SARS-CoV-2 replication and spread in type I interferon-negative ATII pneumocytes. A, Red cells are viral RNA⁺; green cells are napsin A⁺ ATII cells; red-green cells are infected ATII cells; nuclei stained blue with DAPI. The viral RNA⁺ ATII cells in numbered regions 1–5 are spatially contiguous, consistent with spread of infection to susceptible type II cells in close spatial proximity. Region 6 shows a napsin A⁻ viral RNA⁺ cell overlying lysed viral RNA⁺ epithelial syncytium. Region 7 shows a viral RNA⁺ napsin A⁺ and napsin A⁻ cell conjugate, consistent with acquisition of viral RNA in macrophages by phagocytosis. B, SARS-CoV-2 virions and intracellular RNA, green. Virus spread and fusion of spatially contiguous ATII cells generates focal clusters of virus-producing cells. C, SARS-CoV-2 RNA⁺ cells, red; type I interferon, green; nuclei stained blue with DAPI. Viral RNA⁺ cells are type I interferon⁻, and interferon⁺ cells are viral RNA⁻. Abbreviations: AT, alveolar type; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.