Background. COVID-19 patients manifest with pulmonary symptoms reflected by diffuse alveolar damage (DAD), excessive inflammation, and thromboembolism. The mechanisms mediating these processes remain unclear.

Methods. We performed multicolor staining for SARS-CoV-2 proteins and lineage markers to define viral tropism and lung pathobiology in 5 autopsy cases.

Results. Lung parenchyma showed severe DAD with thromboemboli. Viral infection was found in an extensive range of cells including pneumocyte type II, ciliated, goblet, club-like and endothelial cells. Over 90% infiltrating immune cells were positive for viral proteins including macrophages, monocytes, neutrophils, and natural killer (NK), B and T cells. Most but not all infected cells were ACE2-positive. The numbers of infected and ACE2-positive cells are associated with extensive tissue damage. Infected tissues exhibited high inflammatory cells including macrophages, monocytes, neutrophils and NK cells, and low B-but abundant T-cells consisting of mainly T helper cells, few cytotoxic T cells, and no T regulatory cell. Robust interleukin-6 expression was present in most cells, with or without infection.

Conclusions. In fatal COVID-19 lungs, there are broad SARS-CoV-2 cell tropisms, extensive infiltrated innate immune cells, and activation and depletion of adaptive immune cells, contributing to severe tissue damage, thromboemboli, excess inflammation and compromised immune responses.