Age-related differences in immune dynamics during SARS-CoV-2 infection in rhesus macaques

Abstract

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.

Advances and gaps in SARS-CoV-2 infection models

“…A multiomics study comparing subadult and aged rhesus macaques showed that age did not substantially affect acute disease; however, an age-specific divergence of immune responses emerged during the postacute phase of infection (7 to 21 dpi). As in humans, advanced age resulted in a delayed or impaired induction of antiviral cellular immune responses and a delay in the efficient return to immune homeostasis [ 85 ].…”

Machine learning of flow cytometry data reveals the delayed innate immune responses correlate with the severity of COVID-19

“…And this delayed innate immune response subsequently failed to prime an adaptive immune response, the study of Carolina Lucas et al (40) indicated that COVID-19 mortality did not correlated with the crosssectional antiviral antibody levels per se but, rather, with the delayed kinetics of neutralizing antibody(NAb) production. What's more, advanced age has been widely recognized as a significant factor associated with severe disease, multi-omics profiling (41) suggests that age may delay or impair antiviral cellular immune responses and delay efficient return to immune homeostasis. The above data linked the general evidence for the pathogenesis of SARS-CoV-2, for instance, the target: type I and type III IFN; the mechanism: delaying the innate immune responses; the immunological characteristics: the delayed innate immune cell counts and the delayed kinetics of NAb production; and the clinical characteristics: advanced age.…”

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“…However, older animals showed signs of delayed T cell responses and return to immune homeostasis. 54 De Wit also shared work on animal models for Nipah virus infection and disease. The origin of several human Nipah virus cases was traced to the consumption of date palm sap contaminated with virus from bat excrement.…”