Aramburu, Iker Valle;
Hoving, Dennis;
Vernardis, Spyros I;
Tin, Martha;
Ioannou, Marianna;
Temkin, Mia I;
De Vasconcelos, Nathalia M;
... Papayannopoulos, Venizelos; + view all
(2022)
Functional proteomic profiling links deficient DNA clearance with increased mortality in individuals with severe COVID-19 pneumonia.
Immunity
, 55
(12)
2436-2453.e5.
10.1016/j.immuni.2022.11.007.
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Abstract
The factors influencing survival during severe infection are unclear. Extracellular chromatin drives pathology, but the mechanisms enabling its accumulation remain elusive. Here, we showed that in murine sepsis models, splenocyte death interfered with chromatin clearance through the release of the DNase I inhibitor actin. Actin 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.
| Type: | Article |
|---|---|
| Title: | Functional proteomic profiling links deficient DNA clearance with increased mortality in individuals with severe COVID-19 pneumonia |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.immuni.2022.11.007 |
| Publisher version: | https://doi.org/10.1016/j.immuni.2022.11.007 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | DNA, degradation, proteomics, SARS-CoV-2, sepsis, DNase I, NETs, actin, COVID-19, histoneJournal Pre-proof |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Population Science and Experimental Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10160002 |
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