Broad SARS-CoV-2 cell tropism and immunopathology in lung tissues from fatal COVID-19

ABSTRACT

Background Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection in patients with Coronavirus Disease 2019 (COVID-19) prominently manifests with pulmonary symptoms histologically reflected by diffuse alveolar damage (DAD), excess inflammation, pneumocyte hyperplasia and proliferation, and formation of platelet aggregates or thromboemboli. However, the mechanisms mediating these processes remain unclear. Methods We performed multicolor staining for viral proteins, and lineage cell markers to identify SARS-CoV-2 tropism and to define the lung pathobiology in postmortem tissues from five patients with fatal SARS-CoV-2 infections. Findings The lung parenchyma showed severe DAD with thromboemboli in all cases. SARS-CoV-2 infection was found in an extensive range of cells including alveolar epithelial type II/pneumocyte type II (AT2) cells (HT2-280), ciliated cells (tyr--tubulin), goblet cells (MUC5AC), club-like cells (MUC5B) and endothelial cells (CD31 and CD34). Greater than 90% of infiltrating immune cells were positive for viral proteins including macrophages and monocytes (CD68 and CD163), neutrophils (ELA-2), natural killer (NK) cells (CD56), B-cells (CD19 and CD20), and T-cells (CD3{varepsilon}). Most but not all infected cells were positive for the viral entry receptor angiotensin-converting enzyme-2 (ACE2). The numbers of infected and ACE2-positive cells correlated with the extent of tissue damage. The infected tissues exhibited low numbers of B-cells and abundant CD3{varepsilon}+ T-cells consisting of mainly T helper cells (CD4), few cytotoxic T cells (CTL, CD8), and no T regulatory cell (FOXP3). Antigen presenting molecule HLA-DR of B and T cells was abundant in all cases. Robust interleukin-6 (IL-6) expression was present in most uninfected and infected cells, with higher expression levels observed in cases with more tissue damage. Interpretation In lung tissues from severely affected COVID-19 patients, there is evidence for broad SARS-CoV-2 cell tropisms, activation of immune cells, and clearance of immunosuppressive cells, which could contribute to severe tissue damage, thromboemboli, excess inflammation and compromised adaptive immune responses.