Infection with Zika virus (ZIKV) is associated with human congenital fetal anomalies. To model fetal outcomes in nonhuman primates, we administered Asian-lineage ZIKV subcutaneously to four pregnant rhesus macaques. While non-pregnant animals in a previous study contemporary with the current report clear viremia within 10–12 days, maternal viremia was prolonged in 3 of 4 pregnancies. Fetal head growth velocity in the last month of gestation determined by ultrasound assessment of head circumference was decreased in comparison with biparietal diameter and femur length within each fetus, both within normal range. ZIKV RNA was detected in tissues from all four fetuses at term cesarean section. In all pregnancies, neutrophilic infiltration was present at the maternal-fetal interface (decidua, placenta, fetal membranes), in various fetal tissues, and in fetal retina, choroid, and optic nerve (first trimester infection only). Consistent vertical transmission in this primate model may provide a platform to assess risk factors and test therapeutic interventions for interruption of fetal infection. The results may also suggest that maternal-fetal ZIKV transmission in human pregnancy may be more frequent than currently appreciated.
Pregnancy complications such as preterm birth, miscarriage, maternal and/or neonatal morbidities, and mortality can be manifestations of underlying placental pathology. Hofbauer cells refer to a heterogeneous population of fetal macrophages that reside within the functional unit of the placenta known as the chorionic villus. Hofbauer cells can be detected within the connective tissue matrix of the placenta as early as 4 weeks post-conception and are present throughout pregnancy. These cells are implicated in a wide array of functions important for a successful pregnancy including placental morphogenesis, immune regulation, control of stromal water content, and the transfer of ions and serum proteins across the maternal-fetal barrier. Derangements in Hofbauer cell homeostasis are associated with placental pathologies involving infection, inflammation, and inadequate placental development. Despite a growing body of evidence that these cells are important, our knowledge about Hofbauer cell function in both normal and dysfunctional pregnancy is rudimentary. The goal of this chapter is to provide an overview of what is known about Hofbauer cell origins and their potential roles in normal and complicated pregnancy. We also review established and emerging methodologies available for the study of Hofbauer cells during in vitro and in vivo conditions.
Infection with Zika virus (ZIKV) is associated with human congenital fetal anomalies. To model fetal outcomes in nonhuman primates, we administered Asian-lineage ZIKV subcutaneously to four pregnant rhesus macaques. While non-pregnant animals in a previous study contemporary with the current report clear viremia within 10-12 days, maternal viremia was prolonged in 3 of 4 pregnancies. Fetal head growth velocity in the last month of gestation determined by ultrasound assessment of head circumference was decreased in comparison with biparietal diameter and femur length within each fetus, both within normal range. ZIKV RNA was detected in tissues from all four fetuses at term cesarean section. In all pregnancies, neutrophilic infiltration was present at the maternal-fetal interface (decidua, placenta, fetal membranes), in various fetal tissues, and in fetal retina, choroid, and optic nerve (first trimester infection only). Consistent vertical transmission in this primate model may provide a platform to assess risk factors and test therapeutic interventions for interruption of fetal infection. The results may also suggest that maternal-fetal ZIKV transmission in human pregnancy may be more frequent than currently appreciated. Author summaryMaternal ZIKV infection in pregnancy is associated with severe fetal anomalies, including microcephaly. It has been shown that infection manifests differently in pregnancy than in the non-pregnant state, with prolonged maternal viremia. ZIKV is spread by mosquitos and through sexual contact and since its first detection in early 2015, has become endemic to the Americas. While much has been learned from studying infected human pregnancies, there are still many questions concerning transmission of ZIKV from mother to fetus. Investigating ZIKV infection in non-human primates could help answer these questions due to similarities in the immune system, and the tissues separating the fetus from the mother during pregnancy. Our study serves to model ZIKV transmission in early and late pregnancy, as well as study the effects of this infection on the fetus and mother at these different times in pregnancy. The data collected provides an important insight on ZIKV in pregnancy where the pregnancies have been monitored throughout the entire infection period until term, and suggests that vertical transmission may be very efficient, although severe fetal outcomes are uncommon.
