{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T09:30:36Z","timestamp":1773048636383,"version":"3.50.1"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,1,11]],"date-time":"2023-01-11T00:00:00Z","timestamp":1673395200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004802","name":"California Breast Cancer Research Program","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004802","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014055","name":"US Army Medical Research Acquisition Activity","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014055","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Biosci."],"abstract":"<jats:p><jats:bold>Introduction:<\/jats:bold> Infection by SARS-CoV-2 and subsequent COVID-19 can cause viral sepsis. We investigated plasma protease activity patterns in COVID-19-induced sepsis with bacterial superinfection, as well as plasma proteomics and peptidomics in order to assess the possible implications of enhanced proteolysis on major protein systems (e.g., coagulation).<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> Patients (=4) admitted to the intensive care units (ICUs) at the University of California, San Diego (UCSD) Medical Center with confirmed positive test for COVID-19 by real-time reverse transcription polymerase chain reaction (RT-PCR) were enrolled in a study approved by the UCSD Institutional Review Board (IRB# 190699, Protocol #20-0006). Informed consent was obtained for the collection of blood samples and de-identified use of the data. Blood samples were collected at multiple time points and analyzed to quantify a) the circulating proteome and peptidome by mass spectrometry; b) the aminopeptidase activity in plasma; and c) the endopeptidase activity in plasma using fluorogenic substrates that are cleaved by trypsin-like endopeptidases, specific clotting factors and plasmin. The one patient who died was diagnosed with bacterial superinfection on day 7 after beginning of the study.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> Spikes in protease activity (factor VII, trypsin-like activity), and corresponding increases in the intensity of peptides derived by hydrolysis of plasma proteins, especially of fibrinogen degradation products and downregulation of endogenous protease inhibitors were detected on day 7 for the patient who died. The activity of the analyzed proteases was stable in survivors.<\/jats:p><jats:p><jats:bold>Discussion:<\/jats:bold> The combination of multiomics and enzymatic activity quantification enabled to i) hypothesize that elevated proteolysis occurs in COVID-19-induced septic shock with bacterial superinfection, and ii) provide additional insight into malfunctioning protease-mediated systems, such as hemostasis.<\/jats:p>","DOI":"10.3389\/fmolb.2022.1051471","type":"journal-article","created":{"date-parts":[[2023,1,11]],"date-time":"2023-01-11T06:55:21Z","timestamp":1673420121000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Plasma enzymatic activity, proteomics and peptidomics in COVID-19-induced sepsis: A novel approach for the analysis of hemostasis"],"prefix":"10.3389","volume":"9","author":[{"given":"Fernando","family":"Dos Santos","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joyce B.","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nathalia","family":"Juocys","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rafi","family":"Mazor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Beretta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole G.","family":"Coufal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael T. Y.","family":"Lam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mazen F.","family":"Odish","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Claudia","family":"Irigoyen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony J.","family":"O\u2019Donoghue","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Federico","family":"Aletti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erik B.","family":"Kistler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,1,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1186\/s13049-016-0197-4","article-title":"ShockOmics: Multiscale approach to the identification of molecular biomarkers in acute heart failure induced by shock","volume":"24","author":"Aletti","year":"2016","journal-title":"Scand. J. Trauma Resusc. Emerg. Med."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1579","DOI":"10.1007\/s00068-020-01591-y","article-title":"Continuous enteral protease inhibition as a novel treatment for experimental trauma\/hemorrhagic shock","volume":"48","author":"Aletti","year":"2022","journal-title":"Eur. J. Trauma Emerg. Surg."