Single-cell analysis of bronchoalveolar cells in inflammatory and fibrotic post-COVID lung disease

Abstract

Rationale: Persistent pulmonary sequelae are evident in many survivors of acute coronavirus disease 2019 (COVID-19) but the molecular mechanisms responsible are incompletely understood. Post-COVID radiological lung abnormalities comprise two broad categories, organising pneumonia and reticulation, interpreted as indicative of subacute inflammation and fibrosis, respectively. Whether these two patterns represent distinct pathologies, likely to require different treatment strategies is not known. Objectives: We sought to identify differences at molecular and cellular level, in the local immunopathology of post-COVID inflammation and fibrosis. Methods: We compared single-cell transcriptomic profiles and T cell receptor (TCR) repertoires of bronchoalveolar cells obtained from convalescent individuals with each radiological pattern of post-COVID lung disease (PCLD). Measurements and Main Results: Inflammatory and fibrotic PCLD single-cell transcriptomes closely resembled each other across all cell types. However, CD4 central memory T cells (TCM) and CD8 effector memory T cells (TEM) were significantly more abundant in inflammatory PCLD. A greater proportion of CD4 TCM also exhibited clonal expansion in inflammatory PCLD. High levels of clustering of similar TCRs from multiple donors was a striking feature of both PCLD phenotypes, consistent with tissue localised antigen-specific immune responses, but there was no enrichment for known SARS-CoV-2 reactive TCRs. Conclusions: There is no evidence that radiographic organising pneumonia and reticulation in PCLD are associated with differential immmunopathological pathways. Inflammatory radiology is characterised by greater bronchoalveolar T cell accumulation. Both groups show evidence of shared antigen-specific T cell responses, but the antigenic target for these T cells remains to be identified.

A 50-gene high-risk profile predictive of COVID-19 and Idiopathic Pulmonary Fibrosis mortality originates from a genomic imbalance in monocyte and T-cell subsets that reverses in survivors with post-COVID-19 Interstitial Lung Disease

“…Lymphopenia has been an established negative prognostic marker in COVID-19 [34], while T cell subpopulations of patients with COVID-19 have exhaustion features [35–37]; yet, this is still a matter of debate [37, 38]. Importantly, single-cell bronchoalveolar lavage transcriptomic profiling comparing post-COVID-19-ILD patients with inflammatory and ‘’fibrotic-like’’ changes, showed more abundant expression of CD4 central memory and CD8 effector memory T cells in the inflammatory arm, suggesting a faster immune response recovery in patients with less pronounced radiographic abnormalities [39]. Our study further expands on the major role of T cell recovery in post-COVID-19-ILD and T-cell exhaustion in IPF [40] ( Figure 5 ).…”

Editorial: Immune-mediated lung injury

“…If not, a less abundant expression of genes that are directly related with monocytes, might mean a gradual "immune recovery" in post-COVID-19-ILD and probably a favorable long-term course. Contrary to IPF, persistence of monocytes and impaired T cell response might not be the case in post-COVID-19-ILD, as the epithelial injury happened only in the acute phase of infection and is not repetitive (17,18). Studies implementing single-cell RNA-sequencing to compare post-COVID-19-ILD and IPF could hopefully address this unmet need and help clinicians "predict" the long-term outcomes of patients with post-COVID-19-ILD.…”