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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.

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We evaluated the impact of premature cell death of antigen-presenting cells (APCs) by Caspase-1- and RipK3-signaling pathways on CD8 T-cell priming during infection of mice with Salmonella typhimurium (ST). Our results indicate that Caspase1 and RipK3 synergize to rapidly eliminate infected APCs, which does not influence the initial activation of CD8 T cells. However, the maintenance of primed CD8 T cells was greatly compromised when both these pathways were disabled. Caspase-1- and RipK3-signaling did not influence NF-κB signaling in APCs, but synergized to promote processing of IL-1 and IL-18. Combined deficiency of Caspase1 and RipK3 resulted in compromised innate immunity and accelerated host fatality due to poor processing of IL-18. In contrast, synergism in cell death by Caspase-1- and RipK3 resulted in restriction of PD-1 and TIM3 expression on primed CD8 T cells, which promoted the survival of activated CD8 T cells.