Host-microbe multiomic profiling reveals age-dependent immune dysregulation associated with COVID-19 immunopathology.
Hoang Van PhanAlexandra TsitsiklisCole P MaguireElias K HaddadPatrice M BeckerSeunghee Kim-SchulzeBrian Hyohyoung LeeJing ChenAnnmarie HochHarry PickeringPatrick van ZalmMatthew C AltmanAlison D AugustineCarolyn S CalfeeSteven E BosingerCharles B CairnsWalter L EckalbarLeying GuanNaresh Doni JayaveluSteven H KleinsteinFlorian KrammerHolden Terry MaeckerAl OzonoffBjoern PetersNadine G Rouphaelnull nullRuth Rebecca MontgomeryElaine ReedJoanna M SchaenmanHanno SteenOfer LevyJoann Diray-ArceCharles R LangelierPublished in: Science translational medicine (2024)
Age is a major risk factor for severe coronavirus disease 2019 (COVID-19), yet the mechanisms behind this relationship have remained incompletely understood. To address this, we evaluated the impact of aging on host immune response in the blood and the upper airway, as well as the nasal microbiome in a prospective, multicenter cohort of 1031 vaccine-naïve patients hospitalized for COVID-19 between 18 and 96 years old. We performed mass cytometry, serum protein profiling, anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody assays, and blood and nasal transcriptomics. We found that older age correlated with increased SARS-CoV-2 viral abundance upon hospital admission, delayed viral clearance, and increased type I interferon gene expression in both the blood and upper airway. We also observed age-dependent up-regulation of innate immune signaling pathways and down-regulation of adaptive immune signaling pathways. Older adults had lower naïve T and B cell populations and higher monocyte populations. Over time, older adults demonstrated a sustained induction of pro-inflammatory genes and serum chemokines compared with younger individuals, suggesting an age-dependent impairment in inflammation resolution. Transcriptional and protein biomarkers of disease severity differed with age, with the oldest adults exhibiting greater expression of pro-inflammatory genes and proteins in severe disease. Together, our study finds that aging is associated with impaired viral clearance, dysregulated immune signaling, and persistent and potentially pathologic activation of pro-inflammatory genes and proteins.
Keyphrases
- sars cov
- respiratory syndrome coronavirus
- coronavirus disease
- single cell
- gene expression
- genome wide
- physical activity
- signaling pathway
- immune response
- innate immune
- dendritic cells
- genome wide identification
- dna methylation
- end stage renal disease
- bioinformatics analysis
- ejection fraction
- emergency department
- poor prognosis
- newly diagnosed
- healthcare
- oxidative stress
- protein protein
- high throughput
- binding protein
- chronic rhinosinusitis
- genome wide analysis
- squamous cell carcinoma
- transcription factor
- induced apoptosis
- amino acid
- toll like receptor
- inflammatory response
- adverse drug
- prognostic factors
- small molecule
- epithelial mesenchymal transition
- rectal cancer
- clinical trial
- endothelial cells
- peripheral blood
- middle aged
- microbial community
- antibiotic resistance genes
- endoplasmic reticulum stress
- patient reported
- double blind