Roles of natural resistance-associated macrophage protein-1 in modulating bacterial distribution and immune responses during Salmonella enterica serovar Typhimurium infection in murine pregnancy.

Abstract

Salmonella enterica serovar Typhimurium (S.Tm) infection in Nramp1+/+ mice during pregnancy can lead to profound bacterial growth in the feto-placental unit and adverse pregnancy outcomes, including fetal loss, maternal illness and death. The kinetics and mechanisms by which S.Tm gains entry within individual feto-placental unit, and disseminates through tissues leading to placental resorption and fetal demise remain unclear. Mice were systemically infected with S.Tm. Bacterial burden within spleen and individual placentas, and placental/fetal resorptions were quantified. Flow cytometric analysis of immune cell types in the spleen and individual placentas was performed. Cytokine expression in maternal serum was determined through cytometric bead array. Systemic infection with S.Tm resulted in preferential bacterial proliferation in placentas compared to the spleen in Nramp1+/+ mice.At 24 h post-infection, the mean infection rate of individual placentas per mouse was ∼50%, increasing to >75% by 72 h post-infection, suggesting that initial infection in few sites progresses to rapid spread of infection through the uterine milieu. This correlated with a steady increase in placental/fetal resorption rates.Placental infection was associated with local increased neutrophil percentages, whereas numbers and percentages in the spleen remained unchanged, suggesting dichotomous modulation of inflammation between the systemic compartment and the feto-maternal interface. Reduced survival rates of pregnant mice during infection correlated with decreased serum IFN-γ but increased IL-10 levels relative to non-pregnant controls. Pregnancy compromises host resistance conferred by Nramp1 against S.Tm through compartment-specific regulation of maternal and placental cellular responses, and modulation of systemic cytokine expression.