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RESEARCH QUESTION

Severely ill COVID-19 patients often show excessive lung inflammation and acute respiratory distress syndrome leading to multiorgan failure and eventually death. Here, we will study the underlying cause of these excessive inflammatory responses and how to specifically counteract them.

 

URGENCE

Current treatment options for the devastating hyperinflammatory responses in COVID-19 patients are very limited. Since the development and distribution of a vaccine will take long (1-2 years), there is an urgent need for treatment of the most severely ill patients.

 

HYPOTHESIS

We hypothesize that the IgG antibodies that are generated against the Spike protein of CoV-2 cause excessive lung inflammation and tissue damage in the most severe cases of COVID-19. It has been shown that the virus leading to SARS, SARS-CoV, causes severe inflammation and lung injury through anti-Spike IgG antibodies, by converting wound-healing lung macrophages into very pro-inflammatory cells. Our preliminary data demonstrates that in COVID-19 patients anti-SARS-CoV-2 IgGs very similarly break the wound-healing phenotype of human lung macrophages and airway epithelium. We identified that it is not only caused by the early rise and high titer of anti-Spike IgGs, but also because the anti-Spike IgGs of severe patients are intrinsically more pathogenic. Moreover, our data demonstrate that we can specifically counteract this hyperinflammation, using the FDA/EMA-approved therapeutic small molecule inhibitor Fostamatinib.

 

APPROACH

We will (1) unravel how anti-SARS-CoV-2 IgGs drive excessive inflammation by human lung macrophages and airway epithelium, and (2) test small molecule inhibitors that can be repurposed to counteract this. Combined, we will provide proof-of-concept for novel treatments of the most severely ill COVID-19 patients.

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