Project Details
Description
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.
Status | Active |
---|---|
Effective start/end date | 9/14/23 → 8/31/24 |
Funding
- Eunice Kennedy Shriver National Institute of Child Health and Human Development: $299,925.00
Fingerprint
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.