Biology subjects

Creisher, P. S.

Publications and source records attributed to Creisher, P. S..

6 recordsLinked to original sources

bioRxiv2025

Mechanisms of sex differences in acute and long COVID sequelae in mice

Males are more likely to suffer severe outcomes during acute COVID-19 and a greater proportion of females develop post-acute sequalae of COVID-19 (PASC). To identify mechanisms of PASC, mice were infected with SARS-CoV-2 and viral, inflammatory, and neurocognitive outcomes were evaluated through 84 days post-infection. Sex differences were not observed in virus replication or persistence of viral RNA in pulmonary or extrapulmonary tissues. After infectious virus clearance, females exhibited persistent neurocognitive impairments, and greater frequencies of inflammatory myeloid cells, neuroinflammation, and dysregulated T cells, including effector memory and Tregs. Sex differences in persistent inflammation and cognitive impairments during PASC were mediated by the presence of two X chromosomes and infection-induced upregulation of the X-linked genes Xist and Tlr7, which was reversed by pharmacological inhibition of TLR7 activity during the PASC phase. Sustained X-linked TLR7-mediated inflammation underlies how the burden of PASC is greater for females and provides a therapeutic target.

immunology↗

bioRxiv2025

Humoral correlates of protection in a mouse model of echovirus infection

Echoviruses commonly infect humans and can cause severe outcomes, including meningitis and liver failure, especially in neonates and immunocompromised individuals. Although recent progress has been made in understanding acute pathogenesis and innate immunity to echoviruses, adaptive immune responses remain poorly defined, in part due to the lack of an appropriate small animal model of infection. Here, we developed a translational mouse model of echovirus infection using hFc mice, which express human FcRn, the echovirus receptor, while maintaining functional IgG circulation. Primary echovirus infection caused acute disease and elicited virus-specific nAbs, IgG, and IgM only in hFc mice, which express human FcRn and support IgG transport, but not in parental Tg32 mice that lack IgG transport. These humoral responses correlated with protection against a homologous lethal-dose challenge. The protective role of these antibodies was confirmed by passive transfer of immune serum, which conferred complete, sterilizing protection. Statistical modeling identified E5-specific nAb, total IgG, and IgG1 titers as the strongest predictors of survival following infection, identifying novel correlates of protection. These findings establish hFc mice as a robust translational model for dissecting echovirus adaptive immunity, define the humoral response to infection, and identify correlates of protection to guide future vaccine development and preclinical evaluation.

immunology↗

bioRxiv2025

Cellular and Immune Adaptations at the Maternal-Fetal Interface in Bats

Bats maintain pregnancy despite extended gestation relative to other small mammals, high fetal investment, recurrent pathogen exposure, and the metabolic demands of flight. These physiological extremes likely drive unique adaptations in placental function and maternal-fetal immune regulation, yet the cellular and molecular basis of these adaptations remains largely unknown. Here, we mapped the cellular landscape of the Jamaican fruit bat (Artibeus jamaicensis) placenta using single-nucleus RNA sequencing (snRNA-seq), integrated with histological and immunohistochemical analyses. We identified diverse trophoblast, stromal, and immune populations at the maternal-fetal interface, including specialized macrophages expressing pregnancy-associated signaling molecules. Trajectory analysis revealed dynamic trophoblast differentiation through proliferative, invasive, and syncytial states. To model these processes in vitro, we derived trophoblast and decidual gland organoids from matched tissues, which recapitulated key in vivo cell types and lineage trajectories. Cross-species transcriptomic comparisons with human and mouse placentas uncovered bat-specific gene programs in trophoblasts, fibroblasts, and immune cells. Notably, bat trophoblast organoids exhibited attenuated antiviral signaling compared to their human counterparts, suggesting species-specific modulation of innate immunity at the maternal-fetal interface. These findings define cellular strategies that support pregnancy under extreme physiological conditions and establish a framework for investigating the evolution of placental adaptations across mammals. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/654282v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@12e7580org.highwire.dtl.DTLVardef@1245751org.highwire.dtl.DTLVardef@e0b9b0org.highwire.dtl.DTLVardef@1bf0694_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstract:C_FLOATNO Using single-nucleus RNA sequencing (snRNA-seq) and placental organoids, we reveal unique trophoblast differentiation, immune cell specialization, and expanded stromal populations in Jamaican fruit bat placentas. Cross-species comparisons underscore bat-specific evolutionary adaptations critical for sustaining pregnancy amid extreme metabolic and immunological challenges. C_FIG SummaryPregnancy in bats occurs under a combination of physiological stressors rarely encountered in other mammals, including extended gestation relative to other small mammals, elevated metabolic load, temperature fluctuations associated with flight, and constant microbial exposure. To investigate how the placenta adapts to these challenges, we profiled Jamaican fruit bat (Artibeus jamaicensis) placenta using single-nucleus RNA sequencing and tissue-derived organoid models. This analysis revealed diverse trophoblast, stromal, and immune cell populations with bat-specific transcriptional programs. We identified dynamic trophoblast differentiation trajectories, fibroblasts with hybrid adventitial-neuronal signatures, and macrophages expressing pregnancy-associated molecules typically restricted to trophoblasts. Cross-species comparisons with human and mouse placentas uncovered both conserved cell states and lineage-specific adaptations, providing insight into the evolution of placental function and immune regulation across mammals. HighlightsO_LISingle-nucleus RNA-seq defines cell types and differentiation pathways in the bat placenta C_LIO_LIBat trophoblast and decidua gland organoids recapitulate in vivo lineage trajectories and cell signatures C_LIO_LIBat-specific transcriptional programs revealed across trophoblast, stromal, and immune lineages C_LIO_LIBat trophoblasts exhibit attenuated antiviral responses compared to human counterparts C_LI

