Nutritional immunity during Salmonella infection

摘要 非伤寒沙门氏菌(NTS)引起严重的炎症性腹泻和感染 据估计，每年有1亿名患者，其中140万在美国。 尽管肠粘膜的早期炎症反应对控制 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 已表明肠道炎症的因素被NTS利用来在 肠道发炎并传染给幼稚的宿主。多种机制--其中许多是 仍然未知--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，这一过程被称为“营养免疫”，是宿主的一只手臂。 被NTS利用来在发炎的肠道中茁壮成长并与 肠道微生物区系。本申请的主要目标是继续阐明 NTS在发炎的肠粘膜中生长的机制，逃避宿主的 营养免疫反应，并与常驻微生物群争夺金属 营养素。我们的中心假设是NTS利用营养免疫力在竞争中取胜 必需金属微量营养素铁、锌和锰的微生物区系。这个 肠道发炎是一种恶劣的环境，在这种环境中，金属离子缺乏会增强 像NTS这样的病原体的增殖，可以有效地获得金属离子。我们推论 了解NTS如何利用营养免疫来获取自身优势将导致 新的方法来限制NTS在发炎的肠道中的复制并阻止其 传输到其他主机。拟议的工作具有创新性，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。这是我们的期望 这项研究的结果将确定NTS和可能的其他 病原体或致病细菌，利用营养免疫在发炎的肠道中茁壮成长， 可能导致新的治疗方法和疫苗，以靶向金属离子的获取 病原体。

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.