Single-cell analysis reveals T cell dysfunction driven by macrophages and differential expression of transposable elements in severe COVID-19 patients

The vastly spreading COVID-19 pneumonia is caused by SARS-CoV-2. Lymphopenia and cytokine levels are tightly associated with disease severity. However, virus-induced immune dysregulation at cellular and molecular levels remains largely undefined. Here, the leukocytes in the pleural effusion, sputum, and peripheral blood biopsies from severe and mild patients were analyzed at single-cell resolution. Drastic T cell hyperactivation accompanying elevated T cell exhaustion was observed, predominantly in pleural effusion. The mechanistic investigation identified a group of CD14+ monocytes and macrophages highly expressing CD163 and MRC1 in the biopsies from severe patients, suggesting M2 macrophage polarization. These M2-like cells exhibited up-regulated IL10, CCL18, APOE, CSF1 (M-CSF), and CCL2 signaling pathways. Further, cell type specific dysregulation of transposable elements was observed in Severe COVID-19 patients. Together, our results suggest that severe SARS-CoV-2 infection causes immune dysregulation by inducing M2 polarization and subsequent T cell exhaustion. This study improves our understanding of COVID-19 pathogenesis. •Comprehensive single-cell resolution analysis of leukocytes from pleural effusion, sputum, and peripheral blood biopsies in severe and mild COVID-19 patients.•Severe COVID-19 cases exhibit drastic T cell hyperactivation and elevated T cell exhaustion, particularly in pleural effusion samples.•Macrophages with high expression of CD163 and MRC1, indicative of M2 macrophage polarization, in severe COVID-19 patients.•Cell-specific transposable element dysreuglation in severe COVID-19 contributes to immunue disruption and disease severity.d