Cellular stress modulates severity of the inflammatory response in lungs via cell surface BiP.

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.

Cellular stress modulates severity of the inflammatory response in lungs via cell surface BiP

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, a common mechanism in frailty and COVID-19, and stem cells as a therapeutic approach.

As our life expectancy increases, specific medical conditions appear, and new challenges are met in terms of global health. Frailty has become a medical and scientific concept to define pathologies where inflammation, depressed immune system, cellular senescence, and molecular aging converge. But more importantly, frailty is the ultimate cause of death that limits our life span and deteriorates health in an increasing proportion of the world population. The difficulty of tackling this problem is the combination of factors that influence frailty appearance, such as stem cells exhaustion, inflammation, loss of regeneration capability, and impaired immunomodulation. To date, multiple research fields have found mechanisms participating in this health condition, but to make progress, science will need to investigate frailty with an interdisciplinary approach. This article summarizes the current efforts to understand frailty from their processes mediated by inflammation, aging, and stem cells to provide a new perspective that unifies the efforts in producing advanced therapies against medical conditions in the context of frailty. We believe this approach against frailty is particularly relevant to COVID-19, since people in a state of frailty die more frequently due to the hyperinflammatory process associated with this infection.