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

Abstract

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.

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

“…We previously showed in our intravenous infection model that the protection conferred by IFNAR1 deficiency against S . Tm in the non‐pregnant state was abrogated during pregnancy 49 . This was associated with decreased serum expression of pro‐inflammatory IL‐12p70 compared to non‐pregnant controls, suggesting a role for the cytokine in the control of systemic and placental infection during pregnancy.…”

“…In particular, fetal survival was enhanced in infected pregnant IFNAR1 −/− mice. The contrasting clinical response following intravenous versus oral infection during pregnancy in IFNAR1 −/− mice suggests that the threshold of systemic infection can determine maternal susceptibility 49 . Following oral infection, as initially fewer bacteria enter the systemic circulation, the resistance conferred by IFNAR1 deficiency can be retained even in pregnant mice.…”

Impact of Type I Interferons on Susceptibility to Bacterial Pathogens

“…A reduction in cell death improved the outcome in Ifnar -/mice infected with Salmonella enterica serovar Typhimurium [70,71], and recent work showed that the absence of STAT2-dependent type I IFN signaling led to decreased reactive oxygen species (ROS) production by neutrophils and disruption of hypoxia in the intestinal epithelium, causing inhibition of respiration in S. Typhimurium and impaired luminal expansion [72], suggesting that type I IFN signaling is beneficial for the bacterium, in this context. However, a unique study recently examined the influence of pregnancy on the outcome of infection with L. monocytogenes and S. Typhimurium in the presence and absence of type I IFN.…”

“…While pregnancy did not influence the detrimental outcome conferred by type I IFNs in L. monocytogenes infection, the protection afforded in Ifnar -/mice to S. Typhimurium infection was lost in pregnant mice. The compromised outcome to Salmonella infection in pregnant mice was attributed to decreased production of several cytokines, including IFN-γ, TNF, MCP-1, and IL-12 [70].…”

Emerging Roles of Autophagy and Inflammasome in Ehrlichiosis

“…Similarly, IFN-I are induced in mice infected with Gram-positive bacteria, such as Group B streptococcus and Listeria monocytogenes . In these cases, IFN-I are protective as evidenced by a higher susceptibility to infection in IFNAR −/− mice compared to WT (119–122). On the other hand, IFN-I play a deleterious role during infection with other pathogens by promoting dysregulated inflammation and host cell death.…”