Taming the SARS-CoV-2-mediated proinflammatory response with BromAc®
Geovane Marques Ferreira, Felipe Alves Clarindo, Ágata Lopes Ribeiro, Letícia Gomes-De-Pontes, Luciana Debortoli De Carvalho, Olindo Assis Martins-Filho, Flávio Guimarães Da Fonseca, Mauro Martins Teixeira, Adriano De Paula Sabino, Mathew Suji Eapen, David L Morris, Sarah J Valle, Jordana Grazziela Alves Coelho-Dos-Reis
Frontiers in Immunology, doi:10.3389/fimmu.2023.1308477
Introduction: In the present study, the impact of BromAc®, a specific combination of bromelain and acetylcysteine, on the SARS-CoV-2-specific inflammatory response was evaluated. Methods: An in vitro stimulation system was standardized using blood samples from 9 healthy donors, luminex assays and flow cytometry were performed. Results and discussion: BromAc® demonstrated robust anti-inflammatory activity in human peripheral blood cells upon SARS-CoV-2 viral stimuli, reducing the cytokine storm, composed of chemokines, growth factors, and proinflammatory and regulatory cytokines produced after short-term in vitro culture with the inactivated virus (iSARS-CoV-2). A combined reduction in vascular endothelial growth factor (VEGF) induced by SARS-CoV-2, in addition to steady-state levels of platelet recruitment-associated growth factor-PDGFbb, was observed, indicating that BromAc® may be important to reduce thromboembolism in COVID-19. The immunophenotypic analysis of the impact of BromAc® on leukocytes upon viral stimuli showed that BromAc® was able to downmodulate the populations of CD16+ neutrophils and CD14+ monocytes observed after stimulation with iSARS-CoV-2. Conversely, BromAc® treatment increased steady-state HLA-DR expression in CD14 + monocytes and preserved this activation marker in this subset upon iSARS-CoV-2 stimuli, indicating improved monocyte activation upon BromAc® treatment. Additionally, BromAc® downmodulated the iSARS-CoV-2-induced production of TNF-a by the CD19+ B-cells. System biology approaches, utilizing comprehensive correlation matrices and networks, showed distinct patterns of connectivity in groups Frontiers in Immunology frontiersin.org 01
Ethics statement The studies involving humans were approved by Ethics Committee of Universidade Estadual de Santa Cruz (UESC) and Federal University of Minas Gerais (UFMG). The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.
Author contributions
Funding The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by Fundacão de Amparo à Pesquisa de Minas Gerais (FAPEMIG, APQ-01499-21), Conselho Nacional de Desenvolvimento Cientıfco e Tecnoloǵico (CNPq MCTI/CNPQ/Universal), EMBRAPII (Process # 30275) and Coordenacão de Aperfeicoamento de Pessoal de Nıvel Superior (CAPES). FF, OM, MT, and JC-d-R received PQ fellowships from CNPq. This work was also funded by extramural resources from Mucpharm Pty Ltd (AU). OF participated in the fellow program supported by the Universidade do Estado do Amazonas (PROVISIT N°005/2023-PROPESP/UEA).
Conflict of interest SV and DM are shareholders of Mucpharm Pty Ltd. and provided scientific input on the protocol and design of the study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Mucpharm Pty Ltd. The funder had the following..
