ABSTRACT
The systemic processes involved in the manifestation of life-threatening COVID-19 and in disease recovery are still incompletely understood, despite investigations focusing on the dysregulation of immune responses after SARS-CoV-2 infection. To define hallmarks of severe COVID-19 in acute disease (n = 58) and in disease recovery in convalescent patients (n = 28) from Hannover Medical School, we used flow cytometry and proteomics data with unsupervised clustering analyses. In our observational study, we combined analyses of immune cells and cytokine/chemokine networks with endothelial activation and injury. ICU patients displayed an altered immune signature with prolonged lymphopenia but the expansion of granulocytes and plasmablasts along with activated and terminally differentiated T and NK cells and high levels of SARS-CoV-2-specific antibodies. The core signature of seven plasma proteins revealed a highly inflammatory microenvironment in addition to endothelial injury in severe COVID-19. Changes within this signature were associated with either disease progression or recovery. In summary, our data suggest that besides a strong inflammatory response, severe COVID-19 is driven by endothelial activation and barrier disruption, whereby recovery depends on the regeneration of the endothelial integrity.
Subject(s)
Antibodies, Viral/blood , Blood Proteins/metabolism , COVID-19/diagnosis , Cytokine Release Syndrome/diagnosis , Endothelium, Vascular/virology , Lymphopenia/diagnosis , SARS-CoV-2/pathogenicity , Biomarkers/blood , C-Reactive Protein/metabolism , COVID-19/immunology , COVID-19/mortality , COVID-19/virology , Chemokine CXCL10/blood , Chemokine CXCL9/blood , Cluster Analysis , Convalescence , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/mortality , Cytokine Release Syndrome/virology , Disease Progression , Endothelium, Vascular/immunology , Granulocytes/immunology , Granulocytes/virology , Hematopoietic Cell Growth Factors/blood , Hepatocyte Growth Factor/blood , Humans , Intensive Care Units , Interleukin-12 Subunit p40/blood , Interleukin-6/blood , Interleukin-8/blood , Killer Cells, Natural/immunology , Killer Cells, Natural/virology , Lectins, C-Type/blood , Lymphopenia/immunology , Lymphopenia/mortality , Lymphopenia/virology , Plasma Cells/immunology , Plasma Cells/virology , Survival Analysis , T-Lymphocytes/immunology , T-Lymphocytes/virologyABSTRACT
COVID-19 includes lung infection ranging from mild pneumonia to life-threatening acute respiratory distress syndrome (ARDS). Dysregulated host immune response in the lung is a key feature in ARDS pathophysiology. However, cellular actors involved in COVID-19-driven ARDS are poorly understood. Here, in blood and airways of severe COVID-19 patients, we serially analyzed unconventional T cells, a heterogeneous class of T lymphocytes (MAIT, γδT, and iNKT cells) with potent antimicrobial and regulatory functions. Circulating unconventional T cells of COVID-19 patients presented with a profound and persistent phenotypic alteration. In the airways, highly activated unconventional T cells were detected, suggesting a potential contribution in the regulation of local inflammation. Finally, expression of the CD69 activation marker on blood iNKT and MAIT cells of COVID-19 patients on admission was predictive of clinical course and disease severity. Thus, COVID-19 patients present with an altered unconventional T cell biology, and further investigations will be required to precisely assess their functions during SARS-CoV-2-driven ARDS.