- Record: found
- Abstract: found
- Article: found
Impaired immune response mediated by prostaglandin E2 promotes severe COVID-19 disease
research-article
Author(s):
Melanie Ricke-Hoch
1
,
* ,
Elisabeth Stelling
1 ,
Lisa Lasswitz
2 ,
Antonia P. Gunesch
2
,
3
,
4 ,
Martina Kasten
1 ,
Francisco J. Zapatero-Belinchón
2
,
5 ,
Graham Brogden
2 ,
Gisa Gerold
2
,
5
,
6 ,
Thomas Pietschmann
2
,
3 ,
Virginie Montiel
7 ,
Jean-Luc Balligand
7 ,
Federica Facciotti
8 ,
Emilio Hirsch
9 ,
Thomas Gausepohl
1 ,
Husni Elbahesh
10 ,
Guus F. Rimmelzwaan
10 ,
Anne Höfer
11
,
12 ,
Mark P. Kühnel
11
,
12 ,
Danny Jonigk
11
,
12 ,
Julian Eigendorf
13 ,
Uwe Tegtbur
13 ,
Lena Mink
13 ,
Michaela Scherr
14 ,
Thomas Illig
15 ,
Axel Schambach
16
,
17 ,
Tobias J. Pfeffer
1 ,
Andres Hilfiker
18 ,
Axel Haverich
18 ,
Denise Hilfiker-Kleiner
1
,
19
Publication date (Electronic):
4 August 2021
Journal:
PLoS ONE
Publisher:
Public Library of Science
Read this article at
There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.
Abstract
The SARS-CoV-2 coronavirus has led to a pandemic with millions of people affected. The present study finds that risk-factors for severe COVID-19 disease courses, i.e. male sex, older age and sedentary life style are associated with higher prostaglandin E2 (PGE2) serum levels in blood samples from unaffected subjects. In COVID-19 patients, PGE2 blood levels are markedly elevated and correlate positively with disease severity. SARS-CoV-2 induces PGE2 generation and secretion in infected lung epithelial cells by upregulating cyclo-oxygenase (COX)-2 and reducing the PG-degrading enzyme 15-hydroxyprostaglandin-dehydrogenase. Also living human precision cut lung slices (PCLS) infected with SARS-CoV-2 display upregulated COX-2. Regular exercise in aged individuals lowers PGE2 serum levels, which leads to increased Paired-Box-Protein-Pax-5 (PAX5) expression, a master regulator of B-cell survival, proliferation and differentiation also towards long lived memory B-cells, in human pre-B-cell lines. Moreover, PGE2 levels in serum of COVID-19 patients lowers the expression of PAX5 in human pre-B-cell lines. The PGE2 inhibitor Taxifolin reduces SARS-CoV-2-induced PGE2 production. In conclusion, SARS-CoV-2, male sex, old age, and sedentary life style increase PGE2 levels, which may reduce the early anti-viral defense as well as the development of immunity promoting severe disease courses and multiple infections. Regular exercise and Taxifolin treatment may reduce these risks and prevent severe disease courses.
