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 胃肠道感染的重要原因。我们的总体目标是 研究的目的是了解先天免疫反应如何帮助保护 对抗沙门氏菌感染先天免疫的第一个方面 研究是PMNs。我们以前报道过，人类上皮细胞使 当被saltamine侵入时，有效的趋化肽IL-8，这意味着 PMNs对于宿主防御这种病原体是重要的。然后我们展示了 中性粒细胞对于防御具有毒性的沙门氏菌至关重要， 质粒，而不是那些没有毒力质粒。该提案的重点是 中性粒细胞在保护肠道免受沙门氏菌感染中的作用， 小鼠口腔感染模型。PMNs的作用将通过以下方式确定： 用抗Ly-6 G的单克隆抗体（RB 6 - 8 C5）使小鼠产生血小板减少症 对髓细胞特异的抗原。我们将寻找证据， 这两种趋化因子都是在感染的小鼠体内制备的， 培养的小鼠肠上皮细胞和结肠器官培养物。第二 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）。我们已经证实了杰克的报告 等（Nature，389，742，1997），LBP缺陷小鼠更易受 沙门氏菌感染，但LBP的作用机制还没有得到证实。 在感染中阐明。我们使用了具有野生型Nramp 1等位基因的小鼠， 对沙门氏菌感染有遗传抵抗力LBP缺陷小鼠 2种ELR+ CXC趋化因子水平较低。我们现在将研究CXC的作用 趋化因子通过阻断CXC受体在宿主抵抗沙门氏菌中的作用 抗体的第三个目标是确定补体介导的 吞噬作用对于沙门氏菌感染的早期抵抗是至关重要的。我们将 研究缺乏C3的小鼠的感染过程， 中性粒细胞减少症是否使他们更容易感染。我们将比较 表达B组或0 LPS的沙门氏菌等基因菌株 抗原在C3缺陷和血小板减少小鼠，以确定如何 LPS的结构影响小鼠的毒力。