First Trimester Typhoid Fever with Vertical Transmission of Salmonella

We report a case in which placental abruption occurred at 16 weeks following first trimester diagnosis and treatment for typhoid fever. Unexpectedly Salmonella enterica serovar Typhi (S. Typhi) was found in fetal tissues at autopsy. Using information from the murine model of typhoid fever in pregnancy, we draw parallels between S. Typhi and L. monocytogenes to develop a plausible hypothesis to explain how this organism was able to cross the placenta in the first trimester to cause abruption, inflammation, and expulsion of the fetus and placenta. We hope that this model for understanding placental infections by the hematogenous route helps to raise awareness that organisms not typically associated with TORCH infection can nevertheless cause placental infection and pregnancy loss

Listeria monocytogenes Traffics from Maternal Organs to the Placenta and Back

Infection with Listeria monocytogenes is a significant health problem during pregnancy. This study evaluates the role of trafficking between maternal organs and placenta in a pregnant guinea pig model of listeriosis. After intravenous inoculation of guinea pigs, the initial ratio of bacteria in maternal organs to placenta was 10(3)–10(4):1. Rapid increase of bacteria in the placenta changed the ratio to 1:1 after 24 h. Utilizing two wild-type strains, differentially marked by their susceptibility to erythromycin, we found that only a single bacterium was necessary to cause placental infection, and that L. monocytogenes trafficked from maternal organs to the placenta in small numbers. Surprisingly, bacteria trafficked in large numbers from the placenta to maternal organs. Bacterial growth, clearance, and transport between organs were simulated with a mathematical model showing that the rate of bacterial clearance relative to the rate of bacterial replication in the placenta was sufficient to explain the difference in the course of listeriosis in pregnant versus nonpregnant animals. These results provide the basis for a new model where the placenta is relatively protected from infection. Once colonized, the placenta becomes a nidus of infection resulting in massive reseeding of maternal organs, where L. monocytogenes cannot be cleared until trafficking is interrupted by expulsion of the infected placental tissues

Placental syncytiotrophoblast constitutes a major barrier to vertical transmission of Listeria monocytogenes.

Listeria monocytogenes is an important cause of maternal-fetal infections and serves as a model organism to study these important but poorly understood events. L. monocytogenes can infect non-phagocytic cells by two means: direct invasion and cell-to-cell spread. The relative contribution of each method to placental infection is controversial, as is the anatomical site of invasion. Here, we report for the first time the use of first trimester placental organ cultures to quantitatively analyze L. monocytogenes infection of the human placenta. Contrary to previous reports, we found that the syncytiotrophoblast, which constitutes most of the placental surface and is bathed in maternal blood, was highly resistant to L. monocytogenes infection by either internalin-mediated invasion or cell-to-cell spread. Instead, extravillous cytotrophoblasts-which anchor the placenta in the decidua (uterine lining) and abundantly express E-cadherin-served as the primary portal of entry for L. monocytogenes from both extracellular and intracellular compartments. Subsequent bacterial dissemination to the villous stroma, where fetal capillaries are found, was hampered by further cellular and histological barriers. Our study suggests the placenta has evolved multiple mechanisms to resist pathogen infection, especially from maternal blood. These findings provide a novel explanation why almost all placental pathogens have intracellular life cycles: they may need maternal cells to reach the decidua and infect the placenta

Invasive Extravillous Trophoblasts Restrict Intracellular Growth and Spread of Listeria monocytogenes

Listeria monocytogenes is a facultative intracellular bacterial pathogen that can infect the placenta, a chimeric organ made of maternal and fetal cells. Extravillous trophoblasts (EVT) are specialized fetal cells that invade the uterine implantation site, where they come into direct contact with maternal cells. We have shown previously that EVT are the preferred site of initial placental infection. In this report, we infected primary human EVT with L. monocytogenes. EVT eliminated ∼80% of intracellular bacteria over 24-hours. Bacteria were unable to escape into the cytoplasm and remained confined to vacuolar compartments that became acidified and co-localized with LAMP1, consistent with bacterial degradation in lysosomes. In human placental organ cultures bacterial vacuolar escape rates differed between specific trophoblast subpopulations. The most invasive EVT—those that would be in direct contact with maternal cells in vivo—had lower escape rates than trophoblasts that were surrounded by fetal cells and tissues. Our results suggest that EVT present a bottleneck in the spread of L. monocytogenes from mother to fetus by inhibiting vacuolar escape, and thus intracellular bacterial growth. However, if L. monocytogenes is able to spread beyond EVT it can find a more hospitable environment. Our results elucidate a novel aspect of the maternal-fetal barrier

Structure and barriers of the human maternal-fetal interface.