Related collections
Most cited references60
- Record: found
- Abstract: found
- Article: found
COVID-19: consider cytokine storm syndromes and immunosuppression
Puja Mehta, Daniel McAuley, Michael Brown … (2020)
As of March 12, 2020, coronavirus disease 2019 (COVID-19) has been confirmed in 125 048 people worldwide, carrying a mortality of approximately 3·7%, 1 compared with a mortality rate of less than 1% from influenza. There is an urgent need for effective treatment. Current focus has been on the development of novel therapeutics, including antivirals and vaccines. Accumulating evidence suggests that a subgroup of patients with severe COVID-19 might have a cytokine storm syndrome. We recommend identification and treatment of hyperinflammation using existing, approved therapies with proven safety profiles to address the immediate need to reduce the rising mortality. Current management of COVID-19 is supportive, and respiratory failure from acute respiratory distress syndrome (ARDS) is the leading cause of mortality. 2 Secondary haemophagocytic lymphohistiocytosis (sHLH) is an under-recognised, hyperinflammatory syndrome characterised by a fulminant and fatal hypercytokinaemia with multiorgan failure. In adults, sHLH is most commonly triggered by viral infections 3 and occurs in 3·7–4·3% of sepsis cases. 4 Cardinal features of sHLH include unremitting fever, cytopenias, and hyperferritinaemia; pulmonary involvement (including ARDS) occurs in approximately 50% of patients. 5 A cytokine profile resembling sHLH is associated with COVID-19 disease severity, characterised by increased interleukin (IL)-2, IL-7, granulocyte-colony stimulating factor, interferon-γ inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α, and tumour necrosis factor-α. 6 Predictors of fatality from a recent retrospective, multicentre study of 150 confirmed COVID-19 cases in Wuhan, China, included elevated ferritin (mean 1297·6 ng/ml in non-survivors vs 614·0 ng/ml in survivors; p 39·4°C 49 Organomegaly None 0 Hepatomegaly or splenomegaly 23 Hepatomegaly and splenomegaly 38 Number of cytopenias * One lineage 0 Two lineages 24 Three lineages 34 Triglycerides (mmol/L) 4·0 mmol/L 64 Fibrinogen (g/L) >2·5 g/L 0 ≤2·5 g/L 30 Ferritin ng/ml 6000 ng/ml 50 Serum aspartate aminotransferase <30 IU/L 0 ≥30 IU/L 19 Haemophagocytosis on bone marrow aspirate No 0 Yes 35 Known immunosuppression † No 0 Yes 18 The Hscore 11 generates a probability for the presence of secondary HLH. HScores greater than 169 are 93% sensitive and 86% specific for HLH. Note that bone marrow haemophagocytosis is not mandatory for a diagnosis of HLH. HScores can be calculated using an online HScore calculator. 11 HLH=haemophagocytic lymphohistiocytosis. * Defined as either haemoglobin concentration of 9·2 g/dL or less (≤5·71 mmol/L), a white blood cell count of 5000 white blood cells per mm3 or less, or platelet count of 110 000 platelets per mm3 or less, or all of these criteria combined. † HIV positive or receiving longterm immunosuppressive therapy (ie, glucocorticoids, cyclosporine, azathioprine).
- Record: found
- Abstract: found
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Virological assessment of hospitalized patients with COVID-2019
Roman Wölfel, Victor M Corman, Wolfgang Guggemos … (2020)
Coronavirus disease 2019 (COVID-19) is an acute infection of the respiratory tract that emerged in late 20191,2. Initial outbreaks in China involved 13.8% of cases with severe courses, and 6.1% of cases with critical courses3. This severe presentation may result from the virus using a virus receptor that is expressed predominantly in the lung2,4; the same receptor tropism is thought to have determined the pathogenicity-but also aided in the control-of severe acute respiratory syndrome (SARS) in 20035. However, there are reports of cases of COVID-19 in which the patient shows mild upper respiratory tract symptoms, which suggests the potential for pre- or oligosymptomatic transmission6-8. There is an urgent need for information on virus replication, immunity and infectivity in specific sites of the body. Here we report a detailed virological analysis of nine cases of COVID-19 that provides proof of active virus replication in tissues of the upper respiratory tract. Pharyngeal virus shedding was very high during the first week of symptoms, with a peak at 7.11 × 108 RNA copies per throat swab on day 4. Infectious virus was readily isolated from samples derived from the throat or lung, but not from stool samples-in spite of high concentrations of virus RNA. Blood and urine samples never yielded virus. Active replication in the throat was confirmed by the presence of viral replicative RNA intermediates in the throat samples. We consistently detected sequence-distinct virus populations in throat and lung samples from one patient, proving independent replication. The shedding of viral RNA from sputum outlasted the end of symptoms. Seroconversion occurred after 7 days in 50% of patients (and by day 14 in all patients), but was not followed by a rapid decline in viral load. COVID-19 can present as a mild illness of the upper respiratory tract. The confirmation of active virus replication in the upper respiratory tract has implications for the containment of COVID-19.
