Circuits between infected macrophages and T cells in SARS-CoV-2 pneumonia

Grant, Rogan A.; Morales-Nebreda, Luisa; Markov, Nikolay S.; Swaminathan, Suchitra; Querrey, Melissa; Guzman, Estefany R.; Abbott, Darryl A.; Donnelly, Helen K.; Donayre, Alvaro; Goldberg, Isaac A.; Klug, Zasu M.; Borkowski, Nicole; Lu, Ziyan; Kihshen, Hermon; Politanska, Yuliya; Sichizya, Lango; Kang, Mengjia; Shilatifard, Ali; Qi, Chao; Lomasney, Jon W.; Argento, A. Christine; Kruser, Jacqueline M.; Malsin, Elizabeth S.; Pickens, Chiagozie O.; Smith, Sean B.; Walter, James M.; Pawlowski, Anna E.; Schneider, Daniel; Nannapaneni, Prasanth; Abdala-Valencia, Hiam; Bharat, Ankit; Gottardi, Cara J.; Budinger, GR Scott; Misharin, Alexander V.; Singer, Benjamin D.; Wunderink, Richard G.

Some patients infected with Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) develop severe pneumonia and the acute respiratory distress syndrome (ARDS)(1). Distinct clinical features in these patients have led to speculation that the immune response to virus in the SARS-CoV-2-infected alveolus differs from other types of pneumonia(2). We collected bronchoalveolar lavage fluid samples from 88 patients with SARS-CoV-2-induced respiratory failure and 211 patients with known or suspected pneumonia from other pathogens and subjected them to flow cytometry and bulk transcriptomic profiling. We performed single-cell RNA-seq on 10 bronchoalveolar lavage fluid samples collected from patients with severe COVID-19 within 48 hours of intubation. In the majority of patients with SARS-CoV-2 infection, the alveolar space was persistently enriched in T cells and monocytes. Bulk and single-cell transcriptomic profiling suggested that SARS-CoV-2 infects alveolar macrophages, which in turn respond by producing T cell chemoattractants. These T cells produce interferon-gamma to induce inflammatory cytokine release from alveolar macrophages and further promote T cell activation. Collectively, our results suggest that SARS-CoV-2 causes a slowly-unfolding, spatially limited alveolitis in which alveolar macrophages harboring SARS-CoV-2 and T cells form a positive feedback loop that drives persistent alveolar inflammation.