References
Abdelrahman, Abd-Elrahman, Bakheet, Persistence of symptoms after improvement of acute COVID-19 infection, a longitudinal study, J Med Virol,
doi:10.1002/jmv.27156Akhter, Queŕomès, Pillai, Kepenekian, Badar et al., The combination of bromelain and acetylcysteine (BromAc) synergistically inactivates SARS-CoV-2, Viruses,
doi:10.3390/v13030425Barnes, Adrover, Baxter-Stoltzfus, Borczuk, Cools-Lartigue et al., Targeting potential drivers of COVID-19: Neutrophil extracellular traps, J Exp Med,
doi:10.1084/jem.20200652Barth, Guseo, Klein, In vitro study on the immunological effect of bromelain and trypsin on mononuclear cells from humans, Eur J Med Res
Bateman, Dear, Thanacoody, Thomas, Eddleston et al., Reduction of adverse effects from intravenous acetylcysteine treatment for paracetamol poisoning: a randomised controlled trial, Lancet,
doi:10.1016/S0140-6736(13)62062-0Bösmüller, Traxler, Bitzer, Häberle, Raiser et al., The evolution of pulmonary pathology in fatal COVID-19 disease: an autopsy study with clinical correlation, Virchows Archiv,
doi:10.1007/s00428-020-02881-xCoelho Dos Reis, Ferreira, Lourenco, Ribeiro, ́l et al., Ex-vivo mucolytic and anti-inflammatory activity of BromAc in tracheal aspirates from COVID-19, Biomed Pharmacother,
doi:10.1016/j.biopha.2022.112753Darif, Hammi, Kihel, Idrissi Saik, Guessous et al., The proinflammatory cytokines in COVID-19 pathogenesis: What goes wrong?, Microb Pathog,
doi:10.1016/j.micpath.2021.104799Declercq, Leeuw, Lambrecht, Inflammasomes and IL-1 family cytokines in SARS-CoV-2 infection: from prognostic marker to therapeutic agent, Cytokine,
doi:10.1016/j.cyto.2022.155934Fitzhugh, Shan, Dewhirst, Hale, Bromelain treatment decreases neutrophil migration to sites of inflammation, Clin Immunol,
doi:10.1016/j.clim.2008.02.015Goncalves, Da Mata, Lourenco, Ribeiro, ́l et al., Timeline kinetics of systemic and airway immune mediator storm for comprehensive analysis of disease outcome in critically ill COVID-19 patients, Front Immunol,
doi:10.3389/fimmu.2022.903903Gusev, Sarapultsev, Solomatina, Chereshnev, SARS-coV-2-specific immune response and the pathogenesis of COVID-19, Int J Mol Sci,
doi:10.3390/ijms23031716Huang, Wu, Hou, Jeng, Bromelain inhibits lipopolysaccharide-induced cytokine production in human THP-1 monocytes via the removal of CD14, Immunol Invest,
doi:10.1080/08820130802083622Jukema, Smit, Hopman, Bongers, Pelgrim et al., Neutrophil and eosinophil responses remain abnormal for several months in primary care patients with COVID-19 disease, Front Allergy,
doi:10.3389/falgy.2022.942699Khan, Khan, Charles, Pratap, Naeem et al., Cytokine storm and mucus hypersecretion in COVID-19: review of mechanisms, J Inflammation Res,
doi:10.2147/JIR.S271292Kleef, Delohery, Bovbjerg, Selective modulation of cell adhesion molecules on lymphocytes by bromelain protease 5, Pathobiology,
doi:10.1159/000164070Knight, Caricchio, Casanova, Combes, Diamond et al., The intersection of COVID-19 and autoimmunity, J Clin Invest,
doi:10.1172/JCI154886Li, Hilgenfeld, Whitley, Clercq, Therapeutic strategies for COVID-19: progress and lessons learned, Nat Rev Drug Discovery,
doi:10.1038/s41573-023-00672-yLourda, Dzidic, Hertwig, Bergsten, Medina et al., High-dimensional profiling reveals phenotypic heterogeneity and disease-specific alterations of granulocytes in COVID-19, Proc Natl Acad Sci,
doi:10.1073/pnas.2109123118Mohanty, Padhy, Das, Meher, Therapeutic potential of N-acetyl cysteine (NAC) in preventing cytokine storm in COVID-19: review of current evidence, Eur Rev Med Pharmacol Sci,
