Innate Immunity to Salmonella Infections

描述(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 研究是为了了解先天免疫反应如何帮助保护 预防沙门氏菌感染。先天免疫的第一个方面，我们将 研究的是PMN。我们之前曾报道，人类上皮细胞使 当沙门氏菌入侵时，强大的趋化肽IL-8，这意味着 中性粒细胞对寄主抵御该病原菌具有重要作用。然后我们展示了 中性粒细胞对防御具有毒力的沙门氏菌至关重要 但不是那些没有毒力质粒的。这项提案的重点是 中性粒细胞在保护肠道免受沙门氏菌感染中的作用 一种小鼠口腔感染模型。PMN的作用将通过以下方式确定 抗Ly-6G单抗(RB6-8C5)诱导小鼠中性粒细胞减少 髓细胞特有的抗原。我们会寻找证据证明一个或 这两种趋化因子都是在感染小鼠体内和体外使用这两种 培养小鼠肠上皮细胞和结肠器官培养。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道 等人(自然，389,742,1997)认为LBP缺陷小鼠更容易患上 沙门氏菌感染，但LBP的作用机制尚不清楚 在感染中被阐明。我们使用了携带野生型Nramp1等位基因的小鼠 对沙门氏菌感染具有遗传抵抗力。LBP缺陷小鼠有 2个ELR+CXC趋化因子水平降低。我们现在将研究CXC的作用 趋化因子阻断CXC受体在宿主对沙门氏菌耐药性中的作用 抗体。第三个目标是确定补体是否通过 吞噬作用对沙门氏菌感染的早期抵抗力至关重要。我们会 研究C3缺陷小鼠的感染过程，并确定 中性粒细胞减少是否使他们更容易受到感染。我们会比较一下 表达B组或0组内毒素的沙门氏菌同基因菌株 C3缺乏和中性粒细胞减少的小鼠的抗原，以确定如何 内毒素的结构影响小鼠的毒力。

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.