Leveraging clinical intervention in severe COVID-19 to reveal treatment and pathogenesis mechanisms

In this proposal, we will leverage two types of treatment interventions in severe COVID-19 to determine mechanisms of action.

Despite that several immunomodulatory treatments now are regularly used to treat severe COVID-19, we have a rudimentary understanding of which cellular targets and pathways that are interrupted and dampened.

In our first aim, we will make use of a large COVID-19 biobank that we have created during the first wave of the pandemic, perform propensity-score matching for corticosteroid treatment, and determine the effects of corticosteroids on the immune system in relation to clinical outcome.

Preliminary results from flow cytometry, proteomics, scRNAseq, and in vitro experiments suggest a model where, after innate sensing, IL-12 propagates a detrimental effector cell response.

In the second aim and in a randomized trial of IL-6 and IL-1b blockade in severe COVID-19, we will move beyond corticosteroid treatment and elucidate treatment mechanisms of these other novel therapeutics now available for severe COVID-19.

Preliminary results suggest that IL-6 and IL-1b blockade have specific but contrasting effects on hyperinflammation in patients.

The proposal builds on combining unique and well-designed clinical interventional treatment trials in severe COVID-19 with cutting-edge immunological methods and has the potential to generate novel insights into treatment mechanisms and disease pathogenesis.