doi:10.26355/eurrev_202103_25442Mokhtari, Afsharian, Shahhoseini, Kalantar, Moini, A review on various uses of N-acetyl cysteine citation, Cell Journal,
doi:10.22074/cellj.2016.4872Montazersaheb, Khatibi, Hejazi, Tarhriz, Farjami et al., COVID-19 infection: an overview on cytokine storm and related interventions, Virol J,
doi:10.1186/s12985-022-01814-1Nasrollahi, Talepoor, Saleh, Vakili, Heydarinezhad et al., Immune responses in mildly versus critically ill COVID-19 patients, Front Immunol,
doi:10.3389/fimmu.2023.1077236Onken, Greer, Calingaert, Hale, Bromelain treatment decreases secretion of pro-inflammatory cytokines and chemokines by colon biopsies in vitro, Clin Immunol,
doi:10.1016/j.clim.2007.11.002Paho, Who, Pan American Health Organization, Update on variant of interest EG.5 and variant under surveillance BA
Potere, Buono, Caricchio, Cremer, Vecchiéa et al., Interleukin-1 and the NLRP3 inflammasome in COVID-19: Pathogenetic and therapeutic implications, EBioMedicine,
doi:10.1016/j.ebiom.2022.104299Proal, Vanelzakker, Long COVID or post-acute sequelae of COVID-19 (PASC): an overview of biological factors that may contribute to persistent symptoms, Front Microbiol,
doi:10.3389/fmicb.2021.698169Rodrıǵuez, Novelli, Rojas, Santis, Acosta-Ampudia et al., Autoinflammatory and autoimmune conditions at the crossroad of COVID-19, J Autoimmun,
doi:10.1016/j.jaut.2020.102506Tysnes, Maurert, Porwol, Probst, Bjerkvig et al., Bromelain reversibly inhibits invasive properties of glioma cells, Neoplasia,
doi:10.1038/sj.neo.7900196Valle, Akhter, Mekkawy, Lodh, Pillai et al., A novel treatment of bromelain and acetylcysteine (BromAc) in patients with peritoneal mucinous tumours: A phase I first in man study, Eur J Surg Oncol,
doi:10.1016/j.ejso.2019.10.033Vj, Illescas-Montes, Puerta-Puerta, Ruiz, Melguizo-Rodrıǵuez, SARS-CoV-2 infection: The role of cytokines in COVID-19 disease, Cytokine Growth Factor Rev,
doi:10.1016/j.cytogfr.2020.06.001Wang, Wong, Ouyang, Rutz, Targeting IL-10 family cytokines for the treatment of human diseases, Cold Spring Harb Perspect Biol,
doi:10.1101/cshperspect.a028548Wilk, Rustagi, Zhao, Roque, Martıńez-Coloń et al., A single-cell atlas of the peripheral immune response in patients with severe COVID-19, Nat Med,
doi:10.1038/s41591-020-0944-yZhang, Qin, Li, Wang, Zhao et al., A novel scoring system for prediction of disease severity in COVID-19, Front Cell Infect Microbiol,
doi:10.3389/fcimb.2020.00318{ 'indexed': { 'date-parts': [[2023, 12, 14]],
'date-time': '2023-12-14T00:58:55Z',
'timestamp': 1702515535915},
'reference-count': 48,
'publisher': 'Frontiers Media SA',
'license': [ { 'start': { 'date-parts': [[2023, 12, 13]],
'date-time': '2023-12-13T00:00:00Z',
'timestamp': 1702425600000},
'content-version': 'vor',
'delay-in-days': 0,
'URL': 'https://creativecommons.org/licenses/by/4.0/'}],
'content-domain': {'domain': ['frontiersin.org'], 'crossmark-restriction': True},
'abstract': '<jats:sec><jats:title>Introduction</jats:title><jats:p>In the present study, the impact of '
'BromAc®, a specific combination of bromelain and acetylcysteine, on the SARS-CoV-2-specific '
'inflammatory response was '
'evaluated.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>An in vitro '
'stimulation system was standardized using blood samples from 9 healthy donors, luminex assays '
'and flow cytometry were performed. </jats:p></jats:sec><jats:sec><jats:title>Results and '
