Alteration of lipid A acyl chain length in Salmonella

描述（由申请方提供）：重组减毒沙门氏菌疫苗（RASV）是一种有效且廉价的方法，可引发强烈的粘膜和体液免疫应答。然而，该领域的一个问题是，尽管RASV在动物模型中是减毒的和安全的，但当施用给人时，它们可能是反应原性的，产生不希望的副作用，包括腹泻、腹痛、胃肠道疾病、神经系统疾病和发热。这些症状中的许多与已知的对脂质A的反应一致。脂质A通过Toll样受体4（TLR4）与人免疫系统相互作用，TLR4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作用的可能性，我们将研究修饰活沙门氏菌细胞中酰基链长度的影响。我们的果阿是通过修饰脂质A的酰基链长度，降低脂质A的总体毒性，而不损害总体免疫原性。我们将构建一系列不同的脂A酰基链长度的沙门氏菌突变体，并评估和比较它们的毒力和能力，在野生型背景下引发先天免疫。然后将在沙门氏菌疫苗中评价不影响毒力或定殖能力的酰化修饰，以确定它们的毒性。 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。该项目的成功可能会导致更安全和更具免疫原性的菌株供人类使用。 公共卫生相关性：表达异源抗原基因的有效活重组减毒沙门氏菌疫苗有望提供低成本、口服给药、针对多种疾病的终身保护。该项目的目标是通过降低沙门氏菌脂质A组分的固有毒性而不损害其佐剂特性来提高安全性和免疫原性。

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.