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.

摘要 怀孕的免疫学是复杂和微妙的平衡。虽然不能耐受胎儿抗原 怀孕期间可能会导致胎儿丧失，对病原体的无效免疫可能会威胁到两者的生存 胎儿和母亲。胎儿组织和母体免疫系统不断地与 保持这种平衡。这一建议侧重于两种未被充分研究的母婴机制。 通讯：细胞外小泡(EVS)--携带免疫调节蛋白的脂质结合颗粒和 由细胞分泌的miRNAs和母体微嵌合体细胞(MMC)-母体免疫的垂直转移 从细胞到胎儿器官。具体地说，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，以更好地了解它们在正常怀孕期间的功能。我们对电动汽车的了解很多 使用常规的无特定病原体(SPF)小鼠发现了怀孕期间的MMC 微生物多样性有限，几乎没有病原体。这些人工卫生的 条件与自然界形成鲜明对比，在自然界，微生物无处不在，种类繁多。事实上，我们和其他人 已经证明在SPF条件下饲养的小鼠的免疫系统相对不发达 人类和野生/宠物商店的老鼠。我们推测EVS和MMC在SPF中的性质和功能 由于缺乏多样化的微生物体验，怀孕受到损害，因此降低了预测能力 SPF研究。我们的实验室开发了一个预想正常微生物体验(PNME)模型，在这个模型中 在繁殖之前，实验室小鼠与宠物商店的小鼠被关在一起，以自然地将它们暴露在不同的 微生物群落。同居在整个怀孕和早期生活中持续进行，确保后代获得 “成熟”的母体因素和遇到的各种微生物从最早的自然时间到复制正常 哺乳动物的免疫发育更准确。使用这个模型，我们发现免疫系统 PNME小鼠的数量得到了广泛的扩大，并且比SPF小鼠更早达到免疫发育里程碑。 与SPF小鼠相比，pNME小鼠的存活率和免疫防御能力也有所增强。中国的差距 传统SPF模型和自然免疫发展之间的免疫导致了缓慢的 母胎免疫沟通与胎儿免疫机制研究进展 发展。这项拟议的研究描述了一种免疫发育的自然模型(PNME)， 将实验室小鼠品种的丰富资源和工具与生理微生物经验相结合， 加深对正常母胎免疫沟通机制及其机制的认识 对胎儿免疫发育的影响。此外，这些实验将为改进奠定基础 临床前模型研究免疫病理的生物标记物、治疗和预防 怀孕和早期生活。