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Microbiome Impact on the Susceptibility and Severity to Cryptosporidium Infection

微生物组对隐孢子虫感染的易感性和严重程度的影响

基本信息

批准号：
10338198
负责人：
JAN R MEAD
金额：
$ 19.56万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-02 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10338198
关键词：
Adult Affect Amino Acids Antibiotics Bacteria C57BL/6 Mouse Cell secretion Cells Child Childhood Chronic Cryptosporidiosis Cryptosporidium Cryptosporidium parvum Data Developing Countries Diarrhea Disease Disease susceptibility Environment Epithelial Cells Exploratory/Developmental Grant FDA approved Germ-Free Goals Growth Gut Mucosa HIV Host resistance Human Immune response Immunocompetent Immunocompromised Host Individual Infection Interferons Intervention Intestines Lead Life Link Lipids Malnutrition Measures Metabolic Mission Mus Nature Organism Parasites Parasitic infection Pattern Pharmaceutical Preparations Phenotype Play Predisposition Preventive Probiotics Research Resistance Resistance profile Resistance to infection Role Rotavirus Severities Severity of illness Small Intestines Structure T cell response T-Cell Activation T-Lymphocyte Testing Therapeutic Transplant Recipients Transplantation United States National Institutes of Health Vaccines Volatile Fatty Acids Vulnerable Populations bacterial community bacterial resistance base cell growth colonization resistance cytokine diarrheal disease drug repurposing fecal transplantation gut microbiome gut microbiota immunological status infection risk metabolic profile microbiome microbiome alteration microbiota microbiota profiles mouse model novel pathogen response treatment strategy

项目摘要

Cryptosporidium spp. are opportunistic protozoan parasites that infect epithelial cells of the small intestine, causing diarrheal illness in humans. In immunodeficient individuals, the disease can be severe, chronic and even fatal. In both adults and children, the disease can range from asymptomatic to severe. These differences in susceptibility and disease severity are known to be due in part to immunological status of the host, malnutrition, or prior exposure. But one important factor that has had limited study, is the role microbiota plays in host resistance. While differences in microbiota have been linked to susceptibility, it is not clear which bacterial microbiota profiles are important in resistance and which might pre-dispose individuals to infections or to more severe disease. It is also not understood how altered microbiota changes the metabolic profile in the intestinal tract and how this impacts the immune response of the host. Our long-term goal is to understand the underlying gut environment and how that may be related to susceptibility and severity of infection. Our objective is to determine how differences in microbiota affect resistance and susceptibility to infections and to determine if overall patterns or profiles can be identified. Additionally, we plan to determine if there is an association between changes in bacterial metabolites and infection levels. The central hypothesis in this proposal is that differences in the microbiota alter susceptibility and host immune response to C. parvum infection which allow for greater expansion of the organism. We will test this hypothesis by treating mice with different antibiotics and a repurposed drug known to alter the intestinal flora and examine how these changes affect susceptibility, infection level, and host immune responses, particularly activation of T cells and cytokine response in the local environment. The rationale for this hypothesis is based on the our preliminary data that show that there are significant changes in the microbiome of mice treated with certain antibiotics compared to vehicle control mice, which results in increased susceptibility. Additionally, metabolic analyses will be performed to determine changes in short chain fatty acid levels, amino acids and lipids. We will correlate difference in metabolites to susceptibility and growth. These changes may subsequently alter the immune response and microbiota-associated metabolites that result in modulation of local T cells and secretion of key cytokines, such as IFN-. These findings would be significant because it would help advance the understanding of mechanisms underlying the expansion of cryptosporidiosis during conditions of increased vulnerability. In addition, by identifying microbiota profiles in individuals that are at greater risk of infection (e.g immunodeficient individuals, transplant recipients, and young children), interventions could be administered to bolster or alter the microbiota to a more resistant profile.

隐孢子虫属类是机会性原生动物寄生虫，感染小的上皮细胞，肠道，导致人类的腹泻疾病。在免疫缺陷个体中，疾病可能是严重的，慢性的甚至致命的在成人和儿童中，这种疾病可以从无症状到严重。这些在易感性和疾病严重程度上的差异被认为部分是由于免疫学上的原因。宿主的状况、营养不良或先前的暴露。但有一个重要因素的研究有限，微生物群在宿主抗性中的作用。虽然微生物群的差异与尽管细菌对细菌的敏感性很高，但尚不清楚哪些细菌微生物群谱在耐药性中是重要的，哪些可能使个体易于感染或更严重的疾病。也不知道是如何改变的微生物群改变肠道中的代谢特征，以及这如何影响免疫反应的主机。我们的长期目标是了解潜在的肠道环境，以及它是如何发生的。与感染的易感性和严重程度有关。我们的目标是确定微生物群影响对感染的抵抗力和易感性，并确定总体模式或概况可以被识别。此外，我们计划确定是否有一个变化之间的关联，细菌代谢物和感染水平。这一建议的核心假设是，微生物群改变了宿主对C.细小病毒感染，更大程度的扩张机体。我们将通过用不同的抗生素治疗小鼠来验证这一假设以及一种改变肠道植物群的药物，并研究这些变化如何影响易感性、感染水平和宿主免疫应答，特别是T细胞和细胞因子活化当地环境的反应。这一假设的基本原理是基于我们的初步数据这些研究表明，接受某些抗生素治疗的小鼠的微生物组发生了显著变化，与载体对照小鼠相比，这导致易感性增加。此外，代谢将进行分析以确定短链脂肪酸水平、氨基酸和脂质的变化。我们将把代谢物的差异与易感性和生长联系起来。这些变化可能随后改变免疫反应和微生物群相关代谢物，导致局部T细胞的调节细胞和分泌关键细胞因子，如IFN-γ。这些发现将是重要的，因为它将有助于促进对隐孢子虫病在人类生殖系统中扩散的机制的理解，脆弱性增加的条件。此外，通过识别个体中的微生物群概况，感染风险更高（例如免疫缺陷个体、移植受者和幼儿），可以进行干预，以支持或改变微生物群，使其更具抗性。