Ekregbesi Phebe, Seibert Brittany, Parish Maclaine A, Flores-Garcia Yevel, Creisher Patrick S, Hoffmann Joseph P, Liu Jennifer A, Brayton Cory, Zavala Fidel, Klein Sabra L
W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
Infect Immun. 2025 Jul 8;93(7):e0002125. doi: 10.1128/iai.00021-25. Epub 2025 Jun 5.
Sequestration of parasites in the placental vasculature contributes to increased morbidity and mortality in pregnant compared to non-pregnant patients in malaria-endemic regions. In this study, outbred pregnant CD1 mice with semi-allogeneic fetuses were infected with transgenic or mock inoculated by mosquito bite at either embryonic day (E)6 (first trimester-equivalent) or 10 (second trimester-equivalent) and were compared to non-pregnant females. -infected mosquitoes had greater biting avidity for E10 dams than uninfected mosquitoes, which was not apparent for E6 dams nor non-pregnant females. Infected E10 dams had greater numbers of parasites than E6 dams in the uterus and spleen, but not in the blood or liver. While parasites were found in placentas, no parasites were present in fetuses. Maternal infection at E6 caused greater maternal morbidity, with greater rates of fetal reabsorption and stillbirths than at E10. Infection at E10 caused adverse offspring outcomes, including growth restriction. To identify possible mechanisms of adverse offspring outcomes, E10 dams were euthanized during peak parasitemia (8 days postinfection [dpi]), and outcomes were compared to mock-infected dams. caused significant systemic maternal immune activation with elevated circulating lymphocytes, eosinophils, and neutrophils and splenic cytokine concentrations. infection at E10 increased corticosterone and decreased progesterone concentrations, which could contribute to adverse perinatal outcomes through immunomodulation. There were limited changes in the maternal fecal microbiome after infection. Mosquito bite infection of outbred dams with causes placental malaria and provides a novel, tractable model to investigate therapeutic treatments.
与疟疾流行地区的非孕患者相比，疟原虫在胎盘血管系统中的隔离导致孕妇发病率和死亡率增加。在本研究中，将带有半同种异体胎儿的远交系孕CD1小鼠在胚胎第6天（相当于孕早期）或第10天（相当于孕中期）通过蚊虫叮咬感染转基因疟原虫或进行假接种，并与非孕雌性小鼠进行比较。感染疟原虫的蚊子对E10孕鼠的叮咬偏好性高于未感染的蚊子，而这在E6孕鼠和非孕雌性小鼠中并不明显。感染的E10孕鼠子宫和脾脏中的疟原虫数量多于E6孕鼠，但血液和肝脏中没有。虽然在胎盘中发现了疟原虫，但胎儿中没有疟原虫。E6时的母体感染导致更高的母体发病率，胎儿吸收和死产率高于E10时。E10时感染导致不良的后代结局，包括生长受限。为了确定不良后代结局的可能机制，在疟原虫血症高峰期（感染后8天）对E10孕鼠实施安乐死，并将结果与假感染孕鼠进行比较。疟原虫感染导致显著的全身母体免疫激活，循环淋巴细胞、嗜酸性粒细胞和中性粒细胞以及脾脏细胞因子浓度升高。E10时感染疟原虫会增加皮质酮浓度并降低孕酮浓度，这可能通过免疫调节导致不良的围产期结局。疟原虫感染后母体粪便微生物群的变化有限。远交系孕鼠经蚊虫叮咬感染疟原虫会导致胎盘疟疾，并提供了一个新的、易于处理的模型来研究治疗方法。
