FXIIIA production by mast cells for innate immunity

肥大细胞产生 FXIIIA 以实现先天免疫

• 批准号: 10596086
• 负责人: Adrian M Piliponsky
• 金额: $ 75.55万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-24 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10596086
• 关键词: Adult; Androgenization; Androgens; Anti-Bacterial Agents; Bacterial Infections; Binding Proteins; Blood Coagulation Factor; Bone Marrow; Cell physiology; Cells; Coagulation Process; Complement; Complex; Data; Development; Disease; Elderly; Exhibits; Exposure to; Factor XIIIa; Female; Fetal Death; Fibrin; Fibronectins; Foundations; Future; Glutaminase; Goals; Gonadal Steroid Hormones; Gram-Positive Bacteria; Host Defense; Human; Immobilization; Immune; Immunocompromised Host; In Vitro; Infection; Mediating; Mediator; Membrane Proteins; Modeling; Morbidity - disease rate; Mus; Natural Immunity; Perinatal; Play; Predisposition; Pregnancy; Premature Birth; Prevention; Process; Production; Proto-Oncogene Protein c-kit; Reporting; Role; Stimulus; Streptococcal Infections; Streptococcus CAMP protein; Streptococcus Group B; Systemic infection; Testing; Therapeutic; Umbilical Cord Blood; adverse birth outcomes; adverse outcome; adverse pregnancy outcome; crosslink; diabetic; granule cell; immune system function; in utero; in vivo; inhibitor; innate immune mechanisms; male; mast cell; neonatal infection; neonate; novel; pathogen; pregnant; prenatal; prevent; progenitor; release factor; response; sexual dimorphism; stillbirth; trafficking

PROJECT SUMMARY/ABSTRACT Mast cell response to stimuli was recently described to be sexually dimorphic with female mast cells exhibiting increased ability to produce and release mediators upon activation. This suggests that female mast cells may have evolutionary advantages and an important role in innate immunity. Our studies indicate that mast cells contribute to host defense against systemic Group B Streptococcus (GBS) infection. The finding of sexual dimorphism of mast cell function is particularly relevant as GBS is associated with pregnancy associated infections apart from its ability to infect nonpregnant adults. The overall goal of this proposal is to test the hypothesis that female mast cells are more efficient than male mast cells in supporting innate immune defense against GBS infections. Our preliminary data indicate that female mast cells produce abundant amounts of coagulation factor XIIIA (FXIIIA) and that FXIIIA deficiency exacerbates GBS systemic infections. Based on these observations, we hypothesize that mast cell-derived FXIIIA plays crucial roles in defense against GBS infections. We will use pregnant and non-pregnant models of GBS infection to test our hypothesis. In Aim 1, we will assess the contribution of FXIIIA and mast cell-derived FXIIIA in preventing GBS dissemination and adverse birth outcomes such as preterm birth. In Aim 2, we will elucidate the mechanisms by which interaction between FXIIIA and GBS surface proteins limit bacterial dissemination and adverse outcomes. In Aim 3, we will determine the underlying mechanisms that contribute to the sexual dimorphism of mast cells, release of FXIIIA and the consequent susceptibility to GBS infections. Together, these studies have the potential to provide novel mechanistic understanding into how mast cells contribute to defense against GBS infection and promotes successful pregnancies. Finally, these studies will lay the groundwork for future projects aimed at exploring the therapeutic potential of mast cell-derived FXIIIA and evaluating sexual dimorphism of other immune cells.

项目摘要/摘要 肥大细胞对刺激的反应最近被描述为性二型性，女性肥大细胞表现出 增强了激活时产生和释放介体的能力。这表明女性肥大细胞可能 在先天免疫中具有进化优势和重要作用。我们的研究表明，肥大细胞 有助于宿主防御系统性B组链球菌(GBS)感染。性爱的发现 肥大细胞功能的二型性尤其相关，因为GBS与妊娠相关 除了感染未怀孕的成年人的能力外，它还能感染。这项提案的总体目标是测试 女性肥大细胞在支持天然免疫防御方面比男性肥大细胞更有效的假设 预防GBS感染。 我们的初步数据表明女性肥大细胞产生大量凝血因子XIIIA (FXIIIA)，FXIIIA缺乏会加剧GBS系统感染。基于这些观察，我们 假设肥大细胞来源的FXIIIA在抵御GBS感染方面发挥关键作用。我们将使用 孕妇和非孕妇的GBS感染模型来验证我们的假设。 在目标1中，我们将评估FXIIIA和肥大细胞来源的FXIIIA在预防GBS方面的贡献 传播和不良分娩后果，如早产。在目标2中，我们将阐明这些机制。 FXIIIA和GBS表面蛋白之间的相互作用通过什么限制细菌的传播和不利的 结果。在目标3中，我们将确定导致性二型性的潜在机制。 肥大细胞、FXIIIA的释放以及随后对GBS感染的易感性。 总之，这些研究有可能为肥大细胞是如何 有助于防御GBS感染并促进成功怀孕。最后，这些研究将 为未来旨在探索肥大细胞来源的FXIIIA治疗潜力的项目奠定基础 以及评估其他免疫细胞的性别二型性。