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: 8385355
• 负责人: Qingke Kong
• 金额: $ 23.1万
• 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 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8385355
• 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; 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. PUBLIC HEALTH RELEVANCE: Effective live recombinant attenuated Salmonella vaccines expressing heterologous antigen genes hold the promise of providing low cost, orally administered, life-long protection against a variety of diseases. The goal of this project is to enhance safety and immunogenicity by reducing the inherent toxicity of the lipid A component of Salmonella without compromising its adjuvant properties.

描述(申请人提供)：重组减毒沙门氏菌疫苗(RASV)是一种有效且廉价的方法，可激发强烈的粘膜和体液免疫反应。然而，这一领域的一个问题是，尽管RASV在动物模型中是减毒和安全的，但当给人类使用时，它们可能会产生反应性，产生不想要的副作用，包括腹泻、腹痛、胃肠紊乱、神经系统紊乱和发烧。这些症状中的许多都与已知的对脂A的反应一致。脂A通过Toll样受体4(TLR4)与人类免疫系统相互作用，TLR4识别与脂A相关的特定部分，包括酰链。脂酰链的长度和数量影响脂类A：TLR4相互作用的强度和结果。为了减少活细菌疫苗中潜在的内毒素效应，我们将研究修改活沙门氏菌细胞中的酰链长度的效果。我们的目标是通过改变脂类A的酰链长度来降低脂类A的整体毒性，而不影响整体的免疫原性。我们将构建一系列脂类A酰链长度不同的沙门氏菌突变体，并在野生型背景下评估和比较它们的毒力和诱导天然免疫的能力。不影响毒力或定植能力的酰化修饰随后将在沙门氏菌疫苗中进行评估，以确定它们的 对针对载体抗原和针对挑战的免疫反应能力的影响。该项目的成功可能导致人类使用更安全和更具免疫原性的菌株。 公共卫生相关性：有效的表达异源抗原基因的重组减毒沙门氏菌活疫苗有望提供低成本、口服、终身预防各种疾病的保护。该项目的目标是在不影响其佐剂特性的情况下，通过降低沙门氏菌脂质A组分的固有毒性来提高安全性和免疫原性。