiovascular disease, obesity, lung disease, and renal disease [1, 2]
Principal component analysis (PCA) revealed little evidence of sample clustering according to age through 7 dpi (F = 2.5, P = 0.04)
We identified seven cytokines representing the most likely drivers of the ageassociated variation observed between 10–21 dpi by applying a loadings cutoff of 0.2 and selecting for high loading scores along PC1: IL-2, IL-10, IL-17A, IL-13, IL-6, and macrophage inflammatory protein (MIP)-1α (Fig 6B)
Summary
Increased rates of severe and fatal coronavirus disease 2019 (COVID-19) have been reported in individuals >65 yr of age, males, and those with comorbidities, including hypertension, type II diabetes, cardiovascular disease, obesity, lung disease, and renal disease [1, 2]. A contribution of age-associated changes in the immune landscape to increased disease and tissue damage has been described for a variety of viral respiratory pathogens, including influenza A virus and respiratory syncytial virus [5, 6, 7]. These studies implicate faulty or poorly regulated interactions between the immune system and the local cellular environment (e.g., respiratory epithelium) in the breakdown of protective responses to infectious agents. The confluence of these events may result in greater accrual of tissue damage, sustained local inflammation, severe clinical disease, and suboptimal induction of immune effector and memory responses
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