Impaired immune response mediated by prostaglandin E2 promotes severe COVID-19 disease

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.

[1]  R. Franco,et al.  Interactions between ibuprofen, ACE2, renin‐angiotensin system, and spike protein in the lung. Implications for COVID‐19 , 2021, Clinical and translational medicine.

[2]  F. Cosset,et al.  A longitudinal study of SARS-CoV-2-infected patients reveals a high correlation between neutralizing antibodies and COVID-19 severity , 2021, Cellular & Molecular Immunology.

[3]  R. Webby,et al.  Synergism of TNF-α and IFN-γ Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes , 2020, Cell.

[4]  J. Sevinsky,et al.  Genomic evidence for reinfection with SARS-CoV-2: a case study , 2020, The Lancet Infectious Diseases.

[5]  A. Iwasaki.  What reinfections mean for COVID-19 , 2020, The Lancet Infectious Diseases.

[6]  J. Mascarenhas,et al.  Severe COVID-19 virus reactivation following treatment for B cell acute lymphoblastic leukemia , 2020, Journal of Hematology & Oncology.

[7]  S. Bağhaki,et al.  COX2 inhibition in the treatment of COVID-19: Review of literature to propose repositioning of celecoxib for randomized controlled studies , 2020, International Journal of Infectious Diseases.

[8]  Jacques Fellay,et al.  Inborn errors of type I IFN immunity in patients with life-threatening COVID-19 , 2020, Science.

[9]  Max S. Y. Lau,et al.  Characterizing superspreading events and age-specific infectiousness of SARS-CoV-2 transmission in Georgia, USA , 2020, Proceedings of the National Academy of Sciences.

[10]  Kelsey K. Finn,et al.  Loss of Bcl-6-Expressing T Follicular Helper Cells and Germinal Centers in COVID-19 , 2020, Cell.

[11]  K. Rainsford,et al.  A narrative review of the potential pharmacological influence and safety of ibuprofen on coronavirus disease 19 (COVID-19), ACE2, and the immune system: a dichotomy of expectation and reality , 2020, Inflammopharmacology.

[12]  M. Rudelius,et al.  Immunothrombotic Dysregulation in COVID-19 Pneumonia Is Associated With Respiratory Failure and Coagulopathy , 2020, Circulation.

[13]  J. Q. Brown,et al.  Unexpected Features of Cardiac Pathology in COVID-19 Infection. , 2020, Circulation.

[14]  Michael D Healy,et al.  SARS-CoV-2 viral load is associated with increased disease severity and mortality , 2020, Nature Communications.

[15]  M. Addo,et al.  Next-Generation Sequencing of T and B Cell Receptor Repertoires from COVID-19 Patients Showed Signatures Associated with Severity of Disease , 2020, Immunity.

[16]  C. Svendsen,et al.  Human iPSC-Derived Cardiomyocytes Are Susceptible to SARS-CoV-2 Infection , 2020, Cell Reports Medicine.

[17]  Shaoying Huang,et al.  The cytokine storm and COVID‐19 , 2020, Journal of medical virology.

[18]  M. Hoxha.  What about COVID-19 and arachidonic acid pathway? , 2020, European Journal of Clinical Pharmacology.

[19]  Aaron J. Wilk,et al.  A single-cell atlas of the peripheral immune response in patients with severe COVID-19 , 2020, Nature Medicine.

[20]  M. Catanzaro,et al.  Immune response in COVID-19: addressing a pharmacological challenge by targeting pathways triggered by SARS-CoV-2 , 2020, Signal Transduction and Targeted Therapy.

[21]  Y. Arbel,et al.  Spectrum of Cardiac Manifestations in COVID-19 , 2020, Circulation.

[22]  Axel Haverich,et al.  Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. , 2020, The New England journal of medicine.

[23]  T. Mersha,et al.  Air pollution, racial disparities, and COVID-19 mortality , 2020, Journal of Allergy and Clinical Immunology.

[24]  You Chen,et al.  Immune dysfunction leads to mortality and organ injury in patients with COVID-19 in China: insights from ERS-COVID-19 study , 2020, Signal Transduction and Targeted Therapy.

[25]  J. Wolchok,et al.  The many faces of the anti-COVID immune response , 2020, The Journal of experimental medicine.

[26]  Hangyuan Guo,et al.  Risk factors of critical & mortal COVID-19 cases: A systematic literature review and meta-analysis , 2020, Journal of Infection.

[27]  V. Lougaris,et al.  A possible role for B cells in COVID-19? Lesson from patients with agammaglobulinemia , 2020, Journal of Allergy and Clinical Immunology.

[28]  Rozhgar A. Khailany,et al.  Genomic characterization of a novel SARS-CoV-2 , 2020, Gene Reports.

[29]  M. Huang,et al.  Difference of coagulation features between severe pneumonia induced by SARS-CoV2 and non-SARS-CoV2 , 2020, Journal of Thrombosis and Thrombolysis.

[30]  P. Martelletti,et al.  Air Pollution and the Novel Covid-19 Disease: a Putative Disease Risk Factor , 2020, SN Comprehensive Clinical Medicine.

[31]  P. Vollmar,et al.  Virological assessment of hospitalized patients with COVID-2019 , 2020, Nature.

[32]  Yi Feng,et al.  The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2 , 2020, Cardiovascular research.

[33]  N. G. Davies,et al.  Age-dependent effects in the transmission and control of COVID-19 epidemics , 2020, Nature Medicine.

