Premature Senescence as a Cause of Shortness of Breath in PASC

Introduction: Dyspnea (shortness of breath) is a common symptom in those with post-acute sequelae of SARS-CoV-2 (PASC, aka Long COVID). The incidence of unexplained dyspnea also increases with age, and SARS-CoV-2 infection has been shown to induce premature senescence that contributes to the severity of illness.

Objective: We will test if SARS-CoV-2 infection induces premature senescence that causes chronic inflammation and mitochondrial dysfunction as an underlying mechanism driving unexplained dyspnea in PASC.

Methods: In aim 1, we will determine if PASC patients with unexplained dyspnea have transcriptomic and epigenetic changes consistent with a senescence phenotype. We will use scRNA-seq to identify a senescence signature in the peripheral blood mononuclear cells (PBMCs). In aim 2, we will identify cellular and protein markers of senescence in PASC patients with unexplained dyspnea. We will perform spectral flow cytometry analysis of PBMCs to identify an aging-associated immune signature in the major innate and adaptive immune cells. Additionally, we will measure a senescence-associated secretory panel (SASP) biomarker panel in biospecimens.

Results: Pending.

Conclusion/Discussion: We will use samples from defined populations in the RECOVER biorepository and investigate if there is evidence of premature senescence in the PBMCs and plasma.

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
• Chronic immune dysfunction