Malaria and allergic inflammatory changes to the gut barrier

项目摘要/摘要 与疟疾相关的菌血症是撒哈拉以南非洲儿童死亡的一个重要原因 在一些疟疾地区的成年人中也很流行。细菌性儿童和成人很难辨别 许多人血液感染了多重抗药性的菌株。……的高发生率 菌血症表明疟疾会导致“肠道渗漏”，这是一种促进逃逸的肠道屏障功能障碍。 细菌从肠腔进入血液，造成严重后遗症。最近的研究表明 记录了疟疾中的过敏性炎症，但到目前为止还没有研究表明这种现象与增加 在急性和缓解临床疟疾中观察到肠道通透性。我们已出版的和初步的 研究表明，疟疾诱导的先天信号，包括早期细胞因子合成和嗜碱性粒细胞激活， 导致肥大细胞进入肠道。在这里，激活的肥大细胞破坏物理屏障并抑制 宿主免疫反应，限制穿过受损物理屏障的肠道细菌的传播。在这些 研究中，我们将使用我们已建立的模型来检验早期先天信号和嗜碱性粒细胞的贡献 -尚未被描述在疟疾中起作用的细胞-促进肥大细胞增多症和肠漏 我们观察到的表型。我们还将确定疟疾诱导的肥大细胞降解到什么程度 肠道的物理和免疫屏障依赖于肥大细胞蛋白酶和肥大细胞- 与我们的观察相关的衍生细胞因子。我们期望我们的工作将阐明新的 疟疾中变态反应性炎症对粘膜屏障降解重要性的潜在机制。这个 拟议的研究结果可能会为未来的干预措施提供新的范例，以减少 疟疾相关菌血症的发病率。这项工作意义重大，因为它直接解决了一个重要的 疟疾的共同发病率，并将提供新的机制洞察力，以充分记录-和迄今 未链接--临床观察。

PROJECT SUMMARY/ABSTRACT Bacteremia associated with malaria is a significant cause of mortality among children in sub-Saharan Africa and is also prevalent in adults in some malarious regions. Bacteremic children and adults are difficult to identify and many have blood infections with isolates that are multi-antibiotic-resistant. The high occurrence of bacteremia suggests that malaria induces a “leaky gut,” an intestinal barrier dysfunction that facilitates escape of bacteria from the gut lumen into the blood with resulting serious sequelae. Recent studies have documented allergic inflammation in malaria, but no studies to date have linked this phenomenon to increased intestinal permeability observed in both acute and resolving clinical malaria. Our published and preliminary studies suggest that malaria-induced innate signals, including early cytokine synthesis and basophil activation, lead to mast cell influx into the intestine. Here, activated mast cells damage the physical barrier and suppress host immune responses that limit spread of enteric bacteria that cross the damaged physical barrier. In these studies, we will use our established models to examine the contributions of early innate signals and basophils – cells for which no function in malaria has been described – in promoting mastocytosis and the leaky gut phenotype we have observed. We will also determine to what extent malaria-induced mast cell degradation of the physical and immunological barriers of the intestine is dependent on mast cell proteases and mast cell- derived cytokines that are relevant to our observations. It is our expectation that our work will elucidate new mechanisms underlying the importance of allergic inflammation to mucosal barrier degradation in malaria. The outcome of the proposed research is likely to provide novel paradigms for future interventions to reduce the incidence of malaria-associated bacteremia. This work is significant because it directly addresses an important co-morbidity of malaria and will provide novel mechanistic insights into well-documented – and heretofore unlinked – clinical observations.