Functional proteomic profiling links deficient DNA clearance with increased mortality in individuals with severe COVID-19 pneumonia
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Iker Valle Aramburu Dennis Hoving Spyros Vernardis Martha CF Tin Marianna Ioannou Mia Temkin Nathalia M De Vasconcelos Vadim Demichev Elisa Theresa Helbig Lena Lippert Klaus Stahl Matthew White Helena Radbruch Jana Ihlow David Horst Scott T Chiesa John E Deanfield Sascha David Christian Bode Florian Kurth Markus Ralser Venizelos PapayannopoulosAbstract
The factors that influence survival during severe infection are unclear. Extracellular chromatin drives pathology, but the mechanisms enabling its accumulation remain elusive. Here, we show that in murine sepsis models, splenocyte death interferes with chromatin clearance through the release of the DNase I inhibitor actin. Actin-mediated inhibition was compensated by upregulation of DNase I or the actin scavenger gelsolin. Splenocyte death and neutrophil extracellular trap (NET) clearance deficiencies were prevalent in individuals with severe COVID-19 pneumonia or microbial sepsis. Activity tracing by plasma proteomic profiling uncovered an association between low NET clearance and increased COVID-19 pathology and mortality. Low NET clearance activity with comparable proteome associations was prevalent in healthy donors with low-grade inflammation, implicating defective chromatin clearance in the development of cardiovascular disease and linking COVID-19 susceptibility to pre-existing conditions. Hence, the combination of aberrant chromatin release with defects in protective clearance mechanisms lead to poor survival outcomes.
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Journal Immunity
Volume 55
Issue number 12
Pages 2436-2453.e5
Available online
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Publisher website (DOI) 10.1016/j.immuni.2022.11.007
Europe PubMed Central 36462503
Pubmed 36462503
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