Murine Fetoplacental Infection Models

Abstract

We read with interest the recent article (1) addressing unique aspects of murine placental infection by Salmonella enterica serovar Typhimurium. We would like to call the authors' attention to two other murine fetoplacental infection models that we have studied. Listeria monocytogenes is a facultative intracellular pathogen causing severe fetoplacental infections in many species. We found that placental infection was a stochastic process determined by the size of the initial inoculum on day 14.5 of pregnancy (4). Infection always began in the uterine decidua, with subsequent spread into the placental labyrinth in some mice. Once organisms localized to the uterine decidua, they proliferated to extremely high titers (>108/g) even in preimmunized animals that were protected from infection in other organs. Bacterial titers in the liver and spleen and mortality did not differ between nonpregnant females and mothers without placental organisms. However, mothers with placental infection developed overwhelming sepsis and eventually succumbed. Ineffective immune responses to listeria differed in each placental region (5). In the uterine decidua, there was a paucity of the monocytes-macrophages required in other organs to control infection. Only neutrophils were able to enter the infected tissue. In the labyrinth, virtually no inflammatory cells were present until late in the course of infection. In fetal regions of the placenta, monocytes-macrophages were present but could not be activated. Fusobacterium nucleatum is an anaerobic pathogen implicated in periodontal infections and placental chorioamnionitis. Unlike listeria, intravenous inoculation of organisms on day 14.5 of pregnancy resulted in only transient maternal systemic colonization (2). Similar to the case with listeria, localization of small numbers of organisms to the uterine decidua resulted in overwhelming placental infection, with premature delivery and/or stillbirth. Organisms entered the labyrinth only after ischemic necrosis. The latter point is an important caveat for murine fetoplacental infection models. The possibility that spread into the labyrinth occurs after tissue infarction caused by decidual vascular thrombosis secondary to severe infection cannot be excluded and complicates the interpretation of placental immune responsiveness. Interestingly, infection of Toll-like receptor 4 (TLR4) but not TLR2 knockout mice prevented necrosis and inflammation and reduced stillbirth but did not affect bacterial titers in the placenta (3). Our interpretation of this data is that the uterine decidua is an immunoprivileged environment that normally protects placental tissue from the maternal immune response. The price of protection is enhanced susceptibility to small numbers of bacteria that enter the maternal bloodstream in women with food-borne illnesses (listeria and salmonella) and periodontal infections (fusobacterium) or that ascend from the cervix in acute chorioamnionitis. Once in the placental environment, proliferation of organisms is unchecked, leading to a neutrophil-dominated innate immune response that triggers premature labor and delivery, saving the mother from the risks of systemic infection.