Post-Acute Metabolic Sequelae of SARS-CoV-2 Infection in Nonhuman Primates

Introduction: This study evaluated the effects of pre-existing obesity and insulin resistance on the acute and longer-term responses to the delta variant of SARS-CoV-2 using a nonhuman primate model that included lean, healthy and obese, insulin-resistant adult male rhesus macaques. Assessments included viral dynamics and persistence, systemic measures of metabolic control, and single-nuclei RNAseq analyses of pancreas and adipose tissue. Animal were infected via an intratracheal-intranasal route and followed for 6 months prior to necropsy and tissue isolation.

Objective: The overall objective of the study was to determine the extent to which SARS-COV-2 infection exacerbated of existing metabolic dysfunction in obese animals and the development of de novo metabolic disease in lean animals.

Methods: Specific Aim 1. Determine the effect of SARS-CoV-2 infection on the initiation and progression of metabolic disease. We will infect 10 lean, metabolically healthy and obese, insulin-resistant adult male rhesus macaques with the SARS-CoV-2 delta variant and follow the development of metabolic dysfunction over a 6-month period. Viral loads and respiratory pathology will be assessed during the acute phase of infection and peripheral, BAL, and WAT immune cell profiles determined over the entire study period. Systemic metabolic status will be monitored longitudinally by assessing fasting glucose, insulin, C-peptide, HbA1c and adipocytokine levels. Oral and IV glucose tolerance tests will also be performed and glucose-stimulated insulin secretion determined using freshly isolated islets from pancreas obtained at necropsy. Longitudinal WAT samples and islets will also be used for state-of-the-art single-cell RNA-seq to discern changes in cellular and transcriptome profiles. Tissue samples obtained at necropsy will also be analyzed for SARS-CoV-2 nucleic acid, and SARS-CoV-2 transcript-positive tissue will be further analyzed by RNAScope and IHC to elucidate potential latent SARS-CoV-2 reservoirs in light of recent reports of viral nucleic acid and antigen in the intestine, liver, and lymph nodes of COVID-19 survivors at 6 months post-infection.

Results: This experimental portion of the study is completed and a description of our Long COVID model and the principal findings has been published in PLoS Pathogens (PLoS Pathog. 21:e1012988 (2025) PMCID: PMC12289017). We reported that, while some longitudinal responses to SARS-CoV-2 infection, including overall viral dynamics, IgG induction, cytokine profiles, and persistence of viral RNA, did not differ between lean and obese animals, neutralizing antibody levels, lung pathology, body weight, insulin sensitivity, adipocytokine profiles, body temperature, and nighttime activity levels were significantly different in lean versus obese animals. Furthermore, several parameters in lean animals were altered following SARS-CoV-2 infection to resemble those in obese animals. Gene profiling analyses of pancreas and adipose tissue are in process and manuscripts are in preparation.

Conclusion/Discussion: We found that persistent changes in multiple parameters were present in most animals, suggesting that Long COVID may be more prevalent than estimated from self-reported symptoms in human studies. Intriguingly, in both lean SIV-infected, ART-treated and in lean SARS-CoV-2-infected animals, a decrease in plasma adiponectin levels was observed, which decreased the adiponectin:leptin ratio to a level associated with cardiometabolic risk. These data support a potential common effect of viral infection on risk for metabolic disease.

Key Topics:

• Assay and in vitro studies to gain mechanistic insights
• Biomarker, in-depth phenotyping assays and in vitro studies using tissue and other biospecimens
• Nonhuman primate (NHP) and/or other animal models
• Studies of vascular injury, thrombosis, and other potential mechanisms of Long COVID
• Viral persistence/reactivation