Suchergebnisse

SARS-CoV-2 causes a severe inflammatory syndrome (COVID-19) leading, in many cases, to bilateral pneumonia, severe dyspnea and in ∼5% of these, death. DNA methylation is known to play an important role in the regulation of the immune processes behind COVID-19 progression, however it has not been studied in depth, yet. In this study, we aim to evaluate the implication of DNA methylation in COVID-19 progression by means of a genome-wide DNA methylation analysis combined with DNA genotyping. The results reveal the existence of epigenomic regulation of functional pathways associated with COVID-19 progression and mediated by genetic loci. We found an environmental trait-related signature that discriminates mild from severe cases, and regulates IL-6 expression via the transcription factor CEBP. The analyses suggest that an interaction between environmental contribution, genetics and epigenetics might be playing a role in triggering the cytokine storm described in the most severe cases. ; This work has been supported through Consejería de Transformación Económica, Industria, Conocimiento y Universidades of the regional government of Andalucía cofounded by the European Union through European Regional Development Fund (FEDER, CV20-10150), Consejo Superior de Investigaciones científicas (CSIC-COV19-016/202020E155) and Junta de Castilla y León (Proyectos COVID 07.04.467B04.74011.0 and IBGM excellence programme CLU-2029-02). G.B. is supported by the Instituto de Salud Carlos III (ISCIII, Spanish Health Ministry) through the Sara Borrell subprogram (CD18/00153). ; Peer reviewed

Background: Growth arrest-specific factor 6 (GAS6) and the Tyro3, AXL, and MERTK (TAM) receptors counterbalance pro-inflammatory responses. AXL is a candidate receptor for SARS-CoV-2, particularly in the respiratory system, and the GAS6/AXL axis is targeted in current clinical trials against COVID-19. However, GAS6 and TAMs have not been evaluated in COVID-19 patients at emergency admission. Methods: Plasma GAS6, AXL, and MERTK were analyzed in 132 patients consecutively admitted to the emergency ward during the first peak of COVID-19. Results: GAS6 levels were higher in the SARS-CoV-2-positive patients, increasing progressively with the severity of the disease. Patients with initial GAS6 at the highest quartile had the worst outcome, with a 3-month survival of 65%, compared to a 90% survival for the rest. Soluble AXL exhibited higher plasma concentration in deceased patients, without significant differences in MERTK among SARS-CoV-2-positive groups. GAS6 mRNA was mainly expressed in alveolar cells and AXL in airway macrophages. Remarkably, THP-1 human macrophage differentiation neatly induces AXL, and its inhibition (bemcentinib) reduced cytokine production in human macrophages after LPS challenge. Conclusions: Plasma GAS6 and AXL levels reflect COVID-19 severity and could be early markers of disease prognosis, supporting a relevant role of the GAS6/AXL system in the immune response in COVID-19. ; This research was funded by MINISTERIO DE CIENCIA E INNOVACIÓN (Project# RTI2018-095672-B-I00), Instituto de Salud Carlos III, Fondo de Investigación Sanitaria (grant numbers PI15/00531, PI19/01410), Fundació La Marató TV3 (grant numbers 20153030 and 20153031), and was co-funded by EUROPEAN UNION (ERDF "A way to make Europe"), Consejo Superior de Investigaciones Científicas (CSIC-COV19-016/202020E155), Proyectos COVID-19 de la Junta de Castilla y León (07.04.467B04.74011.0), AGAUR (2017_SGR_177), and CERCA Programme/Generalitat de Catalunya ; Peer reviewed