Neisserial porins and antigen presenting cells

奈瑟氏球菌孔蛋白和抗原呈递细胞

基本信息

批准号：
9761944
负责人：
LEE Mark WETZLER
金额：
$ 68.75万
依托单位：
BOSTON MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-04-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9761944
关键词：
Adaptor Signaling Protein Adjuvant Adjuvanticity Antibodies Antibody Affinity Antibody Formation Antibody Response Antigen-Presenting Cells Antigens B-Lymphocytes CD86 gene Data Defect Dendritic Cells Development Disease Outbreaks Ebola virus Emerging Communicable Diseases Goals Grant Heterodimerization Immune Immune response Immunization Immunize Immunobiology Immunoglobulin G Immunologic Adjuvants Immunology Influenza Journals Knockout Mice Laboratories Ligands LoxP-flanked allele MHC Class II Genes Measures Molecular Mus Mutation MyD88 protein Nucleoproteins Ovalbumin Ovum Pattern recognition receptor PorB porin Process Production Property Proteins Public Health Role Signal Transduction Somatic Cell Spleen Structure of germinal center of lymph node T cell response TLR1 gene TLR2 gene Testing VDAC1 gene Vaccine Adjuvant Vaccines Western Africa Work base cytokine improved lymph nodes macrophage pathogen prevent public health relevance response trafficking uptake vaccine candidate vaccine development vaccine response

项目摘要

DESCRIPTION (provided by applicant): Our laboratory has been investigating the immunobiology of the Neisserial porin PorB for the last two decades and, through our work regarding its use as a vaccine candidate, we found that PorB had unique immune stimulatory abilities above and beyond its own potential use as a vaccine. This was due to its property as a pathogen associated molecular patter (PAMP) inducing significant antigen presenting cell activation via recognition by TOLL-like Receptor 2 (TLR2) along with heterodimerization with TLR1 (but not TLR6). More recent work from our laboratory has greatly enhanced our understanding of the breadth and mechanism of the immune stimulating activity of PorB and allowed comparison to other potential immune adjuvants, including both TLR and non-TLR ligands. PorB adjuvant activity is absolutely dependent on MyD88 expression and almost totally dependent on TLR2 expression as shown by immunizations of MyD88 or TLR2 knockout (KO) mice with PorB/Ovalbumin (OVA - as a test antigen). We have further demonstrated that PorB can enhance antigen uptake in dendritic cells (DC) and macrophages, along with improved APC trafficking to draining lymph nodes (Platt et al., submitted Journal of Immunology). In addition, immunizations of MyD88 conditional KO mice (MyD88 floxed mice) have shown that macrophage, B cell or DC MyD88 signaling is essential for PorB adjuvant activity. Moreover, we have demonstrated that PorB is a potent inducer of germinal center (GC) formation in spleens and lymph nodes of immunized mice, and this induction is MyD88 dependent. Surprisingly, we found that PorB/OVA immunization of macrophage specific MyD88 conditional KO mice failed to induce a robust germinal center response or anti-OVA antibody as normally seen in WT mice. This defect in antibody responses appears to be greater when compared to either B cell or DC MyD88 conditional KO mice, demonstrating that macrophages may be the most important APC involved with PorB adjuvanticity. Based on the information obtained from our preliminary data, we have developed the following aims to further delineate the mechanisms of adjuvant activity PorB and other TLR ligand based immune adjuvants. Aim 1 will examine the overall effect of PorB and other vaccine adjuvants on GC formation and function using OVA as a test antigen and Influenza Nucleoprotein as a pathogen related antigen; Aim 2 will investigate the ability of PorB and other adjuvants to directly influence SHM and antibody affinity; and Aim 3 will delineate the role and potential function of macrophages in the adjuvant activity of PorB, especially in relation to GC formation. Importantly, the impact of findings from the studies in thi proposal go beyond just describing the use of PorB as an adjuvant, but will elucidate here-to-fore under studied mechanisms for the induction of immune responses by immune adjuvants, in general, and will have a great bearing on our overall understanding regarding germinal center formation and effective vaccine responses.

描述（由应用程序提供）：在过去的二十年中，我们的实验室一直在调查奈瑟氏孔孔蛋白PORB的免疫生物学，并且通过我们的工作，我们发现PORB具有独特的免疫刺激能力，并且超出了其自身作为疫苗的潜在用途。这是由于其特性是病原体相关的分子模式（PAMP）通过Toll样受体2（TLR2）识别的细胞激活，以及与TLR1（但不是TLR6）的异二二聚体。我们实验室的最新工作大大增强了我们对PORB免疫刺激活性的广度和机制的理解，并可以与其他潜在的免疫助理（包括TLR和非TLR配体）进行比较。 PORB可调活性绝对取决于MyD88的表达，几乎完全取决于TLR2表达，如MyD88或TLR2敲除（KO）小鼠（用porb/ovalbumin（ova-）作为测试抗原）所示。我们进一步证明，PORB可以增强树突状细胞（DC）和巨噬细胞的抗原摄取，以及改进的APC运输对排水淋巴结的量（Platt等人，提交的免疫学杂志）。此外，MyD88条件KO小鼠的免疫接种（MyD88 floxed小鼠）表明，巨噬细胞，B细胞或DC MyD88信号对于可调节活性至关重要。此外，我们已经证明了PORB是免疫小鼠的脾脏和淋巴结中生发中心（GC）形成的潜力，并且该诱导取决于MYD88。令人惊讶的是，我们发现巨噬细胞的PORB/OVA免疫抑制是特异性MyD88条件KO小鼠未能诱导WT小鼠中通常可以看到的强大生发中心反应或抗OVA抗体。与B细胞或DC MyD88条件KO小鼠相比，抗体反应中的这种缺陷似乎更大，表明巨噬细胞可能是与PORB可调性有关的最重要的APC。基于从我们的初步数据获得的信息，我们开发了以下目的，以进一步描述可调节活性PORB和其他基于TLR配体的免疫调节器的机制。 AIM 1将检查PORB和其他疫苗调节剂对GC形成和功能的总体作用，使用OVA作为测试抗原和流感核蛋白作为病原体相关的抗原； AIM 2将研究PORB和其他调节器直接影响SHM和抗体亲和力的能力； AIM 3将描述巨噬细胞在调整PORB活性中的作用和潜在功能，尤其是与GC形成有关。重要的是，研究中的发现的影响不仅仅是描述了PORB作为可调节的使用，但是在研究iod机制下，将在此处阐明，从而通过免疫可调剂（通常都可以通过免疫反应来诱导免疫反应，并且将在我们的整体理解和有效的疫苗反应上具有很大的影响。

项目成果

期刊论文数量（26）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The amino acid sequence of Neisseria lactamica PorB surface-exposed loops influences Toll-like receptor 2-dependent cell activation.

乳酸奈瑟菌 PorB 表面暴露环的氨基酸序列影响 Toll 样受体 2 依赖性细胞激活。

DOI：
10.1128/iai.00683-12
发表时间：
2012
期刊：
Infection and immunity
影响因子：
3.1
作者：
Toussi,DeanaN;Carraway,Margaretha;Wetzler,LeeM;Lewis,LisaA;Liu,Xiuping;Massari,Paola
通讯作者：
Massari,Paola

Meningococcal PorB induces a robust and diverse antigen specific T cell response as a vaccine adjuvant.