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Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19
Maximilian Ackermann, Stijn Verleden, Mark Kuehnel … (2020)
Progressive respiratory failure is the primary cause of death in the coronavirus disease 2019 (Covid-19) pandemic. Despite widespread interest in the pathophysiology of the disease, relatively little is known about the associated morphologic and molecular changes in the peripheral lung of patients who die from Covid-19.
Author and article information
Contributors
Melanie Ricke-Hoch:
ORCID: https://orcid.org/0000-0001-5479-2275
Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole:
InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole:
VisualizationRole: Writing – original draftRole: Writing – review & editing
Elisabeth Stelling: Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole:
MethodologyRole: ValidationRole: VisualizationRole: Writing – original draftRole:
Writing – review & editing
Lisa Lasswitz: Role: InvestigationRole: MethodologyRole: ResourcesRole: Writing – original draft
Antonia P. Gunesch: Role: InvestigationRole: MethodologyRole: ResourcesRole: Writing – original draft
Martina Kasten: Role: Data curation
Francisco J. Zapatero-Belinchón: Role: InvestigationRole: MethodologyRole: ResourcesRole: Writing – review & editing
Graham Brogden: Role: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: VisualizationRole:
Writing – review & editing
Gisa Gerold:
ORCID: https://orcid.org/0000-0002-1326-5038
Role: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole:
Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: Writing
– review & editing
Thomas Pietschmann: Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: SupervisionRole:
Writing – review & editing
Virginie Montiel: Role: ResourcesRole: Writing – review & editing
Jean-Luc Balligand: Role: Funding acquisitionRole: ResourcesRole: Writing – review & editing
Federica Facciotti: Role: InvestigationRole: Resources
Emilio Hirsch: Role: ConceptualizationRole: Funding acquisitionRole: Resources
Thomas Gausepohl:
ORCID: https://orcid.org/0000-0003-1669-5911
Role: Data curationRole: Writing – review & editing
Husni Elbahesh:
ORCID: https://orcid.org/0000-0003-1243-0967
Role: InvestigationRole: MethodologyRole: Writing – original draftRole: Writing –
review & editing
Guus F. Rimmelzwaan: Role: Funding acquisitionRole: InvestigationRole: Writing – review & editing
Anne Höfer: Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole:
ResourcesRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing
– review & editing
Mark P. Kühnel: Role: Funding acquisitionRole: ResourcesRole: SupervisionRole: Writing – original
draftRole: Writing – review & editing
Danny Jonigk: Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole:
InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole:
ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review
& editing
Julian Eigendorf: Role: Data curationRole: InvestigationRole: Project administrationRole: Writing –
review & editing
Uwe Tegtbur: Role: ConceptualizationRole: InvestigationRole: Project administrationRole: ResourcesRole:
Writing – review & editing
Lena Mink: Role: Data curationRole: InvestigationRole: ResourcesRole: Writing – review & editing
Michaela Scherr: Role: Data curationRole: Visualization
Thomas Illig: Role: Funding acquisitionRole: MethodologyRole: ResourcesRole: Writing – review &
editing
Axel Schambach: Role: ConceptualizationRole: Funding acquisitionRole: Writing – review & editing
Tobias J. Pfeffer: Role: Data curationRole: InvestigationRole: ResourcesRole: Writing – review & editing
Andres Hilfiker: Role: MethodologyRole: ResourcesRole: Writing – review & editing
Axel Haverich: Role: ConceptualizationRole: InvestigationRole: MethodologyRole: ResourcesRole: Writing
– review & editing
Denise Hilfiker-Kleiner: Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole:
InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole:
