Using bulk transcriptomics, proteomics, and single-cell RNA sequencing, scientists reveal early and strong activation of anti-SARS-CoV-2 pro-inflammatory immunity in the Syrian hamster model in a new collaborative study. The authors show migratory immune cells, including pathogen engulfing macrophages, dominate transcriptional responses in the lung to SARS-CoV-2 infection in Syrian hamsters and COVID-19 patients. The authors identify cell type-specific effector functions, providing detailed insights into pathological mechanisms of COVID-19 and informing therapeutic approaches. They note that the Syrian hamsters offers an important model for COVID-19 research, particularly in early stages of infection. The authors establish that COVID-19 activates the lung endothelium that actively drives inflammation and could potentially be targeted as a successful therapeutic strategy.