'discussion</jats:title><jats:p>BromAc® demonstrated robust anti-inflammatory activity in '
'human peripheral blood cells upon SARS-CoV-2 viral stimuli, reducing the cytokine storm, '
'composed of chemokines, growth factors, and proinflammatory and regulatory cytokines produced '
'after short-term in vitro culture with the inactivated virus (iSARS-CoV-2). A combined '
'reduction in vascular endothelial growth factor (VEGF) induced by SARS-CoV-2, in addition to '
'steady-state levels of platelet recruitment-associated growth factor-PDGFbb, was observed, '
'indicating that BromAc® may be important to reduce thromboembolism in COVID-19. The '
'immunophenotypic analysis of the impact of BromAc® on leukocytes upon viral stimuli showed '
'that BromAc® was able to downmodulate the populations of CD16+ neutrophils and CD14+ '
'monocytes observed after stimulation with iSARS-CoV-2. Conversely, BromAc® treatment '
'increased steady-state HLA-DR expression in CD14+ monocytes and preserved this activation '
'marker in this subset upon iSARS-CoV-2 stimuli, indicating improved monocyte activation upon '
'BromAc® treatment. Additionally, BromAc® downmodulated the iSARS-CoV-2-induced production of '
'TNF-a by the CD19+ B-cells. System biology approaches, utilizing comprehensive correlation '
'matrices and networks, showed distinct patterns of connectivity in groups treated with '
'BromAc®, suggesting loss of connections promoted by the compound and by iSARS-CoV-2 stimuli. '
'Negative correlations amongst proinflammatory axis and other soluble and cellular factors '
'were observed in the iSARS-CoV-2 group treated with BromAc® as compared to the untreated '
'group, demonstrating that BromAc® disengages proinflammatory responses and their interactions '
'with other soluble factors and the axis orchestrated by '
'SARS-CoV-2.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>These '
'results give new insights into the mechanisms for the robust anti-inflammatory effect of '
'BromAc® in the steady state and SARS-CoV-2-specific immune leukocyte responses, indicating '
'its potential as a therapeutic strategy for COVID-19.</jats:p></jats:sec>',
'DOI': '10.3389/fimmu.2023.1308477',
'type': 'journal-article',
'created': { 'date-parts': [[2023, 12, 13]],
'date-time': '2023-12-13T04:27:59Z',
'timestamp': 1702441679000},
'update-policy': 'http://dx.doi.org/10.3389/crossmark-policy',
'source': 'Crossref',
'is-referenced-by-count': 0,
'title': 'Taming the SARS-CoV-2-mediated proinflammatory response with BromAc®',
'prefix': '10.3389',
'volume': '14',
'author': [ {'given': 'Geovane Marques', 'family': 'Ferreira', 'sequence': 'first', 'affiliation': []},
{'given': 'Felipe Alves', 'family': 'Clarindo', 'sequence': 'additional', 'affiliation': []},
{'given': 'Ágata Lopes', 'family': 'Ribeiro', 'sequence': 'additional', 'affiliation': []},
{'given': 'Letícia', 'family': 'Gomes-de-Pontes', 'sequence': 'additional', 'affiliation': []},
{ 'given': 'Luciana Debortoli',
'family': 'de Carvalho',
'sequence': 'additional',
'affiliation': []},
{ 'given': 'Olindo Assis',
'family': 'Martins-Filho',
'sequence': 'additional',
'affiliation': []},
{ 'given': 'Flávio Guimarães',
'family': 'da Fonseca',
'sequence': 'additional',
'affiliation': []},
{'given': 'Mauro Martins', 'family': 'Teixeira', 'sequence': 'additional', 'affiliation': []},
{'given': 'Adriano de Paula', 'family': 'Sabino', 'sequence': 'additional', 'affiliation': []},
{'given': 'Mathew Suji', 'family': 'Eapen', 'sequence': 'additional', 'affiliation': []},
