Old versus young: age-related differences in immune dynamics during SARS-CoV-2 infection in rhesus macaques

Older
age is a key predictor of severe COVID-19. In this study, we utilized the
rhesus macaque model to characterize the relationship between age and immune
responses to SARS-CoV-2 infection. Two cohorts of eight older (16-23 years) and
eight younger (3-5 years) rhesus macaques were inoculated with SARS-CoV-2. Four
animals per group were euthanized at 7- and 21-days post inoculation (dpi). Our
time-resolved evaluation included viral RNA quantification, clinical
observations, pulmonary x-rays, single-cell transcriptomics, multiparameter
flow cytometry, multiplex immunohistochemistry, cytokine detection, and
lipidomics analysis. Differences in clinical signs, pulmonary infiltrates, and
virus replication dynamics were limited between age cohorts. Transcriptional
signatures of inflammation-associated genes in cells isolated from
bronchoalveolar lavage fluid at 3 dpi revealed efficient mounting of innate
immune defenses in both younger and older animals. These findings suggest that
age does not substantially skew major outcomes of acute disease in this model.
However, age-specific divergence of immune responses emerged during the
post-acute phase of infection (7-21 dpi). Older animals exhibited sustained
local inflammatory innate responses. Meanwhile, 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, contrasted by persistent pro-inflammatory responses in the older
animals. In summary, despite similar disease outcomes, multi-omics profiling in
SARS-CoV-2-infected rhesus macaques suggests that age may delay or impair the
induction of anti-viral cellular immune responses and efficient recouping of homeostasis
following acute infection.