Innate Immunity to Salmonella Infections

对沙门氏菌感染的先天免疫

• 批准号: 6603098
• 负责人: Joshua Fierer
• 金额: $ 28万
• 依托单位: VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6603098
• 关键词: Salmonella; Salmonella infections; bactericidal immunity; binding proteins; chemokine; host organism interaction; laboratory mouse; lipopolysaccharides; monoclonal antibody; neutropenia; phagocytosis

DESCRIPTION (provided by the applicant): Salmonella are one of the most important causes of gastrointestinal infections. The overall goal of our research is to understand how the innate immune response helps to protect against salmonella infections. The first aspect of innate immunity that we will study is PMNs. We previously reported that human epithelial cells make the potent chemotactic peptide IL-8 when invaded by salmonella, which implies that PMNs are important for the host defense against this pathogen. We then showed that PMNs are crucial for defense against salmonella that have virulence plasmids, but not those without virulence plasmids. This proposal focuses on the role of PMNs in protecting the intestine from salmonella infections, using a model of oral infection in mice. The role of PMNs will be established by making mice neutropenic with a monoclonal antibody (RB6-8C5) to the Ly-6G antigen that is specific for myelocytes. We will look for evidence that one or both chemokines are made in vivo in infected mice and in vitro using both cultured murine intestinal epithelial cells and colon organ culture. The second component of the innate immune response that we will investigate is lipopolysaccharide binding protein (LBP). We have confirmed the report by Jack et al (Nature, 389,742,1997) that LBP-deficient mice are more susceptible to salmonella infections, but the mechanism of action of LBP has not been elucidated in infection. We used mice that had the wild-type Nramp1 allele so are genetically resistant to salmonella infections. LBP deficient mice had lower levels of 2 ELR+ CXC chemokines. We will now study the role of CXC chemokines in host resistance to Salmonella by blocking the CXC receptor with antibody. The third goal is to determine whether complement mediated phagocytosis is critical for early resistance to salmonella infections. We will study the course of infection in mice that are deficient in C3 and determine whether neutropenia makes them more susceptible to infection. We will compare isogenic strains of salmonella that express either the group B or 0 LPS antigens in C3 deficient and neutropenic mice, in order to determine how the structure of the LPS affects virulence in mice.

描述（由申请人提供）：沙门氏菌是最常见的细菌之一。 胃肠道感染的重要原因。我们的总体目标 研究的目的是了解先天免疫反应如何帮助保护 对抗沙门氏菌感染。我们将先天免疫的第一个方面 研究对象是PMN。我们之前报道过人类上皮细胞使 当沙门氏菌入侵时，会产生有效的趋化肽 IL-8，这意味着 PMN 对于宿主防御这种病原体很重要。然后我们展示了 PMN 对于防御具有毒力的沙门氏菌至关重要 质粒，但不是那些没有毒力的质粒。该提案的重点是 PMNs 在保护肠道免受沙门氏菌感染方面的作用，使用 小鼠口腔感染模型。 PMN 的作用将由 使用 Ly-6G 的单克隆抗体 (RB6-8C5) 使小鼠出现中性粒细胞减少症 骨髓细胞特异性抗原。我们将寻找证据表明一个或 这两种趋化因子都是在受感染的小鼠体内产生的，并在体外使用这两种趋化因子产生的 培养小鼠肠上皮细胞和结肠器官培养。第二个 我们将研究的先天免疫反应的组成部分是 脂多糖结合蛋白（LBP）。我们已经确认了杰克的报道 等人 (Nature, 389,742,1997) 指出，LBP 缺陷的小鼠更容易受到 沙门氏菌感染，但 LBP 的作用机制尚未明确 在感染中得到阐明。我们使用具有野生型 Nramp1 等位基因的小鼠，因此 对沙门氏菌感染具有遗传抵抗力。 LBP 缺陷小鼠 2 个 ELR+ CXC 趋化因子水平较低。我们现在来研究CXC的作用 通过阻断 CXC 受体，趋化因子在宿主对沙门氏菌的抵抗中发挥作用 抗体。第三个目标是确定补体是否介导 吞噬作用对于早期抵抗沙门氏菌感染至关重要。我们将 研究缺乏 C3 的小鼠的感染过程并确定 中性粒细胞减少症是否使他们更容易受到感染。我们会比较 表达 B 组或 0 LPS 的沙门氏菌等基因菌株 C3 缺陷和中性粒细胞减少小鼠中的抗原，以确定如何 LPS 的结构影响小鼠的毒力。