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）：正在研究重组无毒沙门氏菌疫苗，以表达异源病原体毒力抗原的克隆基因的能力，以及它们在开发粘膜疫苗保护剂保护各种感染性疾病（包括牙齿）中的潜在使用。但是，这些安全的活载体疫苗介导宿主反应的机制仍然鲜为人知。在宿主细胞中/识别与微生物成分相关的不同分子模式，在宿主细胞中表达了模式识别受体（PRR），包括Toll样受体（TLR）。 TLR对树突状细胞对微生物成分的识别导致先天免疫反应和适应性免疫的激活。我们从免疫研究中使用沙门氏菌载体疫苗表达编码基因编码链球菌链球菌粘附AGI/II的唾液结合区域（SBR）的发现的结果免疫系统的不同，大概是通过TLR。其他证据表明，可能有多个TLR参与介导和增强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，暴露于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由沙门氏菌表达的克隆抗原的适应性免疫反应的结果。我们的研究将着重于定义TLR的调节作用，这些调节作用在粘膜免疫后使用复杂的沙门氏菌载体疫苗介导适应性免疫反应，表达了链球菌的克隆毒力抗原。具体目标是； 1）定义TLR和与沙门氏菌载体疫苗表达的克隆抗原抗原的粘膜和全身反应之间的TLR之间的相互作用，以确定TLR在TLR上对TLR对TLR的作用，以使T细胞和B细胞对salmone的适应性免疫反应，以使TLR在TLR上的作用。使用TLR敲除小鼠以及体外测定系统的体内免疫反应和收养转移模型将用于解决目标。对每种TLR的理解以及介导对疫苗的先天和适应性宿主反应的TLR之间的相互作用，以及在树突状，T和B细胞中TLR信号的贡献，T和B细胞在T和B细胞中对特定微生物抗原的自适应反应，将有助于对不受欢迎的疫苗和免疫化的侵蚀性侵害，从而有助于促进盐疾病的侵害。包括龋齿。 公共卫生相关性：正在开发和测试重组衰减的沙门氏菌疫苗，以促进对各种感染剂的保护性粘膜和全身免疫反应，包括龋齿和牙周疾病的病因。与由纯化的微生物成分组成的疫苗相比，实时载体疫苗在诱导微生物病原体的粘膜免疫反应和生产中更经济。因此，确定宿主识别的机制至关重要包括与口腔相关的那些。