Using omics tools with the SARS-CoV-2 infected Syrian hamster as model for COVID-19, along with published datasets from COVID-19 patients, Nouailles et al. present a detailed longitudinal analysis of systemic and pulmonary quantitative and qualitative immune responses in a moderate disease setting. Targeted analysis of the alveolar and microvascular niche revealed a dominant role for monocyte-derived macrophages and endothelial cells regarding early anti-viral genes as well as pro-inflammatory and T cell recruiting chemokine expression. Recruitment of cytotoxic effector T cells coincided with viral clearance. This combined response was favorable for a moderate and self-limited disease course.