developmental biology↗

bioRxiv2023

Estradiol Mediates Greater Germinal Center Responses to Influenza Vaccination in Female than Male Mice

Adult females of reproductive ages develop greater antibody responses to inactivated influenza vaccine (IIV) than males. How sex, age, and sex steroid changes impact B cells and durability of IIV-induced immunity and protection over 4-months post-vaccination (mpv) was analyzed. Vaccinated adult females had greater germinal center (GC) B cell and plasmablast frequencies in lymphoid tissues, higher neutralizing antibody responses 1-4 mpv, and better protection against live H1N1 challenge than adult males. Aged mice, regardless of sex, had reduced B cell frequencies, less durable antibody responses, and inferior protection after challenge than adult mice, which correlated with diminished estradiol among aged females. To confirm that greater IIV-induced immunity was caused by sex hormones, four core genotype (FCG) mice were used, in which the testes determining gene, Sry, was deleted from ChrY and transferred to Chr3, to separate gonadal sex (i.e., ovaries or testes) from sex chromosome complement (i.e., XX or XY complement). Vaccinated, gonadal female FCG mice (XXF and XYF) had greater numbers of B cells, higher antiviral antibody titers, and reduced pulmonary virus titers following live H1N1 challenge than gonadal FCG males (XYM and XXM). To establish that lower estradiol concentrations cause diminished immunity, adult and aged females received either a placebo or estradiol replacement therapy prior to IIV. Estradiol replacement significantly increased IIV-induced antibody responses and reduced morbidity after the H1N1 challenge among aged females. These data highlight that estradiol is a targetable mechanism mediating greater humoral immunity following vaccination among adult females. ImportanceFemales of reproductive ages develop greater antibody responses to influenza vaccines than males. We hypothesized that female-biased immunity and protection against influenza was mediated by estradiol signaling in B cells. Using diverse mouse models ranging from advanced age mice to transgenic mice that separate sex steroids from sex chromosome complement, those mice with greater concentrations of estradiol consistently had greater numbers of antibody producing B cells in lymphoid tissue, higher antiviral antibody titers, and greater protection against live influenza virus challenge. Treatment of aged female mice with estradiol enhanced vaccine-induced immunity and protection against disease, suggesting that estradiol signaling in B cells is critical for improved vaccine outcomes in females.

immunology↗

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↗

bioRxiv2023

Adverse outcomes in SARS-CoV-2 infected pregnant mice are gestational age-dependent and resolve with antiviral treatment

SARS-CoV-2 infection during pregnancy is associated with severe COVID-19 and adverse fetal outcomes, but the underlying mechanisms remain poorly understood. Moreover, clinical studies assessing therapeutics against SARS-CoV-2 in pregnancy are limited. To address these gaps, we developed a mouse model of SARS-CoV-2 infection during pregnancy. Outbred CD1 mice were infected at embryonic day (E) 6, E10, or E16 with a mouse adapted SARS-CoV-2 (maSCV2) virus. Outcomes were gestational age-dependent, with greater morbidity, reduced anti-viral immunity, greater viral titers, and more adverse fetal outcomes occurring with infection at E16 (3rd trimester-equivalent) than with infection at either E6 (1st trimester-equivalent) or E10 (2nd trimester-equivalent). To assess the efficacy of ritonavir-boosted nirmatrelvir (recommended for pregnant individuals with COVID-19), we treated E16-infected dams with mouse equivalent doses of nirmatrelvir and ritonavir. Treatment reduced pulmonary viral titers, decreased maternal morbidity, and prevented adverse offspring outcomes. Our results highlight that severe COVID-19 during pregnancy and adverse fetal outcomes are associated with heightened virus replication in maternal lungs. Ritonavir-boosted nirmatrelvir mitigated adverse maternal and fetal outcomes of SARS-CoV-2 infection. These findings prompt the need for further consideration of pregnancy in preclinical and clinical studies of therapeutics against viral infections.

microbiology↗