The study investigates the early stages of SARS-CoV-2 infection in human lungs using ex vivo cultured lung slices. Single-cell RNA sequencing (scRNA-seq) and multiplexed single-molecule fluorescence in situ hybridization (smFISH) were employed to analyze the cellular tropism and transcriptomic effects of the virus. The results show that SARS-CoV-2 primarily infects activated interstitial macrophages (IMs), which can accumulate thousands of viral RNA molecules, taking over 60% of the cell transcriptome and forming dense viral RNA bodies. Infected IMs induce a host profibrotic and inflammatory response, including the expression of TGFB1, SPP1, and various chemokines and cytokines. In contrast, infected alveolar macrophages (AMs) show a more limited response. The study also reveals that SARS-CoV-2 entry into AMs depends on SIGLEC-1/CD169 and ACE2, while entry into IMs uses DC-SIGN/CD209, independent of ACE2. These findings suggest that activated IMs are a prominent site of viral takeover and inflammation, highlighting their potential as therapeutic targets in preventing early pathology in COVID-19 pneumonia.The study investigates the early stages of SARS-CoV-2 infection in human lungs using ex vivo cultured lung slices. Single-cell RNA sequencing (scRNA-seq) and multiplexed single-molecule fluorescence in situ hybridization (smFISH) were employed to analyze the cellular tropism and transcriptomic effects of the virus. The results show that SARS-CoV-2 primarily infects activated interstitial macrophages (IMs), which can accumulate thousands of viral RNA molecules, taking over 60% of the cell transcriptome and forming dense viral RNA bodies. Infected IMs induce a host profibrotic and inflammatory response, including the expression of TGFB1, SPP1, and various chemokines and cytokines. In contrast, infected alveolar macrophages (AMs) show a more limited response. The study also reveals that SARS-CoV-2 entry into AMs depends on SIGLEC-1/CD169 and ACE2, while entry into IMs uses DC-SIGN/CD209, independent of ACE2. These findings suggest that activated IMs are a prominent site of viral takeover and inflammation, highlighting their potential as therapeutic targets in preventing early pathology in COVID-19 pneumonia.