Alteration of lipid A acyl chain length in Salmonella

沙门氏菌中脂质 A 酰基链长度的改变

• 批准号: 8518229
• 负责人: Qingke Kong
• 金额: $ 18.1万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8518229
• 关键词: Abdominal Pain; Acylation; Acyltransferase; Adjuvant; Adverse effects; Animal Model; Antigens; Attenuated; Bacteria; Bacterial Vaccines; Biological Assay; C10; C14 isotope; CD14 gene; Cell Membrane Permeability; Cells; Characteristics; Charge; Complex; Cytolysis; Diarrhea; Disease; Endotoxins; Fatty Acids; Fever; Gastrointestinal Diseases; Genes; Genetic; Goals; Heterophile Antigens; Human; Immune response; Immune system; Immunity; In Vitro; Inflammatory; Lead; Legal patent; Length; Life; Lipid A; Lipopolysaccharides; Mediating; Modification; Mus; Mutate; Mutation; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigen 85A; Natural Immunity; Outcome; Pathway interactions; Phase I Clinical Trials; Plasmids; Positioning Attribute; Production; Property; Reaction; Recombinant Vaccines; Recombinants; Safety; Salmonella; Salmonella Vaccines; Salmonella typhi; Salmonella typhimurium; Series; Signal Transduction; Streptococcus pneumoniae; Structure; Symptoms; System; Testing; Tissues; Toxic effect; Vaccines; Virulence; acyl group; cost; cytokine; human TLR4 protein; immunogenic; immunogenicity; inorganic phosphate; mutant; mycobacterial; nervous system disorder; pathogen; public health relevance; research study; success; tissue culture; toll-like receptor 4; vector vaccine

DESCRIPTION (provided by applicant): Recombinant attenuated Salmonella vaccines (RASVs) are an effective and inexpensive way to elicit strong mucosal and humoral immune responses. However, one problematic issue in this field has been that while RASVs are attenuated and safe in animal models, when administered to humans they can be reactogenic, producing unwanted side effects, including diarrhea, abdominal pain, gastrointestinal disorder, nervous system disorders, and fever. Many of these symptoms are consistent with known reactions to lipid A. Lipid A interacts with the human immune system via the toll-like receptor 4 (TLR4) which recognizes specific moieties associated with lipid A, including the acyl chains. The length and number of acyl chains influences the strength and outcome of the lipid A: TLR4 interaction. In an effort to reduce the potential for endotoxic effects in live bacterial vaccines,we will investigate the effects of modifying the acyl chain length in living Salmonella cells. Our goa is to reduce the overall toxicity of lipid A without compromising overall immunogenicity by modifying the length of the acyl chains from lipid A. We will construct a series of Salmonella mutants that differ in lipid A acyl chain length, and evaluate and compare their virulence and ability to elicit innate immunity in wild-type background. Acylation modifications that do not affet virulence or colonization ability will then be evaluated in Salmonella vaccines, to determine their influence on ability to elicit an immune response against a vectored antigen and against challenge. The success of this project could lead to safer and more immunogenic strains for human use.

描述（由申请人提供）：重组减毒沙门氏菌疫苗（RASV）是引发强烈粘膜和体液免疫反应的有效且廉价的方法。然而，这一领域的一个问题是，虽然RASV在动物模型中是减毒且安全的，但当给予人类时，它们可能会产生反应，产生不良副作用，包括腹泻、腹痛、胃肠道疾病、神经系统疾病和发烧。其中许多症状与已知的脂质 A 反应一致。脂质 A 通过 Toll 样受体 4 (TLR4) 与人类免疫系统相互作用，该受体可识别与脂质 A 相关的特定部分，包括酰基链。酰基链的长度和数量影响脂质 A：TLR4 相互作用的强度和结果。为了减少活细菌疫苗中内毒素效应的可能性，我们将研究改变活沙门氏菌细胞中酰基链长度的影响。我们的目标是通过修改脂质 A 酰基链的长度来降低脂质 A 的总体毒性，而不影响总体免疫原性。我们将构建一系列脂质 A 酰基链长度不同的沙门氏菌突变体，并评估和比较它们的毒力和在野生型背景下引发先天免疫的能力。然后将在沙门氏菌疫苗中评估不影响毒力或定植能力的酰化修饰，以确定其 对引发针对载体抗原和针对攻击的免疫应答的能力的影响。该项目的成功可以为人类带来更安全、更具免疫原性的菌株。