Genetically Engineered Oral Vaccines and Caries Immunity

基因工程口服疫苗和龋齿免疫

• 批准号: 8018478
• 负责人: Suzanne M. Michalek
• 金额: $ 33.41万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8018478
• 关键词: Address; Adhesions; Adjuvant; Adoptive Transfer; Agonist; Antibody Formation; Antigen-Presenting Cells; Antigens; Attenuated; B-Lymphocytes; Binding; CD80 gene; Cell Maturation; Cells; Chimeric Proteins; Cholera Toxin; Cholera Toxin Protomer B; Colony-forming units; Communicable Diseases; Complex; Cytosine Nucleotides; Dendritic Cells; Dental caries; Development; Effectiveness; Engineering; Event; Exposure to; Genes; Glucans; Glucosyltransferase; Guanosine; Heterophile Antigens; Immune response; Immune system; Immunity; Immunization; Immunoglobulin A; Infectious Agent; Knock-out; Knockout Mice; Leucine-Rich Repeat; Life; Link; Lipopolysaccharides; Lysine; Mediating; Memory; Modeling; Molecular; Mucosal Immune Responses; Nature; Oral cavity; Outcome; Pattern; Pattern recognition receptor; Periodontal Diseases; Phosphate Buffer; Play; Receptor Signaling; Recombinants; Regimen; Role; Saline; Saliva; Salmonella; Salmonella Vaccines; Secretory Immunoglobulin A; Signal Transduction; Streptococcus mutans; Structure of aggregated lymphoid follicle of small intestine; System; T-Lymphocyte; TP-1; Testing; Toll-like receptors; Vaccines; Virulence; adaptive immunity; design; fetal bovine serum; fluorescence activated cell sorter device; gene cloning; improved; in vitro Assay; in vivo; microbial; microorganism antigen; mucosal vaccine; oral vaccine; pathogen; public health relevance; receptor; research study; response; vaccine candidate; vector; vector vaccine

DESCRIPTION (provided by applicant): Recombinant avirulent Salmonella vaccines are being studied for their ability to express cloned genes of virulence antigens of heterologous pathogens, and for their potential use in the development of mucosal vaccines protective against various infectious diseases including dental caries. However, the mechanism(s) by which these safe, live vector vaccines mediate host responses are still poorly understood. Pattern-recognition receptors (PRRs), including the Toll-like receptors (TLRs), are expressed on/in host cells and recognize distinct molecular patterns associated with microbial components. The recognition of microbial components by TLRs on dendritic cells leads to the induction of an innate immune response and the activation of adaptive immunity. Our findings from immunization studies with a Salmonella vector vaccine expressing the gene encoding the saliva-binding region (SBR) of the adhesion AgI/II of Streptococcus mutans showed that the costimulatory molecules CD80 and CD86 play distinct, as well as redundant roles in mediating mucosal and systemic antibody responses, thus providing evidence that the vector and SBR may be signaling the innate immune system differently, presumably via TLRs. Other evidence suggests that more than one TLR may be involved in mediating and potentiating the immune response to SBR produced by the Salmonella vector. The fundamental hypothesis of our proposed studies is that the interplay between TLRs on various host cells that are engaged following exposure to the Salmonella vector vaccine will influence the outcome of the adaptive immune response to the cloned antigen expressed by the Salmonella. Our studies will focus on defining the regulatory roles of TLRs that mediate the adaptive immune response following mucosal immunization with a complex Salmonella vector vaccine expressing a cloned virulence antigen of S. mutans. The specific aims are; 1) to define the TLRs and the interplay between the TLRs involved in a selective augmentation of mucosal and systemic responses to the cloned antigen of S. mutans expressed by a Salmonella vector vaccine and 2) to determine the role of TLRs on T cells and B cells for an adaptive immune response to a cloned antigen expressed by a Salmonella vector vaccine. In vivo immune response and adoptive transfer models that use TLR knockout mice, as well as in vitro assay systems will be used to address the aims. An understanding of each TLR and the interplay between TLRs involved in mediating the innate and adaptive host responses to a vaccine candidate, and the contribution of TLR signaling in dendritic, T and B cells for the resulting adaptive response to specific microbial antigens will help in the design of improved Salmonella vector vaccines and immunization regimens for the induction of protective immune responses against infectious diseases, including dental caries. PUBLIC HEALTH RELEVANCE: Recombinant attenuated Salmonella vaccines are being developed and tested for their effectiveness in inducing protective mucosal and systemic immune responses to a variety of infectious agents, including the etiologic agents of dental caries and periodontal disease. Live vector vaccines are more effective in inducing mucosal immune responses against microbial pathogens and more economical to produce than vaccines consisting of purified microbial components. Therefore, it is critical to determine the mechanisms involved in host recognition of microbial components of a Salmonella vector vaccine that regulate the nature of the immune response induced to the expressing cloned virulence antigen of a heterologous pathogen, such as mutans streptococci, in order to develop recombinant avirulent Salmonella vaccines that are highly effective in potentiating protective immune responses against mucosal pathogens, including those associated with the oral cavity.

