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Malaria and allergic inflammatory changes to the gut barrier

疟疾和过敏性炎症对肠道屏障的改变

基本信息

批准号：
10170213
负责人：
Shirley Luckhart
金额：
$ 46.03万
依托单位：
UNIVERSITY OF IDAHO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10170213
关键词：
Acute Address Adult Africa South of the Sahara African Allergic Allergic inflammation Antibiotic Resistance Antibiotics Antimalarials Area Bacteremia Bacteria Basophilia Basophils Biology Blood Blood Proteins Blood capillaries Case Fatality Rates Cells Child Chronic Chymase Clinical Country Data Defect Endothelium Enterobacteriaceae Epithelial Failure Falciparum Malaria Functional disorder Future Histamine Hospitalization Human IL3 Gene IgE Immune Immune response Immunity Immunoglobulin Class Switching Immunologics Incidence Infection Inflammatory Interleukin-10 Interleukin-13 Interleukin-15 Interleukin-18 Interleukin-4 Intervention Intestinal permeability Intestines Kenya Lead Leaky Gut Link Literature Malabsorption Syndromes Malaria Modeling Mucous Membrane Mus Outcome Parasitemia Parasites Peptide Hydrolases Permeability Phenotype Plasmodium yoelii Prevalence Publishing Reporting Research Resources Risk Sepsis Severities Signal Transduction TPT1 gene Testing Tissues Work World Health Organization base cell injury comorbidity cytokine expectation gastrointestinal gut bacteria insight intestinal barrier malaria infection mast cell mastocytosis microbial mortality novel recruit transmission process

项目摘要

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.

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。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Anopheles stephensi Feeding, Flight Behavior, and Infection With Malaria Parasites are Altered by Ingestion of Serotonin.

DOI：
10.3389/fphys.2022.911097
发表时间：
2022
期刊：
Frontiers in physiology
影响因子：
4
作者：
通讯作者：

Ingested histamine and serotonin interact to alter Anopheles stephensi feeding and flight behavior and infection with Plasmodium parasites.

DOI：
10.3389/fphys.2023.1247316
发表时间：
2023
期刊：
FRONTIERS IN PHYSIOLOGY
影响因子：
4
作者：
Coles, Taylor A. A.;Briggs, Anna M. M.;Hambly, Malayna G. G.;Cespedes, Nora;Fellows, Abigail M. M.;Kaylor, Hannah L. L.;Adams, Alexandria D. D.;Van Susteren, Grace;Bentil, Ronald E. E.;Robert, Michael A. A.;Riffell, Jeffrey A. A.;Lewis, Edwin E. E.;Luckhart, Shirley
通讯作者：
Luckhart, Shirley

A new mouse SNP genotyping assay for speed congenics: combining flexibility, affordability, and power.

DOI：
10.1186/s12864-021-07698-9
发表时间：
2021-05-24
期刊：
BMC genomics
影响因子：
4.4
作者：
Andrews KR;Hunter SS;Torrevillas BK;Céspedes N;Garrison SM;Strickland J;Wagers D;Hansten G;New DD;Fagnan MW;Luckhart S
通讯作者：
Luckhart S

Histamine Ingestion by Anopheles stephensi Alters Important Vector Transmission Behaviors and Infection Success with Diverse Plasmodium Species.

DOI：
10.3390/biom11050719
发表时间：
2021-05-11
期刊：
Biomolecules
影响因子：
5.5
作者：
Rodriguez AM;Hambly MG;Jandu S;Simão-Gurge R;Lowder C;Lewis EE;Riffell JA;Luckhart S
通讯作者：
Luckhart S

Nonlethal Plasmodium yoelii Infection Drives Complex Patterns of Th2-Type Host Immunity and Mast Cell-Dependent Bacteremia.