{'given': 'David L.', 'family': 'Morris', 'sequence': 'additional', 'affiliation': []},
{'given': 'Sarah J.', 'family': 'Valle', 'sequence': 'additional', 'affiliation': []},
{ 'given': 'Jordana Grazziela Alves',
'family': 'Coelho-dos-Reis',
'sequence': 'additional',
'affiliation': []}],
'member': '1965',
'published-online': {'date-parts': [[2023, 12, 13]]},
'reference': [ { 'key': 'B1',
'unstructured': 'Pan American Health Organization, Update on variant of interest EG.5 and '
'variant under surveillance BA.2.862023'},
{ 'key': 'B2',
'unstructured': 'l World Health Organization, EG.5 Initial Risk Evaluation2023'},
{ 'key': 'B3',
'unstructured': 'l government services United kingdom, SARS-CoV-2 genome sequence '
'prevalence and growth rate update2023'},
{ 'key': 'B4',
'doi-asserted-by': 'publisher',
'DOI': '10.3389/fmicb.2021.698169',
'article-title': 'Long COVID or post-acute sequelae of COVID-19 (PASC): an overview of '
'biological factors that may contribute to persistent symptoms',
'volume': '12',
'author': 'Proal',
'year': '2021',
'journal-title': 'Front Microbiol'},
{ 'key': 'B5',
'doi-asserted-by': 'publisher',
'DOI': '10.1007/s00428-020-02881-x',
'article-title': 'The evolution of pulmonary pathology in fatal COVID-19 disease: an '
'autopsy study with clinical correlation',
'volume': '477',
'author': 'Bösmüller',
'year': '2020',
'journal-title': 'Virchows Archiv'},
{ 'key': 'B6',
'doi-asserted-by': 'publisher',
'first-page': '9915',
'DOI': '10.1038/s41598-022-13986-5',
'article-title': 'A prolonged innate systemic immune response in COVID-19',
'volume': '12',
'author': 'Ekstedt',
'year': '2022',
'journal-title': 'Sci Rep'},
{ 'key': 'B7',
'doi-asserted-by': 'publisher',
'DOI': '10.3389/fimmu.2023.1077236',
'article-title': 'Immune responses in mildly versus critically ill COVID-19 patients',
'volume': '14',
'author': 'Nasrollahi',
'year': '2023',
'journal-title': 'Front Immunol'},
{ 'key': 'B8',
'doi-asserted-by': 'publisher',
'DOI': '10.1002/jmv.27156',
'article-title': 'Persistence of symptoms after improvement of acute COVID-19 infection, '
'a longitudinal study',
'volume': '93',
'author': 'Abdelrahman',
'year': '2021',
'journal-title': 'J Med Virol'},
{ 'key': 'B9',
'doi-asserted-by': 'publisher',
'DOI': '10.1038/s41573-023-00672-y',
'article-title': 'Therapeutic strategies for COVID-19: progress and lessons learned',
'volume': '22',
'author': 'Li',
'year': '2023',
'journal-title': 'Nat Rev Drug Discovery'},
{ 'key': 'B10',
'doi-asserted-by': 'publisher',
'DOI': '10.3390/v13030425',
'article-title': 'The combination of bromelain and acetylcysteine (BromAc) '
'synergistically inactivates SARS-CoV-2',
'volume': '13',
'author': 'Akhter',
'year': '2021',
'journal-title': 'Viruses'},
{ 'key': 'B11',
'doi-asserted-by': 'publisher',
'first-page': '112753',
'DOI': '10.1016/j.biopha.2022.112753',
'article-title': 'Ex-vivo mucolytic and anti-inflammatory activity of BromAc in tracheal '
'aspirates from COVID-19',
'volume': '148',
'author': 'Coelho dos Reis',
'year': '2022',
'journal-title': 'Biomed Pharmacother'},
{ 'key': 'B12',
'doi-asserted-by': 'publisher',
'DOI': '10.2174/1389201024666230331115338',
'article-title': 'Bromelain: an enzyme expanding its horizon from food to pharmaceutical '
'industry',
'volume': '24',
'author': 'Sharma',
'year': '2023',
'journal-title': 'Curr Pharm Biotechnol'},
{ 'key': 'B13',
'article-title': 'A review on various uses of N-acetyl cysteine citation',
'volume-title': 'Cell Journal',
'author': 'Mokhtari',
'year': '2017'},
{ 'key': 'B14',
