Cross talk between the airway epithelium and activated immune cells defines severity in COVID 19

The clinical course of COVID-19 is highly variable, however, underlying host factors and determinants of severe disease are still unknown. Based on single-cell transcriptomes of nasopharyngeal and bronchial samples from clinically well-characterized patients presenting with moderate and critical severities, we reveal the different types and states of airway epithelial cells that are vulnerable for SARS-CoV-2 infection. In COVID-19 patients, we observed a two- to threefold increase of cells expressing the SARS-CoV-2 entry receptor ACE2 within the airway epithelial cell compartment. ACE2 is upregulated in epithelial cells through Interferon signals by immune cells suggesting that the viral defense system may increase the number of potentially susceptible cells in the respiratory epithelium. Infected epithelial cells recruit and activate immune cells by chemokine signaling. Recruited T lymphocytes and inflammatory macrophages were hyperactivated and showed a strong interaction with epithelial cells. In critical patients, increased expression of CCL2, CCL3, CCL5, CXCL9, CXCL10, IL8, IL1B and TNF in macrophages was identified as a likely cause of a hyperinflammatory lung pathology. Moreover, we observed exacerbated epithelial cell death, likely leading to lung injury and respiratory failure in fatal cases. Our study provides novel insights into the pathophysiology of COVID-19 and suggests an immunomodulatory therapy along the CCL2, CCL3/CCR1 axis as promising option to prevent and treat critical course of COVID-19. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by the COVID-19 research program of the Berlin Institute of Health, the German Research Foundation through SFB-TR84 "Innate Immunity of The Lung", the German Ministry of Education and Research in the framework of the CAPSyS project (Grant 01ZX1304B and 01ZX1604B), the Berlin-University Alliance (BUA), the European Commission (ESPACE, 874710, Horizon 2020), Illumina GmbH, and Intel Germany GmbH. ### Author Declarations All relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript. Yes All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Due to potential risk of de-identification of pseudonymized RNA sequencing data the raw data will be available under controlled access in the EGA repository upon journal acceptance. In addition, count and metadata tables containing patient ID, sex, age, cell type and QC metrics for each cell will be available at FigShare. All count and metadata will be integrated for further visualization and analysis in Magellan COVID-19 data explorer at https://digital.bihealth.org. For access to data prior to journal acceptance, please contact the corresponding authors.