PT  - JOURNAL ARTICLE
AU  - Emily Speranza
AU  - Jyothi N. Purushotham
AU  - Julia R. Port
AU  - Benjamin Schwarz
AU  - Meaghan Flagg
AU  - Brandi N. Williamson
AU  - Friederike Feldmann
AU  - Manmeet Singh
AU  - Lizzette Pérez-Pérez
AU  - Gail L. Sturdevant
AU  - Lydia M. Roberts
AU  - Aaron Carmody
AU  - Jonathan E. Schulz
AU  - Neeltje van Doremalen
AU  - Atsushi Okumura
AU  - Jamie Lovaglio
AU  - Patrick W. Hanley
AU  - Carl Shaia
AU  - Ronald N. Germain
AU  - Sonja M. Best
AU  - Vincent J. Munster
AU  - Catharine M. Bosio
AU  - Emmie de Wit
TI  - Age-related differences in immune dynamics during SARS-CoV-2 infection in rhesus macaques
AID  - 10.1101/2021.09.08.459430
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.09.08.459430
4099  - http://biorxiv.org/content/early/2021/09/08/2021.09.08.459430.short
4100  - http://biorxiv.org/content/early/2021/09/08/2021.09.08.459430.full
AB  - Advanced age is a key predictor of severe COVID-19. To gain insight into this relationship, particularly with respect to immune responses, we utilized the rhesus macaque model of 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. 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 pre-defined timepoints in various tissues. 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 suggested that age did not substantially skew major facets 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 while 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, in contrast to 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 delay efficient return to immune homeostasis following acute infection.Competing Interest StatementThe authors have declared no competing interest.