'doi-asserted-by': 'publisher',
'first-page': '697',
'DOI': '10.1016/S0140-6736(13)62062-0',
'article-title': 'Reduction of adverse effects from intravenous acetylcysteine treatment '
'for paracetamol poisoning: a randomised controlled trial',
'volume': '383',
'author': 'Bateman',
'year': '2014',
'journal-title': 'Lancet'},
{ 'key': 'B15',
'doi-asserted-by': 'publisher',
'first-page': '2802',
'DOI': '10.26355/eurrev_202103_25442',
'article-title': 'Therapeutic potential of N-acetyl cysteine (NAC) in preventing cytokine '
'storm in COVID-19: review of current evidence',
'volume': '25',
'author': 'Mohanty',
'year': '2021',
'journal-title': 'Eur Rev Med Pharmacol Sci'},
{ 'key': 'B16',
'doi-asserted-by': 'publisher',
'DOI': '10.1016/j.ejso.2019.10.033',
'article-title': 'A novel treatment of bromelain and acetylcysteine (BromAc) in patients '
'with peritoneal mucinous tumours: A phase I first in man study',
'volume': '47',
'author': 'Valle',
'year': '2021',
'journal-title': 'Eur J Surg Oncol'},
{ 'key': 'B17',
'doi-asserted-by': 'publisher',
'DOI': '10.3389/falgy.2022.942699',
'article-title': 'Neutrophil and eosinophil responses remain abnormal for several months '
'in primary care patients with COVID-19 disease',
'volume': '3',
'author': 'Jukema',
'year': '2022',
'journal-title': 'Front Allergy'},
{ 'key': 'B18',
'doi-asserted-by': 'publisher',
'DOI': '10.3389/fimmu.2022.903903',
'article-title': 'Timeline kinetics of systemic and airway immune mediator storm for '
'comprehensive analysis of disease outcome in critically ill COVID-19 '
'patients',
'volume': '13',
'author': 'Gonçalves',
'year': '2022',
'journal-title': 'Front Immunol'},
{ 'key': 'B19',
'doi-asserted-by': 'publisher',
'DOI': '10.1084/jem.20190418',
'article-title': 'Biology and therapeutic potential of interleukin-10',
'volume': '217',
'author': 'Saraiva',
'year': '2020',
'journal-title': 'J Exp Med'},
{ 'key': 'B20',
'doi-asserted-by': 'publisher',
'DOI': '10.1101/cshperspect.a028548',
'article-title': 'Targeting IL-10 family cytokines for the treatment of human diseases',
'volume': '11',
'author': 'Wang',
'year': '2019',
'journal-title': 'Cold Spring Harb Perspect Biol'},
{ 'key': 'B21',
'doi-asserted-by': 'publisher',
'DOI': '10.1084/jem.20200652',
'article-title': 'Targeting potential drivers of COVID-19: Neutrophil extracellular traps',
'volume': '217',
'author': 'Barnes',
'year': '2020',
'journal-title': 'J Exp Med'},
{ 'key': 'B22',
'doi-asserted-by': 'publisher',
'first-page': '66',
'DOI': '10.1016/j.clim.2008.02.015',
'article-title': 'Bromelain treatment decreases neutrophil migration to sites of '
'inflammation',
'volume': '128',
'author': 'Fitzhugh',
'year': '2008',
'journal-title': 'Clin Immunol'},
{ 'key': 'B23',
'doi-asserted-by': 'publisher',
'DOI': '10.1159/000164070',
'article-title': 'Selective modulation of cell adhesion molecules on lymphocytes by '
'bromelain protease 5',
'volume': '64',
'author': 'Kleef',
'year': '1996',
'journal-title': 'Pathobiology'},
{ 'key': 'B24',
'doi-asserted-by': 'publisher',
'DOI': '10.1038/sj.neo.7900196',
'article-title': 'Bromelain reversibly inhibits invasive properties of glioma cells',
'volume': '3',
'author': 'Tysnes',
'year': '2001',
'journal-title': 'Neoplasia'},
{ 'key': 'B25',
'doi-asserted-by': 'publisher',
'DOI': '10.3389/fimmu.2021.720109',
'article-title': 'Monocytes and macrophages in COVID-19',
'volume': '12',
'author': 'Knoll',
'year': '2021',
'journal-title': 'Front Immunol'},
{ 'key': 'B26',
'doi-asserted-by': 'publisher',