[34]  Xiang Xie,et al.  COVID-19 and the cardiovascular system , 2020, Nature Reviews Cardiology.

[35]  D. Brodie,et al.  The Variety of Cardiovascular Presentations of COVID-19 , 2020, Circulation.

[36]  Markus A. Lill,et al.  Inhibitors for Novel Coronavirus Protease Identified by Virtual Screening of 687 Million Compounds , 2020 .

[37]  P. Mehta,et al.  COVID-19: consider cytokine storm syndromes and immunosuppression , 2020, The Lancet.

[38]  R. Morgan,et al.  COVID-19: the gendered impacts of the outbreak , 2020, The Lancet.

[39]  Rong Chen,et al.  PGE2 ameliorated viral myocarditis development and promoted IL-10-producing regulatory B cell expansion via MAPKs/AKT-AP1 axis or AhR signaling. , 2019, Cellular immunology.

[40]  K. Ohashi,et al.  Prostaglandin E2–Induced Immune Exhaustion and Enhancement of Antiviral Effects by Anti–PD-L1 Antibody Combined with COX-2 Inhibitor in Bovine Leukemia Virus Infection , 2019, The Journal of Immunology.

[41]  A. Burny,et al.  Immune evasion before tumour invasion in early lung squamous carcinogenesis , 2019, Nature.

[42]  S. Barry,et al.  Enzymatic Activity of HPGD in Treg Cells Suppresses Tconv Cells to Maintain Adipose Tissue Homeostasis and Prevent Metabolic Dysfunction. , 2019, Immunity.

[43]  S. Narumiya,et al.  T cell–intrinsic prostaglandin E2-EP2/EP4 signaling is critical in pathogenic TH17 cell–driven inflammation , 2019, The Journal of allergy and clinical immunology.

[44]  Qinwen Wang,et al.  Taxifolin prevents β-amyloid-induced impairments of synaptic formation and deficits of memory via the inhibition of cytosolic phospholipase A2/prostaglandin E2 content , 2018, Metabolic Brain Disease.

[45]  A. Clark,et al.  Macrophage responses to lipopolysaccharide are modulated by a feedback loop involving prostaglandin E2, dual specificity phosphatase 1 and tristetraprolin , 2017, Scientific Reports.

[46]  C. Pohl,et al.  Prostaglandin E2 As a Modulator of Viral Infections , 2017, Front. Physiol..

[47]  Fu-Tong Liu,et al.  Antibody-dependent SARS coronavirus infection is mediated by antibodies against spike proteins , 2014, Biochemical and Biophysical Research Communications.

[48]  F. Full,et al.  Prostaglandin E2: the villain in the host response to influenza virus. , 2014, Immunity.

[49]  G. Wong,et al.  Targeted prostaglandin E2 inhibition enhances antiviral immunity through induction of type I interferon and apoptosis in macrophages. , 2014, Immunity.

[50]  L. Morici,et al.  PGE2 suppression of innate immunity during mucosal bacterial infection , 2013, Front. Cell. Infect. Microbiol..

[51]  A. Ardekani,et al.  Prostaglandin E2 induces growth inhibition, apoptosis and differentiation in T and B cell-derived acute lymphoblastic leukemia cell lines (CCRF-CEM and Nalm-6). , 2012, Prostaglandins, leukotrienes, and essential fatty acids.

[52]  F. Liu,et al.  Influenza A Virus Induces Interleukin-27 through Cyclooxygenase-2 and Protein Kinase A Signaling* , 2012, The Journal of Biological Chemistry.

[53]  J. Balligand,et al.  Erythropoietin preserves the endothelial differentiation capacity of cardiac progenitor cells and reduces heart failure during anticancer therapies. , 2011, Cell stem cell.

[54]  S. Nutt,et al.  Germinal center B and follicular helper T cells: siblings, cousins or just good friends? , 2011, Nature Immunology.

[55]  H. Vapaatalo,et al.  Effects of Flavonoids on Prostaglandin E2 Production and on COX-2 and mPGES-1 Expressions in Activated Macrophages , 2011, Planta medica.

[56]  T. Mcclanahan,et al.  Prostaglandin E2 regulates Th17 cell differentiation and function through cyclic AMP and EP2/EP4 receptor signaling , 2009, The Journal of experimental medicine.

[57]  M. Busslinger,et al.  Transcription factor Pax5 activates the chromatin of key genes involved in B cell signaling, adhesion, migration, and immune function. , 2007, Immunity.

[58]  M. Busslinger,et al.  Gene repression by Pax5 in B cells is essential for blood cell homeostasis and is reversed in plasma cells. , 2006, Immunity.

[59]  C. Tunyaplin,et al.  Regulatory events in early and late B-cell differentiation. , 2005, Molecular immunology.

[60]  C. Spaulding,et al.  Interaction between cyclooxygenase and the renin-angiotensin-aldosterone system: rationale and clinical relevance , 2003, Journal of the renin-angiotensin-aldosterone system : JRAAS.

[61]  M. Yamazaki,et al.  Tumor necrosis factor α (TNF-α)-induced prostaglanding E2 release is mediated by the activation of cyclooxygenase-2 (COX-2)transcription via NFκB in human gingival fibroblasts , 2002, Molecular and Cellular Biochemistry.

[62]  P. Lipsky,et al.  Inhibition of human B cell responsiveness by prostaglandin E2. , 1987, Journal of immunology.