Nutritional immunity during Salmonella infection

沙门氏菌感染期间的营养免疫

• 批准号: 9921201
• 负责人: Manuela Raffatellu
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-15 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9921201
• 关键词: Bacteria; Diarrhea; Elements; Environment; Escherichia coli; Goals; Immune response; Infection; Infection prevention; Inflammatory; Inflammatory Response; Intestinal Mucosa; Ions; Iron; Manganese; Metals; Micronutrients; Mucous Membrane; Nutrient; Nutritional; Nutritional Immunity; Outcome Study; Oxidative Stress; Patients; Play; Probiotics; Process; Role; Salmonella; Salmonella infections; Source; Testing; United States; Work; Zinc; arm; base; deprivation; design; expectation; fungal microbiota; fungus; gut colonization; gut microbiota; inflammatory disease of the intestine; innovation; microbiota; non-typhoidal Salmonella; novel; novel strategies; novel therapeutics; novel vaccines; pathobiont; pathogen; transmission process

SUMMARY Non-typhoidal Salmonella (NTS) cause a severe inflammatory diarrhea and infect an estimated 100 million patients per year, of which 1.4 million are in the United States. Although the early inflammatory response in the intestinal mucosa is critical to control NTS infection and confine it to the gut, recent studies conducted by our group and others have shown that elements of intestinal inflammation are exploited by NTS to thrive in the inflamed gut and to transmit to naïve hosts. Multiple mechanisms - many of which are still unknown - play a role in this process. In this regard, we found that sequestration of essential metal ions, a process known as “nutritional immunity”, is an arm of the host response that is exploited by NTS to thrive in the inflamed gut and to compete with the intestinal microbiota. The primary objective of this application is to continue to elucidate the mechanisms by which NTS thrive in the inflamed intestinal mucosa, evade the host's nutritional immune response, and compete with the resident microbiota for metal nutrients. Our central hypothesis is that NTS exploits nutritional immunity to outcompete the microbiota for the essential metal micronutrients iron, zinc, and manganese. The inflamed gut is a hostile environment where metal ion deprivation enhances the proliferation of pathogens like NTS that can efficiently acquire metal ions. We reason that understanding how NTS exploits nutritional immunity to its own advantage will lead to new approaches to limit the replication of NTS in the inflamed gut and to impede its transmission to other hosts. The proposed work is innovative because it establishes new concepts on how a pathogen can exploit host mucosal defenses. It is our expectation that the outcome of this study will identify mechanisms by which NTS, and likely other pathogens or pathobionts, exploits nutritional immunity to thrive in the inflamed gut, potentially leading to new therapies and vaccines to target metal ion acquisition by the pathogen.

总结 非伤寒沙门氏菌（NTS）引起严重的炎症性腹泻， 每年估计有1亿患者，其中140万在美国。 虽然肠粘膜的早期炎症反应对于控制 NTS感染并将其限制在肠道内，我们小组和其他人最近进行的研究 已经表明，肠道炎症的元素被NTS利用，在肠道中茁壮成长。 感染肠道并传播给幼稚宿主。多种机制-其中许多是 在这一过程中发挥作用。在这方面，我们发现， 必需的金属离子，一个被称为“营养免疫”的过程，是宿主的一个手臂 NTS利用这种反应在发炎的肠道中茁壮成长，并与 肠道微生物群本申请的主要目的是继续阐明 NTS在发炎的肠粘膜中茁壮成长的机制，逃避宿主的 营养免疫反应，并与当地的微生物群竞争金属 营养素我们的中心假设是，NTS利用营养免疫胜过 微生物群的必需金属微量营养素铁，锌和锰。的 发炎的肠道是一个不利的环境，其中金属离子剥夺增强了 病原体如NTS的增殖，可以有效地获取金属离子。我们推理 了解NTS如何利用营养免疫来发挥自己的优势， 新的方法来限制NTS在发炎的肠道中的复制，并阻止其在肠道中的复制。 传输到其他主机。拟议的工作是创新的，因为它建立了新的 关于病原体如何利用宿主粘膜防御的概念。我们期望 这项研究的结果将确定NTS和其他可能的机制， 病原体或致病菌，利用营养免疫在发炎的肠道中茁壮成长， 潜在地导致新的疗法和疫苗以靶向由金属离子捕获。 病原体