The innate immune response is an ancient, non antigen-specific defense system made up countermeasures that restrict the replication of pathogens early in infection. A successful innate response promotes the secretion of cytokines, particularly interferons (IFNs), that shape the later pathogen-specific acquired immune response. Substantial progress has been made in our understanding of the processes that lead to the production of type I interferons (=IFN?/?) via IRFs, and the biological responses elicited by them via STAT proteins. Although IFN?/?, IRFs, and STATs have been extensively studied in the context of pathogen responses in adult organisms, their role in infectious processes during gestation has remained largely unexplored. For instance, even though interferons were discovered decades ago, it is still not clear whether they cross the so-called blood-placenta barrier, or at what point a developing fetus is capable of responding to a pathogen encounter with its own production of interferons. Similarly, it is unclear if interferons contribute to pathogen-associated birth defects. Indeed, many perinatally transmitted pathogens (e.g. hCMV, Rubella, LCMV, more recently Zika virus) are known to give rise to congenital birth defects, however, it is unclear whether the pathogen per se, or the resulting immune response is responsible for developmental deficiencies. A novel reporter mouse strain we conceived allows for the visualization of IFN?/? encounters and provides a time-integrated picture of interferon responses. Additional reporter knock-in strains in the IFN? or IFN? locus permit the monitoring of interferon production. We intend to utilize these mice in the context of crosses to animals lacking components of the interferon system to study the induction, transmission and the effects of interferons at various stages of gestation. PolyI:C, which mimics dsRNA and thus viral infection, is a potent inducer of IFN?/?.
In aim 1 we will investigate whether the IFN?/? eliciting responses in the fetus after injection of the maternal animal with PolyI:C is derived from the fetus itself, or has been transmitted through the placenta from the maternal side. Conversely, we will test whether IFN?/? might be passed from the fetus into the bloodstream of the maternal animal. Lymphocytic choriomeningitis virus (LCMV) is frequently used in labs to study persistent infections by more dangerous related viruses (HIV, HCV, HBV, and now Zika virus), and causes severe birth defects similar to Zika virus. In mice, LCMV rapidly spreads systemically, is transmitted perinatally and strongly induces type I interferon production. IFN?/?-receptor (IFNAR)-deficient mice are unable to clear LCMV and develop a persistent viral infection. Thus, in aim 2 we propose to use our reporter mouse strain, and crosses designed such that either only the maternal animal, or only the fetuses are IRF and/or IFN?/?-receptor deficient, to monitor type I interferon production, responses and viral loads during infection. We expect the proposed studies will significantly extend our understanding of the contributions of IRFs and type I interferons to the unique immunological environment that exists during the gestation period.
Even though interferons were discovered over 50 years ago, very little is known about their physiological role during gestation. For instance, it is not even clear at this point whether IFN?/? cross the placenta barrier, or if interferons contribute to pathogen-associated congenital birth defects. Indeed, many pathogens (e.g. HCMV, Rubella, HIV, Zika) are known to give rise to congenital birth defects, however, it is unclear whether the pathogen per se, or the resulting immune response is responsible for the damage (similar to fatalities resulting from influenza infection, or septic shock syndrome, where overwhelming immune responses are the actual cause of death). Thus, new insights into mechanistic elements of the type I interferon system during gestation ? ranging from their production via IRFs through their biological responses ? are necessary to gain a better understanding of the impact of this clinically widely used cytokine on developmental processes both during infectious processes or clinical uses.