描述（由申请人提供）：正在研究重组无毒力沙门氏菌疫苗表达异源病原体毒力抗原克隆基因的能力，以及它们在开发预防包括龋齿在内的各种传染病的粘膜疫苗中的潜在用途。然而，人们对这些安全的活载体疫苗介导宿主反应的机制仍然知之甚少。模式识别受体 (PRR)，包括 Toll 样受体 (TLR)，在宿主细胞上/内表达，并识别与微生物成分相关的不同分子模式。树突状细胞上的 TLR 对微生物成分的识别导致先天免疫反应的诱导和适应性免疫的激活。我们使用沙门氏菌载体疫苗进行免疫研究，该疫苗表达编码变形链球菌粘附 AgI/II 唾液结合区 (SBR) 的基因，结果表明，共刺激分子 CD80 和 CD86 在介导粘膜免疫反应中发挥着独特且冗余的作用。和全身抗体反应，从而提供证据表明载体和 SBR 可能通过 TLR 向先天免疫系统发出不同的信号。其他证据表明，不止一种 TLR 可能参与介导和增强对沙门氏菌载体产生的 SBR 的免疫反应。我们提出的研究的基本假设是，接触沙门氏菌载体疫苗后参与的各种宿主细胞上的 TLR 之间的相互作用将影响对沙门氏菌表达的克隆抗原的适应性免疫反应的结果。我们的研究将集中于确定 TLR 的调节作用，这些 TLR 在使用表达变异链球菌克隆毒力抗原的复杂沙门氏菌载体疫苗进行粘膜免疫后介导适应性免疫反应。具体目标是； 1) 定义 TLR 以及 TLR 之间的相互作用，这些 TLR 参与选择性增强对沙门氏菌载体疫苗表达的变形链球菌克隆抗原的粘膜和全身反应，以及 2) 确定 TLR 对 T 细胞和 B 细胞的作用细胞对沙门氏菌载体疫苗表达的克隆抗原产生适应性免疫反应。使用 TLR 敲除小鼠的体内免疫反应和过继转移模型以及体外测定系统将用于实现这些目标。了解每个 TLR 以及参与介导对候选疫苗的先天性和适应性宿主反应的 TLR 之间的相互作用，以及树突状细胞、T 细胞和 B 细胞中 TLR 信号传导对特定微生物抗原产生的适应性反应的贡献，将有助于设计改进的沙门氏菌载体疫苗和免疫方案，以诱导针对包括龋齿在内的传染病的保护性免疫反应。 公共健康相关性：正在开发重组沙门氏菌减毒疫苗，并测试其在诱导针对多种感染原（包括龋齿和牙周病的病原体）的保护性粘膜和全身免疫反应方面的有效性。活载体疫苗在诱导针对微生物病原体的粘膜免疫反应方面更有效，并且比由纯化的微生物成分组成的疫苗生产更经济。因此，确定沙门氏菌载体疫苗微生物成分的宿主识别机制至关重要，这些机制可调节对异源病原体（如变形链球菌）的表达克隆毒力抗原诱导的免疫反应的性质，以便开发重组无毒沙门氏菌疫苗，可高度有效地增强针对粘膜病原体（包括与口腔相关的病原体）的保护性免疫反应。