Biology subjects

Parish, M. A.

Publications and source records attributed to Parish, M. A..

3 recordsLinked to original sources

bioRxiv2026

Sex differences in vaccine-induced neuraminidase cross-recognition and protection against H5N1 in mice

H5N1 vaccines have been poorly immunogenic in humans, creating a challenge for vaccine development. Seasonal influenza vaccines offer some cross-protection against H5N1, but there has been no consideration of whether protection differs between the sexes. We investigated sex differences in antibody responses following receipt of either beta-propiolactone inactivated whole virus H1N1 or H5N1 (LAIV backbone) vaccines in C57BL/6 mice. Using systems serology assays, vaccination induced strong homologous and heterologous antibody responses, with females generating greater IgG titers than males against whole virus H1N1 and H5N1, which was primarily mediated by greater IgG responses to neuraminidase (NA) than hemagglutinin (HA) protein. Cross-reactive H5N1 IgG titers were greater among H1N1-vaccinated females, and primarily mediated by greater N1-specific IgG titers. IgG2b and IgG2c were the primary antibody isotypes generated in response to these vaccines, with females having greater IgG2b titers and enhanced binding to Fc{gamma}RIV for avian and human NA than males following either homologous or heterologous vaccination. Antibody-dependent complement deposition was measured as an FcR-mediated non-neutralizing response against HA and NA and was more robust among H1N1 and H5N1 vaccinated females than their male counterparts in response to homologous HA only. Vaccinated females tended to have greater neutralizing antibody titers than males against the homologous vaccine strain, with limited cross-neutralizing antibodies detected in either sexes. Neuraminidase inhibition titers were greater in vaccinated females than males against the heterologous virus following H1N1 vaccination and against both the vaccine and heterologous viruses following H5N1 vaccination. When H1N1 and H5N1 vaccinated mice were challenged with a lethal dose of A/Texas/37/2024 H5N1, all H5N1 vaccinated mice were protected, regardless of sex. Among H1N1 vaccinated mice, while both sexes were protected against disease, H1N1 vaccinated females restricted virus to the upper respiratory tract and had lower pulmonary virus titers than males at 3 days post challenge. These findings highlight that sex differences in vaccine-induced NA-specific antibody responses are associated with differential respiratory dissemination of H5N1 and that sex should be considered in studies of vaccine-induced cross-reactive influenza immunity.

immunology↗

bioRxiv2025

Vertical Transmission of Bovine H5N1 during Pregnancy and Lactation in Mice

Avian influenza H5N1 has pandemic potential and historically has caused more severe disease in pregnant women than the general population. With increasing transmission of H5N1 detected among placental mammals, animal models are necessary for testing countermeasures, including during pregnancy. Pregnant outbred mice were infected with a contemporary strain of bovine H5N1 during the second or third trimester equivalent. Second trimester infection caused in utero transmission, with infectious virus detected in the uterus, placenta, and fetus. Birth following third trimester infection resulted in offspring with decreased size, neurodevelopmental delays, and adolescent behavioral impairments, with infectious virus detected in the neonatal milk ring and lungs, as well as mammary tissues. H5N1 viral protein colocalized with trophoblast cells in the placenta and epithelial cells in mammary tissue that spatially overlapped with lectins for 2,3-linked SA. With the pandemic potential of H5N1, our vertical transmission model in placental mammals is essential for understanding viral spread and evaluating treatments during pregnancy.

microbiology↗

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↗