An infection with SARS-CoV-2 leaves some people almost unaffected, while others develop life-threatening COVID-19 disease. Until now, it has not been understood exactly why individuals show such great differences in the course of the disease, especially in those carrying the variant of origin. Scientists have now discovered that in addition to strong immune activation and inflammatory reactions, severe courses are primarily characterized by a dysfunction of the endothelium, i.e. the vascular system: If this barrier between blood flow and tissue is damaged, the patient's condition worsens.
"In our study, we investigated which immune cells are activated in severe cases and in which way the endothelium, i.e. the blood vessels, and their activation play a role in the disease process," explains Prof. Dr. Christine Falk, a scientist at Hannover Medical School (MHH), a scientist at the German Center for Lung Research (DZL) as well as at the German Center for Infection Research (DZIF). Many clinical symptoms, such as the destruction of blood vessels in the lungs and acute respiratory distress syndrome, pointed to an influence of the endothelium.
The endothelium describes a thin layer of cells that line blood vessels, forming a barrier between blood flow and tissues. Infection with SARS-CoV-2 appears to cause strong activation of immune and endothelial cells in the lung, resulting in the release of various soluble plasma proteins. In severe COVID-19 courses, these are associated with endothelial dysfunction, and the barrier between the alveoli and surrounding vessels is no longer intact.
In their study of 25 patients with severe COVID-19 and 17 recovered patients in the intensive care unit, the scientists were able to prove that the severity of the disease is associated with the disruption of the endothelial barrier and can be measured by inflammatory plasma proteins. A pattern of seven plasma proteins appears to occur in association with severe disease characterized by strong inflammatory processes and in which the endothelium is permanently damaged. Furthermore, recovery from severe COVID-19 cases seems to be related to the regeneration of this endothelial barrier.
Which immune cells were detected in the COVID-19 intensive care patients? The study showed that there is an exaggerated activation of T lymphocytes and natural killer cells, as well as the development of memory T cells and a strong proliferation of plasmablasts, cells that can produce large amounts of antibodies. Furthermore, COVID-19 intensive care patients exhibit high titers of spike and nucleocapsid-specific antibodies. Interestingly, the immune cell phenotype of these patients changed primarily over time and was less related to progressive severity. The progression of COVID-19, on the other hand, was closely associated with elevated levels of several soluble plasma proteins, namely certain inflammatory mediators and especially endothelial factors.
"We were able to show that COVID-19 intensive care patients can be divided into different groups based on their plasma protein profile, which are associated with the severity of the disease," explains first author Louisa Ruhl, a PhD student at MHH. This finding is of great importance for the identification of potential biomarkers for severe COVID-19 progression, as well as for the development and use of new therapeutic approaches.
Christine Falk's team now wants to find out which players of the immune system lead to activation and damage of the endothelium and whether the strong activation of the immune system also leads to the development of virus-specific T lymphocytes, which can recognize and destroy infected cells and thus contribute to overreaction. In addition, the study has shown that there are also shifts in the immune cell repertoire in recovered COVID-19 intensive care patients. This could be related to the development of long COVID disease. These aspects are currently funded within the COFONI initiative of the state of Lower Saxony with a Fasttrack and a Flexfunds project. Along with cooperation partners from pneumology, Prof. Tobias Welte (MHH and DZL) and neurology, Prof. Günter Höglinger, MHH, want to investigate not only whether the endothelial inflammation causes lasting damage due to an overreaction of T- and NK-cells, but also to what extent the regeneration of the lung is impaired and how the nervous system is affected.
The study was conducted jointly with scientists and clinicians from the MHH, the German Center for Lung Research (DZL) and scientists at the University Hospital Erlangen.
Original publication: Ruhl L, Pink I, Kühne JF, Beushausen K, Keil J, Christoph S, Sauer A, Boblitz L, Schmidt J, David S, Jäck HM, Roth E, Cornberg M, Schulz TF, Welte T, Höper MM, Falk CS. Endothelial dysfunction contributes to severe COVID-19 in combination with dysregulated lymphocyte responses and cytokine networks. Signal Transduct Target Ther. 2021 Dec 10;6(1):418. doi: 10.1038/s41392-021-00819-6. PMID: 34893580; PMCID: PMC8661333.