Sherer, M. L. | bioRxiv Science

bioRxiv2023

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

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 H1N1-induced upregulation of pulmonary cyclooxygenase (COX)-1, but not COX-2-, dependent synthesis and secretion of prostaglandin (PG) F2. Treatment with 17--hydroxyprogesterone caproate (17-OHPC), 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. ImportancePregnant 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. We developed an outbred mouse model of 2009 H1N1 influenza virus infection during pregnancy, with semi-allogenic fetuses. When dams are infected with 2009 H1N1, in addition to pulmonary virus replication, tissue damage, and inflammation, the placenta shows evidence of transient damage and inflammation that is mediated by increased activity along the arachidonic acid pathway leading to suppression of circulating progesterone. Placental damage and suppressed progesterone are associated with long-term effects on perinatal growth and developmental delays in offspring. Treatment of H1N1-infected pregnant mice with 17-OHPC, a synthetic progestin treatment safe that is safe to use in pregnancy, prevents placental damage and inflammation and adverse fetal outcomes. This provided a novel therapeutic option for treatment of influenza during pregnancy that should be explored clinically.

microbiology↗

bioRxiv2022

Greater breadth of vaccine-induced immunity in females than males is mediated by increased antibody diversity in germinal center B cells

Inactivated influenza vaccines induce greater antibody responses in females than males among both humans and mice. To test the breadth of protection, we used recombinant mouse-adapted A/California/2009 (maA/Cal/09) H1N1 viruses containing mutations at one (1M), two (2M), or three (3M) antigenic sites, in addition to a virus containing the 1M mutation and a substitution of the Ca2 antigenic site (Sub) with one derived from an H5 hemagglutinin (HA) to challenge mice of both sexes. Following maA/Cal/09 vaccination, females produced greater virus-specific class-switched IgG and IgG2c antibodies against the vaccine and all mutant viruses, and antibodies from females recognized more unique, linear HA epitopes than antibodies from males. While females had greater neutralizing antibody (nAb) titers against the vaccine virus, both sexes showed lower neutralization capacity against mutant viruses. After virus challenge, vaccinated females had lower pulmonary virus titers and reduced morbidity than males against the 1M and 2M viruses, but not the Sub virus. Females generated greater numbers of germinal center (GC) B cells containing superior somatic hypermutation frequencies than vaccinated males. Deletion of activation-induced cytidine deaminase (Aicda) eliminated female-biased immunity and protection against the 2M virus. Harnessing methods to improve GC B cell responses and frequencies of somatic hypermutations, especially in males, should be considered in the development of universal influenza vaccines. SummaryCompared with males, inactivated influenza vaccination of female mice causes greater production of class-switched, somatically-hypermutated antibodies and a more robust germinal center B cell response, leading to more diverse H1N1 antigen recognition and better protection against mutant influenza A viruses.

immunology↗