Phenotypic and functional analysis of immune cells during severe COVID-19

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The consequences of the novel coronavirus disease 2019 (COVID-19) are posing great challenges to the people, public health and healthcare systems worldwide. In order to get the SARS-CoV2 pandemic under control, it is of utmost importance to understand the host response against this virus. On the one hand, characterizing the mechanisms of immune activation will help to identify therapeutic targets in the course of the disease, especially since immune pathology is contributing to tissue damage during COVID-19. On the other hand, an in-depth characterization of the immunological memory response against SARS-CoV2 will help to design efficient, protective vaccination strategies. Here, we propose to combine multiplexed histology with spatially resolved transcriptomic analyses in autopsy tissues, in order to phenotypically characterize and map the immune response during severe COVID-19. We will analyze various time points in the lung as a target organ of the disease, as well as in the corresponding secondary lymphoid organs of the same patients namely the draining lymph nodes and tonsils. We will employ functional fluorescence lifetime imaging in 3D-culture models in order to test the hypothesis that innate mechanisms such as NETosis are one driving force for tissue damage, and assess the communication between macrophages and neutrophils. Since a dysregulated innate immune response against SARS-CoV2 is hypothesized to also impact on the adaptive immune response, we are planning to characterize T cell and B cell responses in the tissues, with a focus on the generation of tissue-specific immunological memory, and on the characterization of the cellular and molecular microenvironment that fosters this process.In a synergistic way, this proposal combines the expertise of the three applicants with respect to pathology, immunology and state-of-the-art imaging technology, in order to elucidate the mechanisms of immune pathology underlying severe COVID-19, and to explore the potential of tissue-specific protection by resident memory cells.