Infiltrative monocyte derived adenosine deaminase 2 is associated with COVID-19 related acute respiratory distress syndrome

Abstract

Abstract Acute respiratory distress syndrome (ARDS) is a severe complication of COVID-19 characterized by immune dysregulation. The pathogenesis for this, particularly the involvement of infiltrative monocytes, is poorly understood. Extracellular ATP released during inflammation and hypoxia is rapidly scavenged into adenosine, which is further converted into inosine by adenosine deaminase (ADA). ADA2 is an extracellular isoform of ADA secreted by activated monocytes and expressed by infiltrated CD16 +CXCR3 +monocytes. Herein, we aim to study the impact of monocyte-derived ADA2 in the pathogenesis of COVID-19 associated ARDS. Critically ill COVID-19 patients were assigned to the ARDS group based on Berlin criteria, while the non-ARDS group included COVID-19 patients without any or with low-flow oxygen therapy. We observed elevated ADA activity in the serum of ARDS patients, reflecting increased level of the secreted ADA2 protein, when compared to the non-ARDS group. ARDS patients exhibited high level of circulating IL-6, CXCL8 and CXCL10. Notably, correlation analysis revealed a significant association between circulating ADA activity and CXCL10, a chemokine for CXCR3 +monocytes. Post-mortem bulk RNAseq analysis of lung tissues showed increased expression of the ADA2 gene, CECR1, along with CXCL10 suggesting intrapulmonary accumulation of ADA2 positive macrophages. These observations were further supported by the analysis of single-nuclear and spatial transcriptomic atlas of lung tissues of severe COVID-19 patients, which demonstrated a strong expression of ADA2 in CD16 +monocytes. In summary, our data suggest a potential role of infiltrative monocyte-derived ADA2 in modulating the immune response in COVID-19 related ARDS. Supported by the German Center for Infection Research (TI 07.005 to STH)