Analysis of respiratory and systemic immune responses in COVID-19 reveals mechanisms of disease pathogenesis

Szabo, P. A.; Dogra, P.; Gray, J. I.; Wells, S. B.; Connors, T. J.; Weisberg, S. P.; Krupska, I.; Matsumoto, R.; Poon, M. M. L.; Idzikowski, E.; Morris, S. E.; Chloe, P.; Yates, A. J.; Ku, A.; Chait, M.; Davis-Porada, J. M.; Zhou, J.; Steinle, M.; Mackay, S.; Saqi, A.; Baldwin, M. R.; Sims, P. A.; Farber, D. L.

Immune responses to respiratory viruses like SARS-CoV-2 originate and function in the lung, yet assessments of human immunity are often limited to blood. Here, we conducted longitudinal, high-dimensional profiling of paired airway and blood samples from patients with severe COVID-19, revealing immune processes in the respiratory tract linked to disease pathogenesis. Survival from severe disease was associated with increased CD4+T cells and decreased monocyte/macrophage frequencies in the airway, but not in blood. Airway T cells and macrophages exhibited tissue-resident phenotypes and activation signatures, including high level expression and secretion of monocyte chemoattractants CCL2 and CCL3 by airway macrophages. By contrast, monocytes in blood expressed the CCL2-receptor CCR2 and aberrant CD163+ and immature phenotypes. Extensive accumulation of CD163+monocyte/macrophages within alveolar spaces in COVID-19 lung autopsies suggested recruitment from circulation. Our findings provide evidence that COVID-19 pathogenesis is driven by respiratory immunity, and rationale for site-specific treatment and prevention strategies.