Microbial-induced maternal factors that influence fetal immune development

ABSTRACT The immunology of pregnancy is complex and delicately balanced. While failure to tolerate fetal antigens during pregnancy can result in fetal loss, ineffective immunity to pathogens can threaten the survival of both the fetus and the mother. Fetal tissues and the maternal immune system continuously communicate to maintain this balance. This proposal focuses on two understudied mechanisms of maternal-fetal communication: extracellular vesicles (EVs) – lipid-bound particles carrying immunomodulatory proteins and miRNAs secreted by cells, and maternal microchimeric cells (MMc) – the vertical transfer of maternal immune cells to fetal organs. Specifically, we aim understand how these processes are influenced by normal microbial experience to better understand their function during normal pregnancies. Much of what we know about EVs and MMc during pregnancy has been discovered using conventional specific pathogen free (SPF) mouse models, which have limited microbial diversity and are nearly devoid of pathogens. These artificially hygienic conditions are in stark contrast to nature, where microbes are ubiquitous and diverse. Indeed, we and others have demonstrated that the immune systems of mice raised under SPF conditions are underdeveloped relative to humans and feral/pet store mice. We posit that the character and function of EVs and MMc in SPF pregnancies are impaired by the lack of diverse microbial experience, thus reducing the predictive power of SPF studies. Our lab has developed a preconception normal microbial experience (pNME) model whereby laboratory mice are cohoused with pet store mice prior to breeding to naturally expose them to the diverse microbial communities. Cohousing continues throughout gestation and early life, ensuring the offspring receive ‘mature’ maternal factors and encounter diverse microbes from the earliest natural time to replicate normal mammalian immune development more accurately. Using this model, we have found that the immune systems of pNME mice are broadly expanded and achieve immune developmental milestones earlier than SPF mice. pNME mice also demonstrate enhanced survival and immune defense relative to SPF mice. The gap in immunity between conventional SPF models and natural immune development has contributed to the slow progress toward mechanistic understanding of maternal-fetal immune communication and fetal immune development. The proposed research describes a natural model of immune development (pNME) that combines the ample resources and tools of laboratory mouse strains with physiological microbial experience to gain a deeper understanding of the mechanisms of normal maternal-fetal immune communication and their influence on fetal immune development. Further, these experiments will lay the groundwork for improved preclinical models investigating biomarkers, treatments, and preventions for immune pathologies during pregnancy and early life.