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Inflammation is a central pathogenic feature of the acute respiratory distress syndrome (ARDS) in COVID-19. Previous pathologies such as diabetes, autoimmune or cardiovascular diseases become risk factors for the severe hyperinflammatory syndrome. A common feature among these risk factors is the subclinical presence of cellular stress, a finding that has gained attention after the discovery that BiP (GRP78), a master regulator of stress, participates in the SARS-CoV-2 recognition. Here, we show that BiP serum levels are higher in COVID-19 patients who present certain risk factors. Moreover, early during the infection, BiP levels predict severe pneumonia, supporting the use of BiP as a prognosis biomarker. Using a mouse model of pulmonary inflammation, we observed increased levels of cell surface BiP (cs-BiP) in leukocytes during inflammation. This corresponds with a higher number of neutrophiles, which show naturally high levels of cs-BiP, whereas alveolar macrophages show a higher than usual exposure of BiP in their cell surface. The modulation of cellular stress with the use of a clinically approved drug, 4-PBA, resulted in the amelioration of the lung hyperinflammatory response, supporting the anti-stress therapy as a valid therapeutic strategy for patients developing ARDS. Finally, we identified stress-modulated proteins that shed light into the mechanism underlying the cellular stress-inflammation network in lungs.

Inflammation is a central pathogenic feature of the acute respiratory distress syndrome (ARDS) in COVID-19. Previous pathologies such as diabetes, autoimmune or cardiovascular diseases become risk factors for the severe hyperinflammatory syndrome. A common feature among these risk factors is the subclinical presence of cellular stress, a finding that has gained attention after the discovery that BiP (GRP78), a master regulator of stress, participates in the SARS-CoV-2 recognition. Here, we show that BiP serum levels are higher in COVID-19 patients who present certain risk factors. Moreover, early during the infection, BiP levels predict severe pneumonia, supporting the use of BiP as a prognosis biomarker. Using a mouse model of pulmonary inflammation, we demonstrate that cell surface BiP (cs-BiP) responds by increasing its levels in leukocytes. Neutrophiles show the highest levels of cs-BiP and respond by increasing their population, whereas alveolar macrophages increase their levels of cs-BiP. The modulation of cellular stress with the use of a clinically approved drug, 4-PBA, resulted in the amelioration of the lung hyperinflammatory response, supporting the anti-stress therapy as a valid therapeutic strategy for patients developing ARDS. Finally, we identified stress-modulated proteins that shed light into the mechanism underlying the cellular stress-inflammation network in lungs.

SARS-CoV-2 infection can cause an inflammatory syndrome (COVID-19) leading, in many cases, to bilateral pneumonia, severe dyspnea, and in ~5% of these, death. DNAmethylation 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. 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 andmediated by genetic loci.We find an environmental trait-related signature that discriminatesmild from severe cases and regulates, among other cytokines, 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., Consejeria de Transformacion Economica, Industria, Conocimiento y Universidades of the regional government of Andalucia, European Union through European Regional Development Fund CV20-10150, Consejo Superior de Investigaciones cientificas CSIC-COV19-016/202020E155, Junta de Castilla y Leon COVID 07.04.467B04.74011.0, Consejeria de Salud y Familias of the regional government of Andalucia PECOVID-0072-2020, Instituto de Salud Carlos III (ISCIII, Spanish Health Ministry) through the Sara Borrell subprogram CD18/00153, Programa Estrategico Instituto de Biologia y Genetica Molecular, IBGM excellence programme CLU-2029-02 CCVC8485

Cocaine induces neuroinflammatory response and interleukin-1 beta (IL1β) is suggested a final effector for many cocaine-induced inflammatory signals. Recently, the chemokine fractalkine (CX