<p>(A) Structure of the human placenta. Maternal and fetal tissues are in tones of red and blue, respectively. Adapted from <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002804#ppat.1002804-Robbins1" target="_blank">[6]</a>. See text for detailed explanation. (B) Enlargement of boxed area in panel A showing points of direct contact between mother and fetus. EVT, extravillous trophoblasts; SYN, syncytium. Adapted from <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002804#ppat.1002804-Robbins1" target="_blank">[6]</a>. (C) Scanning electron micrograph of first trimester human placenta showing the syncytial surface with profuse branched microvilli (courtesy of Susan Fisher, UCSF). (D) False-colored transmission electron micrograph of primary human EVT. <i>Listeria monocytogenes</i> (green) is trapped in endolysosomes (orange). Adapted from <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002804#ppat.1002804-Zeldovich1" target="_blank">[23]</a>. Bar, 1 µm.</p

Placental pathogens.

a<p>Generally thought to be extracellular, but has been documented in intracellular compartments. For a more detailed review of placental pathogens, their route of horizontal transmission, and host range, please see <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002804#ppat.1002804-Robbins3" target="_blank">[20]</a>.</p

Limited Colonization Undermined by Inadequate Early Immune Responses Defines the Dynamics of Decidual Listeriosis

The bacterial pathogen Listeria monocytogenes causes foodborne systemic disease in pregnant women, which can lead to preterm labor, stillbirth, or severe neonatal disease. Colonization of the maternal decidua appears to be an initial step in the maternal component of the disease as well as bacterial transmission to the placenta and fetus. Host-pathogen interactions in the decidua during this early stage of infection remain poorly understood. Here, we assessed the dynamics of L. monocytogenes infection in primary human decidual organ cultures and in the murine decidua in vivo A high inoculum was necessary to infect both human and mouse deciduas, and the data support the existence of a barrier to initial colonization of the murine decidua. If successful, however, colonization in both species was followed by significant bacterial expansion associated with an inability of the decidua to mount appropriate innate cellular immune responses. The innate immune deficits included the failure of bacterial foci to attract macrophages and NK cells, cell types known to be important for early defenses against L. monocytogenes in the spleen, as well as a decrease in the tissue density of inflammatory Ly6Chi monocytes in vivo These results suggest that the infectivity of the decidua is not the result of an enhanced recruitment of L. monocytogenes to the gestational uterus but rather is due to compromised local innate cellular immune responses

Listeriosis in the Pregnant Guinea Pig: a Model of Vertical Transmission

Feto-placental infections represent a major cause of pregnancy complications, and yet the underlying molecular and cellular mechanisms of vertical transmission are poorly understood. Listeria monocytogenes, a facultative intracellular pathogen, is one of a group of pathogens that are known to cause feto-placental infections in humans and other mammals. The purpose of this study was to evaluate possible mechanisms of vertical transmission of L. monocytogenes. Humans and guinea pigs have a hemochorial placenta, where a single layer of fetally derived trophoblasts separates maternal from fetal circulation. We characterized L. monocytogenes infection of the feto-placental unit in a pregnant guinea pig model and in primary human trophoblasts and trophoblast-derived cell lines. The clinical manifestations of listeriosis in the pregnant guinea pigs and the tropism of L. monocytogenes to the guinea pig placenta resembled those in humans. Trophoblast cell culture systems were permissive for listerial growth and cell-to-cell spread and revealed that L. monocytogenes deficient in internalin A, a virulence factor that mediates invasion of nonphagocytic cells, was 100-fold defective in invasion. However, crossing of the feto-placental barrier in the guinea pig model was independent of internalin A, suggesting a negligible role for internalin-mediated direct invasion of trophoblasts in vivo. Further understanding of vertical transmission of L. monocytogenes will help in designing more effective means of treatment and disease prevention