FXIIIA production by mast cells for innate immunity

项目总结/摘要 肥大细胞对刺激的反应最近被描述为具有性二态性，雌性肥大细胞表现为 在激活时产生和释放介质的能力增加。这表明女性肥大细胞可能 具有进化优势并在先天免疫中发挥重要作用。我们的研究表明肥大细胞 有助于宿主防御系统性B族链球菌（GBS）感染。性的发现 肥大细胞功能的二型性特别相关，因为GBS与妊娠相关 除了感染未怀孕的成年人的能力外。本提案的总体目标是测试 女性肥大细胞在支持先天免疫防御方面比男性肥大细胞更有效假说 对抗GBS感染 我们的初步数据表明，女性肥大细胞产生大量的凝血因子XIIIA （FXIIIA），并且FXIIIA缺乏加剧GBS全身性感染。根据这些观察，我们 假设肥大细胞衍生FXIIIA在抵抗GBS感染中起关键作用。我们将使用 妊娠和非妊娠的GBS感染模型来检验我们的假设。 在目标1中，我们将评估FXIIIA和肥大细胞衍生的FXIIIA在预防GBS中的作用。 传播和不良出生结果，如早产。在目标2中，我们将阐明 FXIIIA和GBS表面蛋白之间的相互作用限制了细菌的传播和不利影响， 结果。在目标3中，我们将确定导致性二型的潜在机制， 肥大细胞、FXIIIA的释放以及随之而来的对GBS感染的易感性。 总之，这些研究有可能提供新的机制了解肥大细胞如何 有助于防御GBS感染，促进成功怀孕。最后，这些研究将 为未来探索肥大细胞衍生FXIIIA治疗潜力的项目奠定基础 以及评估其他免疫细胞的性二型性。

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.