'DOI': '10.1038/s41591-020-0944-y',
'article-title': 'A single-cell atlas of the peripheral immune response in patients with '
'severe COVID-19',
'volume': '26',
'author': 'Wilk',
'year': '2020',
'journal-title': 'Nat Med'},
{ 'key': 'B27',
'doi-asserted-by': 'publisher',
'DOI': '10.1111/j.1600-065X.1999.tb01360.x',
'article-title': 'Proteases involved in MHC dass II antigen presentation',
'volume': '172',
'author': 'Villadangos',
'year': '1999',
'journal-title': 'Immunol Rev'},
{ 'key': 'B28',
'doi-asserted-by': 'publisher',
'DOI': '10.3389/fcimb.2020.00318',
'article-title': 'A novel scoring system for prediction of disease severity in COVID-19',
'volume': '10',
'author': 'Zhang',
'year': '2020',
'journal-title': 'Front Cell Infect Microbiol'},
{ 'key': 'B29',
'doi-asserted-by': 'publisher',
'first-page': '92',
'DOI': '10.1186/s12985-022-01814-1',
'article-title': 'COVID-19 infection: an overview on cytokine storm and related '
'interventions',
'volume': '19',
'author': 'Montazersaheb',
'year': '2022',
'journal-title': 'Virol J'},
{ 'key': 'B30',
'doi-asserted-by': 'publisher',
'DOI': '10.1016/j.micpath.2021.104799',
'article-title': 'The pro-inflammatory cytokines in COVID-19 pathogenesis: What goes '
'wrong',
'volume': '153',
'author': 'Darif',
'year': '2021',
'journal-title': 'Microb Pathog'},
{ 'key': 'B31',
'doi-asserted-by': 'publisher',
'DOI': '10.1016/j.jaut.2020.102506',
'article-title': 'Autoinflammatory and autoimmune conditions at the crossroad of COVID-19',
'volume': '114',
'author': 'Rodríguez',
'year': '2020',
'journal-title': 'J Autoimmun'},
{ 'key': 'B32',
'doi-asserted-by': 'publisher',
'DOI': '10.1172/JCI154886',
'article-title': 'The intersection of COVID-19 and autoimmunity',
'volume': '131',
'author': 'Knight',
'year': '2021',
'journal-title': 'J Clin Invest'},
{ 'key': 'B33',
'doi-asserted-by': 'publisher',
'DOI': '10.1016/j.clim.2021.108694',
'article-title': 'Coronavirus-induced autoimmunity',
'volume': '226',
'author': 'Salle',
'year': '2021',
'journal-title': 'Clin Immunol'},
{ 'key': 'B34',
'doi-asserted-by': 'publisher',
'first-page': '1716',
'DOI': '10.3390/ijms23031716',
'article-title': 'SARS-coV-2-specific immune response and the pathogenesis of COVID-19',
'volume': '23',
'author': 'Gusev',
'year': '2022',
'journal-title': 'Int J Mol Sci'},
{ 'key': 'B35',
'doi-asserted-by': 'publisher',
'first-page': '261',
'DOI': '10.1186/s12931-019-1239-z',
'article-title': 'Strategies for measuring airway mucus and mucins',
'volume': '20',
'author': 'Atanasova',
'year': '2019',
'journal-title': 'Respir Res'},
{ 'key': 'B36',
'doi-asserted-by': 'publisher',
'first-page': '62',
'DOI': '10.1016/j.cytogfr.2020.06.001',
'article-title': 'SARS-CoV-2 infection: The role of cytokines in COVID-19 disease',
'volume': '54',
'author': 'Costela-Ruiz',
'year': '2020',
'journal-title': 'Cytokine Growth Factor Rev'},
{ 'key': 'B37',
'doi-asserted-by': 'publisher',
'DOI': '10.1177/03009858211058837',
'article-title': 'Influence of SARS-CoV-2 on airway mucus production: A review and '
'proposed model',
'volume': '59',
'author': 'Meyerholz',
'year': '2022',
'journal-title': 'Vet Pathol'},
{ 'key': 'B38',
'doi-asserted-by': 'publisher',
'DOI': '10.2147/JIR.S271292',
'article-title': 'Cytokine storm and mucus hypersecretion in COVID-19: review of '
'mechanisms',
'volume': '14',
'author': 'Khan',
'year': '2021',
'journal-title': 'J Inflammation Res'},
{ 'key': 'B39',
'doi-asserted-by': 'publisher',
'DOI': '10.1038/s41422-020-00435-z',
