Male and female sexes appear to be overrepresented in the “EP3 up” and “EP3 down” categories, respectively. Greater EP3 expression in males and reduced EP3 expression in females may provide a mechanistic explanation for the following findings:
Male patients are, on average, more vulnerable to severe COVID-19 than female patients¹ and among male infants, the mortality rate following infections is higher than among female infants².

The general symptoms of viral infection are stimulated through EP3³. Among female LC patients and among female infants, the prevalence of autoimmune conditions is higher². Autoimmune responses are primarily stimulated through EP4 and EP2 ^4,5 (see section 5.1.1).

Estrogen alone or in combination with progesterone has been reported to modulate EP receptor expression and mRNA levels in bovine tissues⁶. These findings raise the possibility that developmental or hormonal changes in sex steroid levels may also influence EP receptor balance in humans particularly during puberty. Within the framework of the PGE2 hypothesis, such sex-hormone-dependent modulation could contribute to sex-related differences in clinical presentation and may also be relevant to age-specific patterns observed between younger children (6 – 11 years) and peri-pubertal adolescents (12 – 17 years) with Long COVID^7,8.

If women are indeed found to have, on average, significantly lower EP3 capacity compared to men, leading to proportionally greater capacity through EP2 and EP4, this could help explain sex-based medical differences observed in LC and its comorbidities. For more detailed information on hypothetical EP receptor expression clusters and supporting references, see Hypothetical biomarkers.

1              Ricke-Hoch, M. et al. Impaired immune response mediated by prostaglandin E2 promotes severe COVID-19 disease. PLOS ONE 16, e0255335 (2021). https://doi.org/10.1371/journal.pone.0255335

2              Muenchhoff, M. & Goulder, P. J. Sex differences in pediatric infectious diseases. J Infect Dis 209 Suppl 3, S120-126 (2014). https://doi.org/10.1093/infdis/jiu232

3              Bin, N. R. et al. An airway-to-brain sensory pathway mediates influenza-induced sickness. Nature 615, 660-667 (2023). https://doi.org/10.1038/s41586-023-05796-0

4              Tsuge, K., Inazumi, T., Shimamoto, A. & Sugimoto, Y. Molecular mechanisms underlying prostaglandin E2-exacerbated inflammation and immune diseases. Int Immunol 31, 597-606 (2019). https://doi.org/10.1093/intimm/dxz021

5              Fedyk, E. R. & Phipps, R. P. Prostaglandin E2 receptors of the EP2 and EP4 subtypes regulate activation and differentiation of mouse B lymphocytes to IgE-secreting cells. Proc Natl Acad Sci U S A 93, 10978-10983 (1996). https://doi.org/10.1073/pnas.93.20.10978

6              Blesson, C. S., Büttner, E., Masironi, B. & Sahlin, L. Prostaglandin receptors EP and FP are regulated by estradiol and progesterone in the uterus of ovariectomized rats. Reproductive Biology and Endocrinology 10, 3 (2012). https://doi.org/10.1186/1477-7827-10-3

7              Gross, R. S. et al. Characterizing Long COVID in Children and Adolescents. Jama 332, 1174-1188 (2024). https://doi.org/10.1001/jama.2024.12747

8              Kikkenborg Berg, S. et al. Long COVID symptoms in SARS-CoV-2-positive children aged 0-14 years and matched controls in Denmark (LongCOVIDKidsDK): a national, cross-sectional study. Lancet Child Adolesc Health 6, 614-623 (2022). https://doi.org/10.1016/s2352-4642(22)00154-7