Neutrophil dysregulation and sustained inflammation in PASC with pulmonary complications 2457

Abstract Description Neutrophil dysregulation plays a central role in COVID-19 severity, yet its role in post-acute sequelae of SARS-CoV-2 infection (PASC) remains unclear. To investigate neutrophil contribution in PASC with pulmonary complications, we analyzed plasma cytokines, neutrophil immunophenotyping, and transcriptome profiles. Blood was collected from healthy controls (HC, n = 16), recovered controls without symptoms (RC, n = 17), and PASC participants with pulmonary symptoms (PPASC; n = 41). NET markers and pro-inflammatory cytokines were assessed via Luminex assays. Neutrophil phenotyping was conducted using flow cytometry, and RNA sequencing was performed on a subset of participants’ neutrophils (PPASC, n = 13; RC, n = 4; HC, n = 4). Median ages were 64.5 (PPASC), 53 (RC), and 63 (HC). Plasma NET markers, dsDNA and CitH3, were elevated in PPASC compared to RC and HC and correlated with TNF-α, IL-1β, IL-10, and IFN-γ. NET-forming neutrophils and MPO+ neutrophils tended to be increased in PPASC. RNA sequencing in PPASC neutrophils revealed upregulation of degranulation and NET pathways, with increased MPO, ELANE, CTSG, and PRNT3 expression, aligning with dsDNA, CitH3, and inflammatory markers. Pathway analysis indicated enriched JAK-STAT and IL-6 pathway in PPASC compared to RC. Neutrophil dysregulation continues beyond the acute infection stage, contributing chronic inflammation and coagulation in PASC. Targeting NETs and neutrophil activation offers a potential therapeutic strategy for PPASC. Funding Sources This study was supported by NIH/NIMHD (U54MD007601). Topic Categories Viral Immunology (VIR)