'article-title': 'Mucus production stimulated by IFN-AhR signaling triggers hypoxia of '
'COVID-19',
'volume': '30',
'author': 'Liu',
'year': '2020',
'journal-title': 'Cell Res'},
{ 'key': 'B40',
'doi-asserted-by': 'publisher',
'DOI': '10.1002/jmv.26232',
'article-title': 'The cytokine storm and COVID-19',
'volume': '93',
'author': 'Hu',
'year': '2021',
'journal-title': 'J Med Virol'},
{ 'key': 'B41',
'article-title': 'In vitro study on the immunological effect of bromelain and trypsin on '
'mononuclear cells from humans',
'volume': '10',
'author': 'Barth',
'year': '2005',
'journal-title': 'Eur J Med Res'},
{ 'key': 'B42',
'doi-asserted-by': 'publisher',
'DOI': '10.1080/08820130802083622',
'article-title': 'Bromelain inhibits lipopolysaccharide-induced cytokine production in '
'human THP-1 monocytes via the removal of CD14',
'volume': '37',
'author': 'Huang',
'year': '2008',
'journal-title': 'Immunol Invest'},
{ 'key': 'B43',
'doi-asserted-by': 'publisher',
'DOI': '10.1016/j.clim.2007.11.002',
'article-title': 'Bromelain treatment decreases secretion of pro-inflammatory cytokines '
'and chemokines by colon biopsies in vitro',
'volume': '126',
'author': 'Onken',
'year': '2008',
'journal-title': 'Clin Immunol'},
{ 'key': 'B44',
'doi-asserted-by': 'publisher',
'DOI': '10.1016/j.ebiom.2022.104299',
'article-title': 'Interleukin-1 and the NLRP3 inflammasome in COVID-19: Pathogenetic and '
'therapeutic implications',
'volume': '85',
'author': 'Potere',
'year': '2022',
'journal-title': 'EBioMedicine'},
{ 'key': 'B45',
'doi-asserted-by': 'publisher',
'DOI': '10.1016/j.cyto.2022.155934',
'article-title': 'Inflammasomes and IL-1 family cytokines in SARS-CoV-2 infection: from '
'prognostic marker to therapeutic agent',
'volume': '157',
'author': 'Declercq',
'year': '2022',
'journal-title': 'Cytokine'},
{ 'key': 'B46',
'doi-asserted-by': 'publisher',
'first-page': '89',
'DOI': '10.4167/jbv.2021.51.3.089',
'article-title': 'Roles of interleukin-17 and th17 responses in COVID-19',
'volume': '51',
'author': 'Kang',
'year': '2021',
'journal-title': 'J Bacteriol Virol'},
{ 'key': 'B47',
'doi-asserted-by': 'publisher',
'DOI': '10.1073/pnas.2109123118',
'article-title': 'High-dimensional profiling reveals phenotypic heterogeneity and '
'disease-specific alterations of granulocytes in COVID-19',
'volume': '118',
'author': 'Lourda',
'year': '2021',
'journal-title': 'Proc Natl Acad Sci'},
{ 'key': 'B48',
'doi-asserted-by': 'publisher',
'DOI': '10.3390/biomedicines10020382',
'article-title': 'SARS-coV-2 dysregulates neutrophil degranulation and reduces lymphocyte '
'counts',
'volume': '10',
'author': 'Muralidharan',
'year': '2022',
'journal-title': 'Biomedicines'}],
'container-title': 'Frontiers in Immunology',
'original-title': [],
'link': [ { 'URL': 'https://www.frontiersin.org/articles/10.3389/fimmu.2023.1308477/full',
'content-type': 'unspecified',
'content-version': 'vor',
'intended-application': 'similarity-checking'}],
'deposited': { 'date-parts': [[2023, 12, 13]],
'date-time': '2023-12-13T04:28:07Z',
'timestamp': 1702441687000},
'score': 1,
'resource': {'primary': {'URL': 'https://www.frontiersin.org/articles/10.3389/fimmu.2023.1308477/full'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2023, 12, 13]]},
'references-count': 48,
'alternative-id': ['10.3389/fimmu.2023.1308477'],
'URL': 'http://dx.doi.org/10.3389/fimmu.2023.1308477',
'relation': {},
'ISSN': ['1664-3224'],
'subject': ['Immunology', 'Immunology and Allergy'],
'container-title-short': 'Front. Immunol.',
'published': {'date-parts': [[2023, 12, 13]]}}
