Modulation of Th17 and Regulatory T cell responses during murine pregnancy contributes to increased maternal susceptibility to Salmonella Typhimurium infection

Wachholz

Murphy

et al. 2018

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Problem: IFN-alpha receptor deficiency (IFNAR−/−) enhances immunity to Listeria monocytogenes (LM) and Salmonella enterica serovar Typhimurium (ST) in the non-pregnant state by inhibiting pathogen-induced immune cell death. However, the roles of IFNAR signaling in modulating immunity to infection during pregnancy are not well-understood. Method of Study: WT and IFNAR−/− mice were infected systemically with LM or ST. Bacterial burden in spleen and individual placentas was enumerated at day 3 post-infection. Immune cell numbers and percentages were quantified in spleen and individual placentas, respectively, through flow cytometry. Cytokine expression in serum, spleen and individual placentas was measured through cytometric bead array. Results: IFNAR−/− mice exhibited decreased splenic monocyte numbers in non-pregnant and pregnant state, and an altered distribution of placental immune cell types in the non-infected state. IFNAR−/− mice controlled LM infection more effectively than wild-type even during pregnancy, and this correlated with enhanced serum IL-12 expression, despite reduced splenic monocyte numbers relative to WT controls. In contrast, pregnant IFNAR−/− mice unlike their non-pregnant counterparts exhibited increased susceptibility to ST infection which was associated with decreased serum IL-12 expression. Conclusion: Type I IFN responses differentially impact host resistance to LM and ST infection during pregnancy through modulation of immune cell distribution and cytokine responses.

Section: Resultsmentioning

confidence: 75%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Type I interferons differentially modulate maternal host immunity to infection by Listeria monocytogenes and Salmonella enterica serovar Typhimurium during pregnancy

Wachholz

Murphy

et al. 2018

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IFN‐alpha receptor deficiency enhances host resistance to oral Salmonella enterica serovar Typhimurium infection during murine pregnancy

Clark

Sandhu

et al. 2021

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Problem Maternal tolerance during pregnancy increases the risk of infection with certain intracellular pathogens. Systemic Salmonella enterica serovar Typhimurium (S.Tm) infection during pregnancy in normally resistant 129X1/SvJ mice leads to severe placental infection, as well as fetal and maternal deaths. However, the effect of oral infection with S.Tm in pregnant mice and the roles of infection‐induced inflammation and cell death pathways in contributing to susceptibility to infection are unclear. Method of Study Non‐pregnant and pregnant C57BL/6J wild‐type (WT) and cell death pathway‐altered mice (IFNAR1−/−, Caspase‐1, 11−/−, RIP3−/−) were infected orally with S.Tm. Host survival and fetal resorption were determined. Bacterial burden in mesenteric lymph nodes (MLNs), spleen, liver, and placentas was enumerated at various time points post‐infection. Serum cytokine expression was measured through cytometric bead array. Results Oral infection of WT mice with S.Tm on days 9–10 of gestation resulted in systemic dissemination of the bacteria, substantial placental colonization, and fetal loss 5 days post‐infection. Histopathological examination of the placentas indicated that infection‐induced widespread focal necrosis and neutrophil infiltration throughout the spongiotrophoblast (SpT) layer. In the non‐pregnant state, IFNAR1−/− mice exhibited increased survival following oral S.Tm infection relative to Caspase‐1, 11−/−, RIP3−/−, and WT mice. The increased resistance to S.Tm infection in IFNAR1−/− mice was seen during pregnancy as well, with decreased bacterial burden within MLNs, spleen, and placenta, which correlated with the decreased resorptions relative to WT and Caspase‐1, 11−/− mice. Conclusion Oral S.Tm exposure leads to placental infection, inflammation, and resorption, whereas IFNAR1 deficiency enhances host resistance both in the non‐pregnant and pregnant states.

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

Clark

Sad

et al. 2022

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Problem 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. Method of Study 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. Results 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. Conclusion 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.