Functional proteomic profiling links deficient DNA clearance with increased mortality in individuals with severe COVID-19 pneumonia

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...

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Published in:	Immunity (Cambridge, Mass.) Mass.), 2022-12, Vol.55 (12), p.2436-2453.e5
Main Authors:	Aramburu, Iker Valle, Hoving, Dennis, Vernardis, Spyros I., Tin, Martha C.F., Ioannou, Marianna, Temkin, Mia I., De Vasconcelos, Nathalia M., Demichev, Vadim, Helbig, Elisa Theresa, Lippert, Lena, Stahl, Klaus, White, Matthew, Radbruch, Helena, Ihlow, Jana, Horst, David, Chiesa, Scott T., Deanfield, John E., David, Sascha, Bode, Christian, Kurth, Florian, Ralser, Markus, Papayannopoulos, Venizelos
Format:	Article
Language:	eng
Subjects:	actin Actins Animals Chromatin COVID-19 degradation Deoxyribonuclease I DNA DNase I histone inflammation Mice NETs Neutrophils Proteomics Sepsis
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Summary:	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. [Display omitted] •Infection drives actin release, blocks DNA degradation, and upregulates DNase I•DNA clearance is defective in sepsis, COVID-19 pneumonia, and chronic inflammation•Plasma proteomic profiling can track plasma DNA and NET degradation activity•Low protective NET degradation activity is linked to pathology and high mortality What determines survival during severe infection remains unclear. Aramburu, Hoving, et al. profile the plasma proteome of individuals with COVID-19 pneumonia or sepsis and link low extracellular chromatin clearance with increased mortality and inflammation that may pre-dispose healthy individuals to metabolic syndrome and pathology upon infection. Hence, poor survival results from a combination of aberrant release and low chromatin clearance.
ISSN:	1074-7613 1097-4180