VisualizationRole: Writing – original draftRole: Writing – review & editing
Paulo Lee Ho: Role: Editor
Journal
Journal ID (nlm-ta): PLoS One
Journal ID (iso-abbrev): PLoS One
Journal ID (publisher-id): plos
Title:
PLoS ONE
Publisher:
Public Library of Science
(San Francisco, CA USA
)
ISSN
(Electronic):
1932-6203
Publication date
(Electronic):
4
August
2021
Publication date Collection: 2021
Publication date PMC-release: 4
August
2021
Volume: 16
Issue: 8
Electronic Location Identifier: e0255335
Affiliations
[2
]
Institute of Experimental Virology, TWINCORE, Center for Experimental and Clinical
Infection Research Hannover, Hanover, Germany
[4
]
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School,
Hanover, Germany
[5
]
Department of Clinical Microbiology, Virology & Wallenberg Centre for Molecular Medicine
(WCMM), Umeå University, Umeå, Sweden
[7
]
Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique,
and Cliniques Universitaires Saint-Luc, Université catholique de Louvain (UCLouvain),
Brussels, Belgium
[9
]
Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology
Center, University of Torino, Torino, Italy
[10
]
Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary
Medicine in Hannover (TiHo), Hannover, Germany
[11
]
Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), German Center
for Lung Research, Hanover, Germany
[14
]
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover
Medical School, Hanover, Germany
[17
]
Division of Hematology and Oncology, Boston Children’s Hospital, Harvard Medical School,
Boston, MA, United States of America
[18
]
Department of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical
School, Hanover, Germany
Author notes
* E-mail:
hoch.melanie@
123456mh-hannover.de
Author information
Melanie Ricke-Hoch
https://orcid.org/0000-0001-5479-2275
Gisa Gerold
https://orcid.org/0000-0002-1326-5038
Thomas Gausepohl
https://orcid.org/0000-0003-1669-5911
Husni Elbahesh
https://orcid.org/0000-0003-1243-0967
Article
Publisher ID: PONE-D-21-08028DOI: 10.1371/journal.pone.0255335
PMC ID: 8336874
PubMed ID: 34347801
SO-VID: 6c61cae6-f8b5-4eb1-9404-0fb8b439f6c4
Copyright © © 2021 Ricke-Hoch et al
License:
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
History
Date
received
: 11
March
2021
Date
accepted
: 14
July
2021
Page count
Figures: 6,
Tables: 1,
Pages: 24
Funding
Funded by:
funder-id http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
Award ID: HI 842/3-2
Award Recipient
:
Denise Hilfiker-Kleiner
Funded by:
funder-id http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
Award ID: HI 842/10-1
Award Recipient
:
Denise Hilfiker-Kleiner
Funded by:
funder-id http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
Award ID: HI 842/10-2
Award Recipient
:
Denise Hilfiker-Kleiner
Funded by:
funder-id http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
Award ID: RI 2531/2-1
Award Recipient
:
ORCID: https://orcid.org/0000-0001-5479-2275
Melanie Ricke-Hoch
Funded by:
funder-id http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
Award ID: RI 2531/2-2
Award Recipient
:
ORCID: https://orcid.org/0000-0001-5479-2275
Melanie Ricke-Hoch
Funded by:
funder-id http://dx.doi.org/10.13039/100011937, Niedersächsische Ministerium für Wissenschaft und Kultur;
Award ID: REBIRTH I/II
Award Recipient
:
Denise Hilfiker-Kleiner
Funded by:
Foundation Leducq
Award ID: ID 19CVD02
Award Recipient
:
Denise Hilfiker-Kleiner
Funded by:
foundation leducq
Award ID: ID 19CVD02
Award Recipient
:
Emilio Hirsch
Funded by:
funder-id http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
Award ID: EXC 2155 RESIST
Award Recipient
:
Danny Jonigk
Funded by:
The DEFEAT PANDEMIcs
Award ID: AP6-9
Award Recipient
:
Danny Jonigk
Funded by:
The DEFEAT PANDEMIcs
Award ID: AP6-9
Award Recipient
:
Mark P. Kühnel
Funded by:
funder-id http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
Award ID: GE 2145/3-2
Award Recipient
:
ORCID: https://orcid.org/0000-0002-1326-5038