Infection with Listeria monocytogenes during pregnancy is associated with miscarriage, preterm birth, and neonatal complications, including sepsis and meningitis. While the risk of these conditions is thought to be greatest during the third trimester of pregnancy, the determinants of fetoplacental susceptibility to infection, the contribution of gestational age, and the in vivo progression of disease at the maternal-fetal interface are poorly understood. We developed a nonhuman primate model of listeriosis to better understand antecedents of adverse pregnancy outcomes in early pregnancy. Four pregnant cynomolgus macaques (Macaca fascicularis) received a single intragastric inoculation between days 36 and 46 of gestation with 107 CFU of an L. monocytogenes strain isolated from a previous cluster of human listeriosis cases that resulted in adverse pregnancy outcomes. Fecal shedding, maternal bacteremia, and fetal demise were consistently noted within 7 to 13 days. Biopsy specimens of maternal liver, spleen, and lymph node displayed variable inflammation and relatively low bacterial burden. In comparison, we observed greater bacterial burden in the decidua and placenta and the highest burden in fetal tissues. Histopathology indicated vasculitis, fibrinoid necrosis, and thrombosis of the decidual spiral arteries, acute chorioamnionitis and villitis in the placenta, and hematogenous infection of the fetus. Vascular pathology suggests early impact of L. monocytogenes infection on spiral arteries in the decidua, which we hypothesize precipitates subsequent placentitis and fetal demise. These results demonstrate that L. monocytogenes tropism for the maternal reproductive tract results in infection of the decidua, placenta, and the fetus itself during the first trimester of pregnancy.
Porphyromonas gingivalis is a Gram-negative, anaerobic bacterium considered to be an important pathogen of periodontal disease that is also implicated in adverse pregnancy outcome (APO). Until recently, our understanding of the role of P. gingivalis in APO has been limited and sometimes contradictory. The purpose of this review is to provide an overview of past and current research on P. gingivalis that addresses some of the controversies concerning the role of this organism in the pathogenesis of APO.ARTICLE HISTORY
Listeria monocytogenes (Lm) is a common environmental bacterium that thrives on vegetation and soil matter, but can infect humans if contaminated food products are ingested, resulting in severe disease in immunosuppressed populations, including pregnant women and newborns. To better understand how the unique immunological milieu of pregnancy increases susceptibility to infection, we study listeriosis in cynomolgus macaques, a non-human primate that closely resembles humans in placentation and in the physiology, and immunology of pregnancy. Non-human primates are naturally susceptible to Lm infection, and spontaneous abortions due to listeriosis are known to occur in outdoor macaque colonies, making them ideal models to understand the disease pathogenesis and host-pathogen relationship of listeriosis. We have previously shown that Lm infection in the first trimester has a high rate of miscarriage. This study expands on our previous findings by assessing how the quantity of Lm as well as stage of pregnancy at the time of exposure may influence disease susceptibility. In the current study we inoculated a cohort of macaques with a lower dose of Lm than our previous study and although this did not result in fetal demise, there was evidence of in utero inflammation and fetal distress. Animals that were reinfected with an equivalent or higher dose of the same strain of Lm resulted in approximately half of cases continuing to term and half ending in fetal demise. These cases had inconsistent bacterial colonization of the fetal compartment, suggesting that Lm does not need to directly infect the placenta to cause adverse pregnancy outcomes. Timed surgical collection of tissues following inoculation demonstrated that transmission from mother to fetus can occur as soon as 5 days post-inoculation. Lastly, third trimester inoculation resulted in pregnancy loss in 3 out of 4 macaques, accompanied by characteristic pathology and Lm colonization. Collectively, our studies demonstrate that common laboratory culture tests may not always recover Lm despite known maternal ingestion. Notably, we also find it is possible for maternal infection to resolve in some cases with no discernible adverse outcome; however, such cases had evidence of a sterile intrauterine inflammatory response, with unknown consequences for fetal development.
Impaired spiral artery remodeling (IRSA) underpins the great obstetrical syndromes. We previously demonstrated that intrauterine infection with the periodontal pathogen, Porphyromonas gingivalis, induces IRSA in rats. Since our previous studies only examined the end stage of arterial remodeling, the aim of this study was to identify the impact of P. gingivalis infection on the earlier stages of remodeling. Gestation day (GD) 11 specimens, a transition point between trophoblast-independent remodeling and the start of extravillous trophoblast invasion, were compared to late stage GD18 tissues. P. gingivalis was found in decidual stroma of GD11 specimens that already had reduced spiral artery remodeling defined as smaller arterial lumen size, increased retention of vascular smooth muscle, and decreased invasion by extravillous trophoblasts. At GD11, P. gingivalis-induced IRSA coincided with altered uterine natural killer (uNK) cell populations, decreased placental bed expression of interleukin-18 (IL-18) with increased production of temperature requirement A1 (Htra1), a marker of oxidative stress. By GD18, placental bed IL-18 and Htra1 levels, and uNK cell numbers were equivalent in control and infected groups. However, infected GD18 placental bed specimens had decreased TNF + T cells. These results suggest disturbances in placental bed decidual stroma and uNK cells are involved in P. gingivalis-mediated IRSA.
Workshops are an important part of the IFPA annual meeting as they allow for discussion of specialized topics. At IFPA meeting 2018 there were nine themed workshops, five of which are summarized in this report. These workshops discussed new perspectives and knowledge in the following areas of research: 1) preeclampsia; 2) abnormally invasive placenta; 3) placental infection; 4) gestational trophoblastic disease; 4) drug delivery to treat placental dysfunction.
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