Malaria and allergic inflammatory changes to the gut barrier

项目总结/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 并且在一些疟疾流行地区的成年人中也很普遍。菌血症儿童和成人很难识别 许多人血液中感染了对多种抗生素具有抗药性的分离株。高发生率 菌血症表明疟疾会导致“肠漏”，这是一种肠道屏障功能障碍， 细菌从肠腔进入血液，导致严重的后遗症。最近的研究 记录了疟疾中的过敏性炎症，但迄今为止还没有研究将这种现象与疟疾的增加联系起来。 在急性和缓解中的临床疟疾中都观察到肠渗透性。我们已公布的和初步的 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活化， 导致肥大细胞流入肠道。在这里，激活的肥大细胞破坏物理屏障， 宿主免疫反应，限制肠道细菌穿过受损的物理屏障的传播。在这些 研究中，我们将使用我们建立的模型来检查早期先天信号和嗜碱性粒细胞的贡献 - 在疟疾中没有功能的细胞-促进肥大细胞增多症和肠漏 我们观察到的表型。我们还将确定在何种程度上疟疾诱导的肥大细胞降解， 肠的物理和免疫屏障依赖于肥大细胞蛋白酶和肥大细胞- 与我们的观察结果相关的衍生细胞因子。我们期望我们的工作将阐明新的 疟疾中过敏性炎症对粘膜屏障降解的重要性的潜在机制。的 拟议研究的结果可能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，因为它直接涉及一个重要的 疟疾的并发症，并将提供新的机制的见解， 不相关-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.