Gisa Gerold
Funded by:
funder-id http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
Award ID: Project 158989968
Award Recipient
:
ORCID: https://orcid.org/0000-0002-1326-5038
Gisa Gerold
Funded by:
niedersächsische ministerium für wissenschaft und kultur and volkswagen foundation
Award ID: Project 76251-99-3/19
Award Recipient
:
ORCID: https://orcid.org/0000-0002-1326-5038
Gisa Gerold
Funded by:
the knut and alice wallenberg foundation
Award Recipient
:
ORCID: https://orcid.org/0000-0002-1326-5038
Gisa Gerold
Funded by:
funder-id http://dx.doi.org/10.13039/100010663, H2020 European Research Council;
Award ID: XHale 771883
Award Recipient
:
Danny Jonigk
Funded by:
funder-id http://dx.doi.org/10.13039/501100007601, Horizon 2020;
Award ID: No 871029
Funded by:
funder-id http://dx.doi.org/10.13039/100005156, Alexander von Humboldt-Stiftung;
Award ID: Alexander von Humboldt Professorship
Award Recipient
:
Guus F. Rimmelzwaan
Funded by:
funder-id http://dx.doi.org/10.13039/100011937, Niedersächsische Ministerium für Wissenschaft und Kultur;
Award ID: 14 - 76103-184 CORONA-15/20
Award Recipient
:
Guus F. Rimmelzwaan
Funded by:
federal ministry of education and research
Award ID: 01KI20143C
Award Recipient
:
ORCID: https://orcid.org/0000-0002-1326-5038
Gisa Gerold
Funded by:
funder-id http://dx.doi.org/10.13039/100009139, Deutsches Zentrum für Infektionsforschung;
Award ID: TTU 05.81600
Award Recipient
:
Thomas Pietschmann
Funded by:
Fonds National de la Recherche Scientifique and WEBIO
Award Recipient
:
Jean-Luc Balligand
Funded by:
cariplo foundation
Award ID: #2018-0498
Award Recipient
:
Emilio Hirsch
This work was supported by: The German Research Foundation (DFG, HI 842/3-2 to D.H.-K.),
by the DFG Clinical Research Group (DFG KFO311, HI 842/10-1, HI 842/10-2 to D.H.-K.;
RI 2531/2-1, RI 2531/2-2 to M.R.-H.), by REBIRTH I/II to D.H.-K., by the Foundation
Leducq (Project ID 19CVD02) to D.H.-K. and E.H., DFG as part of the German Strategy
for Excellence (EXC 2155 “RESIST”, Project ID 39087428 to D.J.), The DEFEAT PANDEMIcs
(AP6-9, to D.J. and M.P.K.), by the (DFG – Projektnummer 158989968 - SFB 900 project
C7 and DFG project GE 2145/3-2 to G.G.), the ‘Niedersächsischen Vorab’ program (project
76251-99-3/19 to G.G.) through the Ministry of Lower Saxony (MWK) and the Volkswagen
Foundation (Volkswagen Stiftung), by the Federal Ministry of education and research
(project COVID-Protect, Project: 01KI20143C to G.G.), the Knut and Alice Wallenberg
Foundation and the Federal Ministry of Education and Research together with the the
Ministry for Science and Culture (MWG) through the ‘Professorinnen Programm III’ to
G.G., by the European Research Council Consolidator Grant (XHale; 771883 to D.J.),
by REBIRTH I/II and REBIRTH Center for Regenerative Translational Medicine (MWK, project
ZN3440) to A.S., by Cariplo Foundation (Project #2018-0498 to E.H.), by MWG project
14-76103-184 CORONA-1/20 to T.I. and by the European Virus Archive GLOBAL (EVA-GLOBAL)
project funded by the European Union’s Horizon 2020 research and innovation program
under grant agreement No 871029 (to Christian Drosten). This work was partly supported
by the Alexander von Humboldt Foundation in the framework of the Alexander von Humboldt
Professorship endowed by the German Federal Ministry of Education and Research and
by funding from the Ministry for Science and Culture (MWK), Lower Saxony, Germany
(14 - 76103-184 CORONA-15/20 to G.F.R.). A.P.G. was supported by the Deutsches Zentrum
für Infektionsforschung (DZIF; German Center for Infection Research; Grant No. TTU
05.816 00 to T.P.). Work by J.L.B. was supported by grants from Fonds National de
la Recherche Scientifique (FNRS) and WEBIO. J.L.B is an established investigator of
the WELBIO institute. The funders had no role in study design, data collection and
analysis, decision to publish, or preparation of the manuscript.
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