Role of CD39 in COVID-19 Severity: Dysregulation of Purinergic Signaling and Thromboinflammation
Authors:   Respiratory Diseases Group, Respiratory Service, La Paz University Hospital, Instituto de Investigación Biomédica del Hospital Universitario la Paz (IdiPAZ), Madrid, Spain, Díaz García Elena ,   Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain., García-Tovar Sara ,   Respiratory Diseases Group, Respiratory Service, La Paz University Hospital, Instituto de Investigación Biomédica del Hospital Universitario la Paz (IdiPAZ), Madrid, Spain, Alfaro Enrique ,   Respiratory Diseases Group, Respiratory Service, La Paz University Hospital, Instituto de Investigación Biomédica del Hospital Universitario la Paz (IdiPAZ), Madrid, Spain,   Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain., Zamarrón Ester ,   Respiratory Diseases Group, Respiratory Service, La Paz University Hospital, Instituto de Investigación Biomédica del Hospital Universitario la Paz (IdiPAZ), Madrid, Spain,   Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain., Mangas Alberto ,   Respiratory Diseases Group, Respiratory Service, La Paz University Hospital, Instituto de Investigación Biomédica del Hospital Universitario la Paz (IdiPAZ), Madrid, Spain, Galera Raúl ,   Respiratory Diseases Group, Respiratory Service, La Paz University Hospital, Instituto de Investigación Biomédica del Hospital Universitario la Paz (IdiPAZ), Madrid, Spain,   Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain., Ruíz Hernández José Juan ,   Department of Internal Medicine, Gran Canaria Dr Negrín University Hospital, Gran Canaria, Spain., Solé-Violán Jordi ,   Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain.,   Intensitive Care Medicine, Gran Canaria Dr Negrín University Hospital, Gran Canaria, Spain, Rodríguez-Gallego Carlos ,   Departament of Immunology, Gran Canaria Dr Negrín University Hospital, Gran Canaria, Spain.,   Department of Clinical Sciences, University Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain, Van-Den-Rym Ana ,   Laboratory of Immunogenetics of Human Diseases, La Paz University Hospital, Instituto de Investigación Biomédica del Hospital Universitario la Paz (IdiPAZ), Madrid, Spain,   Interdepartmental Group of Immunodeficiencies, Madrid, Spain., Pérez-de-Diego Rebeca ,   Laboratory of Immunogenetics of Human Diseases, La Paz University Hospital, Instituto de Investigación Biomédica del Hospital Universitario la Paz (IdiPAZ), Madrid, Spain,   Interdepartmental Group of Immunodeficiencies, Madrid, Spain., Nanwani Nanwani Kapil ,   Department of Intensive Medicine, La Paz University Hospital, Madrid, Spain., López- Collazo Eduardo ,   The Innate Immune Response Group, La Paz University Hospital, Instituto de Investigación Biomédica del Hospital Universitario la Paz (IdiPAZ), Madrid, Spain., García-Rio Francisco ,   Respiratory Diseases Group, Respiratory Service, La Paz University Hospital, Instituto de Investigación Biomédica del Hospital Universitario la Paz (IdiPAZ), Madrid, Spain,   Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain.,   1Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain., Cubillos-Zapata Carolina ,   Respiratory Diseases Group, Respiratory Service, La Paz University Hospital, Instituto de Investigación Biomédica del Hospital Universitario la Paz (IdiPAZ), Madrid, Spain,   Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain.
Published: June 2022

CD39/NTPDase1 has emerged as an important molecule that contributes to maintain inflammatory and coagulatory homeostasis. Various studies have hypothesized the possible role of CD39 in COVID-19 pathophysiology since no confirmatory data shed light in this regard. Therefore, we aimed to quantify CD39 expression on COVID-19 patients exploring its association with severity clinical parameters and ICU admission, while unraveling the role of purinergic signaling on thromboinflammation in COVID-19 patients. We selected a prospective cohort of patients hospitalized due to severe COVID-19 pneumonia (n=75), a historical cohort of Influenza A pneumonia patients (n=18) and sex/age-matched healthy controls (n=30). CD39 was overexpressed in COVID-19 patients' plasma and immune cell subsets and related to hypoxemia. Plasma soluble form of CD39 (sCD39) was related to length of hospital stay and independently associated with intensive care unit admission (adjusted odds ratio 1.04, 95%CI 1.0-1.08, p=0.038), with a net reclassification index of 0.229 (0.118-0.287; p=0.036). COVID-19 patients showed extracellular accumulation of adenosine nucleotides (ATP and ADP), resulting in systemic inflammation and pro-coagulant state, as a consequence of purinergic pathway dysregulation. Interestingly, we found that COVID-19 plasma caused platelet activation, which was successfully blocked by the P2Y12 receptor inhibitor, ticagrelor. Therefore, sCD39 is suggested as a promising biomarker for COVID-19 severity. As a conclusion, our study indicates that CD39 overexpression in COVID-19 patients could be indicating purinergic signaling dysregulation, which might be at the basis of COVID-19 thromboinflammation disorder