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

Melanie Ricke‐Hoch ,T Gausepohl ,Jean‐Luc Balligand ,Mark Philipp Kühnel ,Tobias Jonathan Pfeffer ,Lisa Laßwitz ,Denise Hilfiker‐Kleiner ,Julian Eigendorf,Antonia P Gunesch,Uwe Tegtbur,Anne Höfer,Axel Schambach,Francisco J Zapatero-Belinchón,Elisabeth Stelling,Lena Mink,Axel Haverich,Guus F Rimmelzwaan,Virginie Montiel,Michaela Scherr,Gisa Gerold,Thomas Illig,Thomas Pietschmann,Federica Facciotti,Andres Hilfiker,Martina Kasten,Danny Jonigk,Graham Brogden,Emilio Hirsch,Husni Elbahesh

doi:10.1371/journal.pone.0255335

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.

Highlights

The 2019 strain of coronavirus caused a pandemic with COVID-19 disease affecting millions of people worldwide
All AC patients used in this study showed typical acute respiratory distress syndrome (ARDS) histopathology typical for COVID-19 disease
We set to explore whether prostaglandin E2 (PGE2) levels changes in COVID-19 and whether differences in PGE2 levels could explain severe disease courses after SARS-CoV-2 infection

Summary

Introduction

The 2019 strain of coronavirus (severe acute respiratory syndrome coronavirus-2 SARS-CoV2) caused a pandemic with COVID-19 disease affecting millions of people worldwide. Immunothrombosis integrates innate immunity, activation of platelets, and clotting factors to fight invading pathogens and concurrently promotes inflammation-related tissue damage; in the context of COVID-19 disease, this may explain the systemic hypercoagulability frequently present in COVID-19 patients [8]. Reduced lymphocyte populations seem to correlate with more severe organ injury and higher mortality in hospitalized COVID-19 patients [16] In this regard, T-cell exhaustion [3, 17], reduced circulating and resident B-cell population and loss of germinal centers associated with viral persistence and severe disease courses correlate with high mortality in the acute phase [3, 18, 19]. SARS-CoV-2 induced formation of autoantibodies, tissue and organ injury as well as secondary infection with bacteria and fungi [23, 24]

Results

Discussion

Conclusion