},{"key":"B3","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1097\/SHK.0000000000000532","article-title":"Peptidomic analysis of rat plasma: Proteolysis in hemorrhagic shock","volume":"45","author":"Aletti","year":"2016","journal-title":"Shock"},{"key":"B4","doi-asserted-by":"publisher","first-page":"e219","DOI":"10.1097\/CCM.0000000000004899","article-title":"Surviving sepsis campaign guidelines on the management of adults with coronavirus disease 2019 (COVID-19) in the ICU: First update","volume":"49","author":"Alhazzani","year":"2021","journal-title":"Crit. Care Med."},{"key":"B5","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1007\/s12185-020-03029-y","article-title":"COVID-19-associated coagulopathy and disseminated intravascular coagulation","volume":"7","author":"Asakura","year":"2020","journal-title":"Int. J. Hematol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1065","DOI":"10.1016\/j.bja.2018.05.072","article-title":"Proteolysis in septic shock patients: Plasma peptidomic patterns are associated with mortality","volume":"121","author":"Bauz\u00e1-Martinez","year":"2018","journal-title":"Br. J. Anaesth."},{"key":"B7","doi-asserted-by":"publisher","first-page":"3205072","DOI":"10.1155\/2019\/3205072","article-title":"Ficolins and the recognition of pathogenic microorganisms: An overview of the innate immune response and contribution of single nucleotide polymorphisms","volume":"2019","author":"Bidula","year":"2019","journal-title":"J. Immunol. Res."},{"key":"B8","doi-asserted-by":"publisher","first-page":"2100377","DOI":"10.1183\/13993003.00377-2021","article-title":"Between inflammation and thrombosis: Endothelial cells in COVID-19","volume":"58","author":"Birnhuber","year":"2021","journal-title":"Eur. Respir. J."},{"key":"B9","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1186\/s13054-019-2670-8","article-title":"A longitudinal study highlights shared aspects of the transcriptomic response to cardiogenic and septic shock","volume":"23","author":"Braga","year":"2019","journal-title":"Crit. Care"},{"key":"B10","doi-asserted-by":"publisher","first-page":"6681","DOI":"10.1038\/s41598-018-25035-1","article-title":"An innovative approach for the integration of proteomics and metabolomics data in severe septic shock patients stratified for mortality","volume":"8","author":"Cambiaghi","year":"2018","journal-title":"Sci. Rep."},{"key":"B11","doi-asserted-by":"publisher","first-page":"9748","DOI":"10.1038\/s41598-017-09619-x","article-title":"Characterization of a metabolomic profile associated with responsiveness to therapy in the acute phase of septic shock","volume":"7","author":"Cambiaghi","year":"2017","journal-title":"Sci. Rep."},{"key":"B12","doi-asserted-by":"publisher","first-page":"2200803","DOI":"10.1183\/13993003.00803-2022","article-title":"Update june 2022: Management of hospitalised adults with coronavirus disease 2019 (COVID-19): A European respiratory society living guideline","volume":"57","author":"Chalmers","year":"2021","journal-title":"Eur. Respir. J."},{"key":"B13","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1007\/s12195-021-00693-w","article-title":"Digestive enzyme activity and protein degradation in plasma of heart failure patients","volume":"14","author":"Courelli","year":"2021","journal-title":"Cell Mol. Bioeng."},{"key":"B14","doi-asserted-by":"publisher","first-page":"780","DOI":"10.1016\/j.cels.2021.05.005","article-title":"A time-resolved proteomic and prognostic map of COVID-19","volume":"12","author":"Demichev","year":"2021","journal-title":"Cell Syst."},{"key":"B15","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/j.cmi.2020.07.041","article-title":"Incidence of co-infections and superinfections in hospitalized patients with COVID-19: A retrospective cohort study","volume":"27","author":"Garcia-Vidal","year":"2021","journal-title":"Clin. Microbiol. Infect."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1133","DOI":"10.1021\/acs.jproteome.0c00764","article-title":"Proteomic approaches to study SARS-CoV-2 Biology and COVID-19 pathology","volume":"20","author":"Haas","year":"2021","journal-title":"J. Proteome Res."},{"key":"B17","doi-asserted-by":"publisher","first-page":"2103","DOI":"10.1111\/jth.14975","article-title":"Coagulopathy in COVID-19","volume":"18","author":"Iba","year":"2020","journal-title":"J. Thromb. Haemost."},{"key":"B18","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1186\/s13054-020-03079-y","article-title":"VEGF-D: A novel biomarker for detection of COVID-19 progression","volume":"24","author":"Kong","year":"2020","journal-title":"Crit. Care"},{"key":"B19","doi-asserted-by":"publisher","first-page":"100745","DOI":"10.1016\/j.blre.2020.100745","article-title":"Coagulation dysfunction in COVID-19: The interplay between inflammation, viral infection and the coagulation system","volume":"46","author":"Lazzaroni","year":"2021","journal-title":"Blood Rev."