Intravascular crosstalk of interleukin-6 and therapeutic glucocorticoids in SARS-CoV2 infection
SARS-CoV2 is highly infectious and causes the disease COVID-19. 10-20 % of patients infected with SARS-CoV2 develop severe symptoms. In these patients, SARS-CoV2 can trigger a cytokine storm that leads to the life-threatening Cytokine Release Syndrome (CRS). Among the cytokines released, Interleukin-6 (IL-6), a paradigm pro-inflammatory cytokine with deleterious functions, correlates strongly with and predicts the severity of COVID-19. Noteworthy, systemic vascular complications in critically ill COVID-19 patients represent a main risk. The expression of SARS-CoV2 entry factors on vascular cells in virtually all organs suggests that vascular damage could be a consequence of lytic viral infection of vascular cells. However, it is also discussed that impaired vessel function is mediated by loss of function of non-infected vascular cells exposed to systemically elevated levels of IL-6. In addition, SARS-CoV2 may locally affect IL-6 signalling pathways by controlling the expression and release of IL-6 receptor subunits and IL-6 itself. The suspected role of IL-6 in the development of COVID-19 is the basis for several ongoing clinical trials with approved drugs that either inhibit IL-6 function extracellularly or intervene in intracellular IL-6 signal processing. However, the molecular mechanisms and pathophysiological consequences of IL-6 and the causes of vascular damage in COVID-19 are still unknown.
Preliminary results from clinics show that immunosuppressive glucocorticoids (GC) reduce deaths in certain patient groups by for so far unknown reasons. Remarkedly, both extracellular and intracellular IL-6 signalling is influenced by GC and vice versa IL-6 influences GC signalling. To address the increasing concerns about the efficacy of GC treatment for COVID-19 and possible (adverse) effects of GCs on the vascular system, the molecular mechanisms of GC action in SARS-CoV2-infected cells and the crosstalk of GC and IL-6 must be elucidated.
The aim of this project is to gain profound translational knowledge about molecular mechanisms and pathophysiological consequences of IL-6 and GC action in SARS-CoV2-infected cells and non-infected vascular cells. For this purpose, we will use highly defined 2D and 3D in vitro vascular models and single cell techniques to define the consequences of SARS-CoV2 infection in the two integral vessel cell types, endothelial cells and smooth muscle cells. The results obtained will be a prerequisite for understanding SARS-CoV2 infection and targeted development of treatments to cope with COVID-19.