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

• 批准号: 10252399
• 负责人: JAN R MEAD
• 金额: $ 23.43万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 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/10252399
• 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

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。是感染小鼠上皮细胞的机会性原生动物寄生虫 肠道，导致人类腹泻疾病。在免疫缺陷个体中，这种疾病可能会很严重， 慢性的，甚至是致命的。在成人和儿童中，这种疾病的范围从无症状到严重。 这些易感性和疾病严重程度的差异被认为部分是由于免疫学上的原因。 宿主状况、营养不良或以前的接触情况。但有一个重要因素的研究有限，那就是 微生物区系在寄主抗性中的作用。虽然微生物区系的差异与 敏感性，目前还不清楚哪些细菌微生物区系在耐药性中起重要作用，哪些可能 使个人预先准备好感染或更严重的疾病。人们也不知道它是如何改变的 微生物区系改变肠道中的新陈代谢及其对免疫反应的影响 主人的名字。我们的长期目标是了解潜在的肠道环境及其可能发生的原因 与感染的易感性和严重程度有关。我们的目标是确定 微生物区系影响对感染的抵抗力和易感性，并确定总体模式或概况 可以辨认出来。此外，我们计划确定以下变化之间是否存在关联 细菌代谢物和感染水平。这一提议的中心假设是， 微生物群改变了对微小弧菌感染易感性和宿主免疫反应，从而允许 更大的有机体扩张。我们将通过用不同的抗生素治疗小鼠来检验这一假设 以及一种已知可以改变肠道菌群并检查这些变化如何影响的改变用途的药物 易感性、感染水平和宿主免疫反应，特别是T细胞和细胞因子的激活 在当地环境中做出反应。这一假设的理论基础是基于我们的初步数据 这表明，用某些抗生素处理的小鼠的微生物群发生了显著的变化 与车辆对照组小鼠相比，这导致了更高的敏感性。此外，新陈代谢 将进行分析，以确定短链脂肪酸水平、氨基酸和脂质的变化。 我们将把代谢产物的不同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区系相关代谢产物，导致局部T细胞的调节 细胞和关键细胞因子的分泌，如干扰素-。这些发现将具有重要意义，因为它将 有助于促进对隐孢子虫病扩大潜在机制的理解 脆弱性增加的条件。此外，通过识别符合以下条件的个体的微生物区系特征 感染风险更大(例如，免疫缺陷个人、移植受者和幼儿)； 可以采取干预措施来支持或改变微生物区系，使其具有更强的抗药性。