Single-cell multi-omics show disruption of blood and airway T cells in pulmonary long COVID

Background Approximately 10% of individuals who recover from COVID-19 experience residual respiratory symptoms impacting their quality of life, but the mechanisms behind pulmonary long COVID (PLC) are largely unknown. Objectives We characterized airway and circulating immune cells in patients with and without PLC. Methods Participants were recruited and allocated into two groups: 1) PLC, defined by a St. George's Respiratory Questionnaire (SGRQ) total score of >10 at least three months following an acute SARS-CoV-2 infection with self-reported new or worsening symptoms, and 2) controls, defined by SGRQ ≤10 with or without a prior history of COVID. We performed research bronchoscopy and obtained bronchoalveolar lavage (BAL) in seven PLC patients and seven age- and sex-matched control subjects. Single-cell RNA sequencing (scRNAseq) was performed on the BAL cells. Peripheral blood mononuclear cells (PBMCs) were cryopreserved in 30 participants (17 PLC, 13 controls) for proteomic analysis. Serum was submitted for microarray detection of auto-IgG antibodies. Results We annotated 105 836 cells using scRNAseq and found that CD4 + T cells were credibly increased in participants with PLC. scRNAseq revealed up-regulation of anti-viral pathways including those related to interferon signaling in T cells as well as antigen presenting cells. In PBMCs, T cells expressing both CD4 and CD8 were elevated in PLC participants. Autoantibodies targeting histone 2B and histone 3 were significantly increased in PLC participants (adj.p<0.05). Conclusions PLC is associated with dysregulation of T cell mediated immunity, which may be related to autoimmunity. These cells represent potential novel therapeutic targets in patients suffering from PLC.