},{"key":"B20","doi-asserted-by":"publisher","first-page":"593223","DOI":"10.3389\/fphys.2021.593223","article-title":"Pathogenesis of multiple organ injury in COVID-19 and potential therapeutic strategies","volume":"12","author":"Lopes-Pacheco","year":"2021","journal-title":"Front. Physiol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"4071","DOI":"10.3390\/molecules25184071","article-title":"High-resolution mass spectrometry-based approaches for the detection and quantification of peptidase activity in plasma","volume":"25","author":"Maffioli","year":"2020","journal-title":"Molecules"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1039","DOI":"10.1093\/infdis\/jiz585","article-title":"Toward rapid sepsis diagnosis and patient stratification: What's new from microbiology and omics Science","volume":"221","author":"Mangioni","year":"2020","journal-title":"J. Infect. Dis."},{"key":"B23","doi-asserted-by":"publisher","first-page":"712","DOI":"10.1021\/acs.jproteome.6b00751","article-title":"Peptigram: A web-based application for peptidomics data visualization","volume":"16","author":"Manguy","year":"2017","journal-title":"J. Proteome Res."},{"key":"B24","doi-asserted-by":"publisher","first-page":"4627","DOI":"10.1021\/acs.jproteome.1c00475","article-title":"Discovery proteomics for COVID-19: Where we are now","volume":"20","author":"McArdle","year":"2021","journal-title":"J. Proteome Res."},{"key":"B25","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.cels.2020.05.012","article-title":"Ultra-high-throughput clinical proteomics reveals classifiers of COVID-19 infection","volume":"11","author":"Messner","year":"2020","journal-title":"Cell Syst."},{"key":"B26","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1097\/SHK.0000000000001565","article-title":"SARS-CoV-2\/COVID-19: Evolving reality, global response, knowledge gaps, and opportunities","volume":"54","author":"Osuchowski","year":"2020","journal-title":"Shock"},{"key":"B27","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1016\/S2213-2600(21)00218-6","article-title":"The COVID-19 puzzle: Deciphering pathophysiology and phenotypes of a new disease entity","volume":"9","author":"Osuchowski","year":"2021","journal-title":"Lancet Respir. Med."},{"key":"B28","doi-asserted-by":"publisher","first-page":"e12642","DOI":"10.15252\/emmm.202012642","article-title":"Rationale for targeting complement in COVID-19","volume":"12","author":"Polycarpou","year":"2020","journal-title":"EMBO Mol. Med."},{"key":"B29","doi-asserted-by":"publisher","first-page":"3487","DOI":"10.3390\/jcm9113487","article-title":"Covid-19-Associated coagulopathy: Biomarkers of thrombin generation and fibrinolysis leading the outcome","volume":"9","author":"Ranucci","year":"2020","journal-title":"J. Clin. Med."},{"key":"B30","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1186\/s40635-021-00383-x","article-title":"Sepsis: Deriving biological meaning and clinical applications from high-dimensional data","volume":"9","author":"Schuurman","year":"2021","journal-title":"Intensive Care Med. Exp."},{"key":"B31","doi-asserted-by":"publisher","first-page":"15606","DOI":"10.1038\/s41598-017-15755-1","article-title":"Proteomic study revealed cellular assembly and lipid metabolism dysregulation in sepsis secondary to community-acquired pneumonia","volume":"7","author":"Sharma","year":"2017","journal-title":"Sci. Rep."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1708","DOI":"10.3389\/fimmu.2020.01708","article-title":"Cytokine storm in COVID-19: The current evidence and treatment strategies","volume":"11","author":"Tang","year":"2020","journal-title":"Front. Immunol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"200384","DOI":"10.1183\/16000617.0384-2020","article-title":"Current evidence for COVID-19 therapies: A systematic literature review","volume":"30","author":"Welte","year":"2021","journal-title":"Eur. Respir. Rev."},{"key":"B34","doi-asserted-by":"publisher","first-page":"782","DOI":"10.1001\/jama.2020.12839","article-title":"Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): A review","volume":"324","author":"Wiersing","year":"2020","journal-title":"JAMA"}],"container-title":["Frontiers in Molecular Biosciences"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2022.1051471\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,11]],"date-time":"2023-01-11T06:55:25Z","timestamp":1673420125000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2022.1051471\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,11]]},"references-count":34,"alternative-id":["10.3389\/fmolb.2022.1051471"],"URL":"https:\/\/doi.org\/10.3389\/fmolb.2022.1051471","relation":{},"ISSN":["2296-889X"],"issn-type":[{"value":"2296-889X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,11]]},"article-number":"1051471"}}