Background: Prostaglandin (PG)-E2, generated by Cyclooxygenases (COX) and degraded by Hydroxyprostaglandin Dehydrogenase 15-(NAD) (HPGD), modulates viral infection and the hosts’ immune response. Here, we investigated whether SARS-CoV-2 or risk factors for severe COVID-19 disease such as male sex, age, air pollution and sedentary life style influence the secretion of PGE2 and how elevated PGE2 levels could modulate the immune response.  

Methods and results: In COVID-19 patients (n=89), n=41 presented with mild/moderate (mortality 0%) and n=48 with severe disease (mortality 23%, significantly older and more men than women), the median circulating PGE2 levels were significantly higher (+82%, P<0.05) than in healthy individuals and positively correlated with disease severity (Figure). SARS-CoV-2 infection of human lung epithelial cells (Calu-3) upregulated COX-2 (+343%, P<0.01), reduced HPGD (-90%, P<0.01) and increased PGE2 secretion (+290%, P<0.01), which could be prevented by the PGE2 inhibitor taxifolin. PGE2 (dose comparable to COVID-19 patients’ serum) and serum from healthy aged individuals with high PGE2 levels reduced paired box protein PAX-5 (PAX-5), a key B-cell survival-, proliferation and differentiation factor, which could be prevented by the PGE2 receptor 4 (EP4) blocker GW. In human lungs from patients with COVID-19 disease, the B-cell (CD20) density and total number was significantly lower compared to healthy and transplant rejection lungs. Furthermore, we investigated potential risk factors that may modulate PGE2 production. Air pollution mimicked by diesel exhaust particles (DEP) increased PGE2 secretion (+91%, P<0.01) from human cardiac endothelial cells that could be prevented by taxifolin. PGE2 serum levels correlated positively with male sex and age (n=66, P 0.0277) and negatively with physical fitness in healthy individuals. Impaired androgen receptor signaling in male mice with a cardiomyocyte-restricted deficiency of STAT3 (CKO) was associated with enhanced cardiomyocyte PGE2 secretion and down-regulation of PAX-5 in cardiac pre-B-cells, which could be prevented by the COX inhibitor ibuprofen.

In conclusion, SARS-CoV-2, age, male sex, sedentary life style and air pollution, promote high circulating PGE2 levels, which lead to impaired B-cell-mediated immune response and immunity. Physical exercise, treatment with taxifolin or ibuprofen reduce PGE2 production and may reduce the risk for severe disease courses and may improve healing and immunity in COVID-19 patients.