Microbial-induced maternal factors that influence fetal immune development

微生物诱导的影响胎儿免疫发育的母体因素

• 批准号: 10748437
• 负责人: Nathan Schuldt
• 金额: $ 29.99万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-14 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10748437
• 关键词: Adult; Affect; Animal Model; Biological Assay; Biological Markers; Biological Models; Biometry; Birth; Breeding; Calibration; Cell secretion; Cells; Circulation; Coculture Techniques; Communication; Complex; Conceptions; Data; Development; Disease; Ensure; Environment; Equilibrium; Exposure to; Extracellular Space; Failure; Female; Fetal Development; Fetal Tissues; Fetus; Flow Cytometry; Future; Hematopoiesis; Hematopoietic; Host Defense; Human; Immune; Immune response; Immune system; Immunity; Immunohistochemistry; Immunological Models; Immunologics; Immunology; Immunosuppression; Impairment; In Vitro; Infection; Inflammation; Knowledge; Laboratory mice; Life; Lipid Binding; Mass Spectrum Analysis; Maternal antibody; Maternal-Fetal Exchange; Maternally-Acquired Immunity; Measures; MicroRNAs; Microbe; Microchimerism; Modeling; Mothers; Mouse Strains; Mus; Nature; Newborn Infant; Organ; Output; Pathology; Perinatal; Physiological; Pre-Clinical Model; Pregnancy; Premature Birth; Prevention; Prevention strategy; Process; Proteins; Research; Resources; Risk; Shapes; Spontaneous abortion; T-Lymphocyte; Techniques; Testing; Time; Work; congenic; coping; embryo/fetus antigen; experience; experimental study; extracellular vesicles; fetal; fetal infection; fetal loss; germ free condition; immune function; immunoregulation; improved; innovation; insight; maternal immune system; microbial; microbial community; mortality; mouse model; neonatal death; novel; offspring; particle; pathogen; pregnancy immunology; pregnant; preservation; prevent; risk minimization; tool; trafficking; transcriptome sequencing; treatment strategy

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.

抽象的 怀孕的免疫学很复杂且平衡。而不耐受胎儿抗原 在怀孕期间可能导致胎儿丧失，病原体的免疫学无效可能威胁到两者的生存 胎儿和母亲。胎儿组织和母体免疫系统不断通信 保持这种平衡。该提案重点介绍了两个理解的母校机制 交流：细胞外蔬菜（EV） - 携带免疫调节蛋白和的脂质结合颗粒 由细胞分泌的miRNA和母体微chimeric细胞（MMC） - 母体免疫的垂直转移 细胞到胎儿器官。具体而言，我们的目标是了解这些过程如何受到正常微生物的影响 经验以更好地了解正常怀孕期间的功能。我们对电动汽车的了解的大部分 使用常规的特定病原体（SPF）小鼠发现了怀孕期间的MMC 模型，其微生物多样性有限，几乎没有病原体。这些人为卫生的 与自然的形成鲜明对比的是，微生物无处不在和潜水。确实，我们和其他人 已经证明，在SPF条件下提出的小鼠的免疫系统欠发达相对相对 到人类和野生/宠物商店的老鼠。我们指出SPF中电动汽车和MMC的特征和功能 缺乏潜水微生物的经验使怀孕受到损害，从而降低了预测能力 SPF研究。我们的实验室已经开发了一个均见的正常微生物体验（PNME）模型 在繁殖之前，实验室小鼠与宠物店小鼠共同容纳，以自然暴露于潜水员 微生物社区。在妊娠和早期生活中，共同体继续进行，确保后代接受 从最早的自然时间复制正常的“成熟”母校因素并遇到潜水的微生物 哺乳动物免疫发育更准确。使用此模型，我们发现免疫系统 与SPF小鼠相比，PNME小鼠的PNME小鼠大致扩展和实现了免疫发育里程碑。 PNME小鼠还表现出相对于SPF小鼠的生存和免疫防御的增强。差距 常规SPF模型与自然免疫发育之间的免疫力导致了缓慢 朝着对母性免疫传播和胎儿免疫的机械理解的进展 发展。拟议的研究描述了免疫发育（PNME）的自然模型，该模型是 将充足的实验室鼠标菌株的资源和工具与物理微生物经验相结合 对正常的母校免疫沟通的机制有更深入的了解 对胎儿免疫发育的影响。此外，这些实验将为改进的基础奠定基础 临床前模型研究了生物标志物，治疗和预防免疫病理学的预防 怀孕和早期生活。