Anna Pascual-Reguant

Deutsches Rheuma-Forschungszentrum Berlin, ein Leibniz-Institut, Berlin, Germany

Imaging Session: Wednesday, September, 29th, 2021, 12:00pm – 1:30pm

Multi-omics analysis reveals mechanisms of tissue remodeling upon severe COVID-19: stromal-immune crosstalk induces aberrant immune cell infiltration and lung fibrosis

The main histopathological manifestations of COVID-19 infection occur in the lung and jeopardize its physiological functions. The breakdown of the vasculo-epithelial barriers during an acute viral infection necessarily progress to a tissue remodeling phase that, if not adequately resolved, eventually leads to lung fibrosis. From early on, COVID-19 pathology has been linked to an abnormal host response. Nevertheless, very few studies have analyzed the local immune reaction within affected tissues at different disease stages, while retaining the spatial context. Such an approach could shed light into the complex interplay between immune cells and lung structural components that might impair tissue recovery.

By combining Multi-Epitope-Ligand-Cartography (MELC), Spatial Transcriptomics (ST), single- nucleus RNA-sequencing (snRNA-seq) and three-dimensional light sheet microscopy on lungs from COVID-19-deceased patients, we find that tissue signatures of endothelial cell damage, heme scavenging pathways, complement activation and fibrosis are up-regulated upon SARS- CoV-2 infection and spatially co-localize in areas enriched in CD163 transcripts. Additionally, we show that CD163+ macrophages accumulate in COVID-19 lungs and produce the pro-fibrotic chemokine CCL18, particularly in later diseases stages. We also report an increase in the production of the secondary lymphoid chemokine CCL21 with COVID-19 disease progression in fibrovascular lung niches. This CCL21 increase correlates temporally and spatially with the exacerbated T cell infiltration that extends far beyond viral clearance and that accounts for the difference in immune cell counts observed between COVID-19 lungs and non-COVID-pneumonia control tissues. T cells infiltrating COVID-19 lungs show variable expression of the CCL21 receptor CCR7 and variable activation / functional profiles, but broad expression of the immunomodulatory molecule PD1.

Altogether, we gained insights into the mechanisms that govern aberrant immune cell infiltration and induce lung fibrosis in COVID-19. This has implications not only for the treatment of severe cases, but also for the emerging Long-COVID syndrome, which represents a considerable burden on individuals post-infection and on the health care systems.