Suppression of progesterone by influenza A virus mediates adverse maternal and fetal outcomes in mice

Patrick S. Creisher, Maclaine A. Parish, Jun Lei, Jin Liu, Jamie L. Perry, Ariana D. Campbell, Morgan L. Sherer, Irina Burd, Sabra L. Klein

Research output: Contribution to journalArticlepeer-review

Abstract

Influenza A virus infection during pregnancy can cause adverse maternal and fetal outcomes but the mechanism responsible remains elusive. Infection of outbred mice with 2009 H1N1 at embryonic day (E) 10 resulted in significant maternal morbidity, placental tissue damage and inflammation, fetal growth restriction, and developmental delays that lasted through weaning. Restriction of pulmonary virus replication was not inhibited during pregnancy, but infected dams had suppressed circulating and placental progesterone (P4) concentrations that were caused by H1N1induced upregulation of pulmonary cyclooxygenase (COX)1, but not COX2, dependent synthesis and secretion of prostaglandin (PG) F2α. Treatment with 17αhydroxyprogesterone caproate (17OHPC), a synthetic progestin that is safe to use in pregnancy, ameliorated the adverse maternal and fetal outcomes from H1N1 infection and prevented placental cell death and inflammation. These findings highlight the therapeutic potential of progestin treatments for influenza during pregnancy. IMPORTANCE Pregnant individuals are at risk of severe outcomes from both seasonal and pandemic influenza A viruses. Influenza infection during pregnancy is associated with adverse fetal outcomes at birth and adverse consequences for offspring into adulthood. When outbred dams, with semiallogenic fetuses, were infected with 2009 H1N1, in addition to pulmonary virus replication, lung damage, and inflammation, the placenta showed evidence of transient cell death and inflammation that was mediated by increased activity along the arachidonic acid pathway leading to suppression of circulating progesterone. Placental damage and suppressed progesterone were associated with detrimental effects on perinatal growth and developmental delays in offspring. Treatment of H1N1infected pregnant mice with 17OHPC, a synthetic progestin treatment that is safe to use in pregnancy, prevented placental damage and inflammation and adverse fetal outcomes. This novel therapeutic option for the treatment of influenza during pregnancy should be explored clinically.

Original languageEnglish (US)
JournalmBio
Volume15
Issue number2
DOIs
StatePublished - Feb 2024

Keywords

  • cytokine storm
  • macrophages
  • placenta
  • pregnancy
  • progestins
  • prostaglandins

ASJC Scopus subject areas

  • Microbiology
  • Virology

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