Alveolitis in severe SARS-CoV-2 pneumonia is driven by self-sustaining circuits between infected alveolar macrophages and T cells

Grant, Rogan A.; Morales-Nebreda, Luisa; Markov, Nikolay S.; Swaminathan, Suchitra; 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; Argento, A. Christine; Kruser, Jacqueline M.; Malsin, Elizabeth S.; Pickens, Chiagozie O.; Smith, Sean; 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 86 patients with SARS-CoV-2-induced respiratory failure and 252 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 in 5 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 at the onset of mechanical ventilation, the alveolar space is persistently enriched in alveolar macrophages and T cells without neutrophilia. Bulk and single cell transcriptomic profiling suggest SARS-CoV-2 infects alveolar macrophages that respond by recruiting T cells. These T cells release interferon-gamma to induce inflammatory cytokine release from alveolar macrophages and further promote T cell recruitment. Our results suggest SARS-CoV-2 causes a slowly unfolding, spatially-limited alveolitis in which alveolar macrophages harboring SARS-CoV-2 transcripts and T cells form a positive feedback loop that drives progressive alveolar inflammation. This manuscript is accompanied by an online resource: https://www.nupulmonary.org/covid-19/ One sentence summary SARS-CoV-2-infected alveolar macrophages form positive feedback loops with T cells in patients with severe COVID-19.