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Complement Activation on Neisseria meningitidis

脑膜炎奈瑟菌的补体激活

基本信息

批准号：
8604350
负责人：
SANJAY RAM
金额：
$ 36.64万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-01-01 至 2015-10-12
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8604350
关键词：
Address Affect Animal Model Antibiotics Antibodies Antibody Specificity Antigens Bacteria Binding Binding Proteins Blood Blood Circulation Cerebrospinal Fluid Child Classical Complement Pathway Clinical Complement Complement 4b Complement Activation Complement Factor B Complement Factor H Complement Membrane Attack Complex Complex Defense Mechanisms Deposition Development Disease Encapsulated Epidemiology Equilibrium Fc domain Feedback Funding Genome Goals Gold Health Host Defense Human Hybrids IgG1 Immune Immunization Immunoglobulin G Immunoglobulin M Inactivated Vaccines Infection Invaded Knowledge Lead Ligands Lipoproteins Mediating Membrane Membrane Proteins Meningococcal Infections Meningococcal meningitis Microbe Modeling Molecular Morbidity - disease rate Mucous Membrane Nasopharynx Neisseria Neisseria meningitidis Organism Oryctolagus cuniculus Outcome Pathogenesis Pathway interactions Persons Polysaccharides Properdin Protein Binding Proteins Recurrence Regulation Resistance Role Sepsis Serum Site Specificity Surface System Vaccination Vaccines Virulence arm bactericide base blocking factor capsule complement deficiency complement pathway complement system design disorder prevention improved inhibitor/antagonist insight killings lipooligosaccharide mortality novel pathogen phosphoethanolamine polyanion public health relevance vaccine candidate vaccine development vaccine efficacy vaccine evaluation young adult

项目摘要

DESCRIPTION (provided by applicant): Complement (C) is a key arm of innate immune defenses against invasive meningococcal infections. Neisseria meningitidis (Nm) have evolved several sophisticated mechanisms to evade host C. A balance between the hosts' efforts to activate C on the bacterium and the microbe's C evasion strategies dictates whether the organism is cleared from the mucosa, remains an asymptomatic colonizer in the nasopharynx, or proceeds to cause invasive disease. In the previous funding period we characterized interactions between Nm and C4b, a component of the classical pathway (CP). Almost all Nm isolates recovered from the blood or cerebrospinal fluid are encapsulated and capsule is important for resistance to C. The molecular basis for capsule-mediated C resistance remains undefined. In Aim 1 will define the role of capsular polysaccharide (CPS) in regulating C. First, in Aim 1a, we will elucidate the reason for differences in the level of CP activation mediated by anti-CPS and anti-outer membrane Abs. On a molar basis, mAbs directed against CPS fix less C4b than mAbs against membrane structures, suggesting that efficient C4b binding may require activation of C4 proximate to the meningococcal molecules that serve as C4b acceptors such as LOS and opacity protein. Chimeric mAbs containing human IgG1 Fc and directed against either CPS or the Nm vaccine candidate, factor H-binding protein (fHbp) will be used to symmetrically compare the C-activating functions of these mAbs. The positive feedback loop of the alternative pathway (AP) is also important for bacterial killing by vaccine Abs. Our preliminary studies indicate that the group A, C, W-135 and Y (but not B) CPSs block activation of human C3 by purified human factors B and D. In Aim 1b we will define the molecular basis of AP inhibition by examining the interaction of CPS with purified AP components. These studies may identify a common mechanism of action for polyanions that block AP activation. AP regulation by CPS is human-specific; assembly of the rabbit AP (not regulated by CPS) will be examined in Aim 1c to provide a better understanding of the human-specificity of AP regulation by CPS. Surface proteins also contribute to C resistance; fHbp binds to the AP inhibitor, factor H (fH) and inhibits C activation. In Aim 2, we will we will exploit our knowledge of fH- fHbp interactions and use chimeric molecules to block fH binding to Nm and manipulate the C cascade to precisely define the roles of the CP and AP in killing Nm. We will also attempt to 'boost' the bactericidal function of an otherwise nonbactericidal anti-fHbp mAb (JAR 4). Such knowledge could lead to optimization of vaccine strategies. Finally, in Aim 3 we will define novel C evasion strategies in strains that express low levels of fHbp. Preliminary evidence indicates that low fHbp expressing/low fH binding Nm regulate C at the level of C5b-9 formation or insertion and we will characterize the molecular basis for C resistance at this level. These studies will help define novel mechanisms of C evasion by Nm; information that will advance understanding of meningococcal pathogenesis and improve ongoing efforts to develop effective protein-based vaccines.

描述（由申请人提供）：补体（C）是抵抗侵袭性脑膜炎球菌感染的先天免疫防御的关键武器。脑膜炎奈瑟菌（Nm）已经进化出几种复杂的机制来逃避宿主C。宿主激活细菌上的C的努力与微生物的C逃避策略之间的平衡决定了生物体是否从粘膜中清除，在鼻咽中保持无症状的定殖者，或继续引起侵袭性疾病。在上一个资助期，我们表征了Nm和C4 b之间的相互作用，C4 b是经典途径（CP）的一个组成部分。几乎所有从血液或脑脊液中回收的Nm分离株都被包囊化，并且包囊对于抵抗C.胶囊介导的C抗性的分子基础仍然不确定。目的1将明确荚膜多糖（CPS）在调节C。首先，在目标1a中，我们将阐明抗CPS和抗外膜Ab介导的CP激活水平差异的原因。在摩尔基础上，针对CPS的mAb比针对膜结构的mAb固定更少的C4 b，这表明有效的C4 b结合可能需要激活邻近脑膜炎球菌分子的C4，所述脑膜炎球菌分子充当C4 b受体，例如LOS和不透明蛋白。将使用含有人IgG 1 Fc并针对CPS或Nm候选疫苗H因子结合蛋白（fHbp）的嵌合mAb来对称比较这些mAb的C激活功能。旁路途径（AP）的正反馈环对于疫苗Ab的细菌杀伤也很重要。我们的初步研究表明，A、C、W-135和Y组（但不包括B）CPS阻断了纯化的人因子B和D对人C3的激活。在目标1b中，我们将通过检查CPS与纯化的AP组分的相互作用来定义AP抑制的分子基础。这些研究可能确定了聚阴离子阻断AP激活的共同作用机制。CPS对AP的调节是人类特异性的;将在目标1c中检查兔AP（不受CPS调节）的组装，以更好地理解CPS对AP调节的人类特异性。表面蛋白也有助于C抗性; fHbp结合AP抑制剂，因子H（fH）并抑制C活化。在目的2中，我们将利用我们对fH-fHbp相互作用的了解，并使用嵌合分子阻断fH与Nm的结合，并操纵C级联以精确定义CP和AP在杀死Nm中的作用。我们还将尝试“增强”一种非杀菌性抗fHbp mAb的杀菌功能（1994）。这些知识可以导致疫苗策略的优化。最后，在目标3中，我们将在表达低水平fHbp的菌株中定义新的C逃避策略。初步证据表明，低fHbp表达/低fH结合Nm在C5 b-9形成或插入水平上调节C，我们将在该水平上表征C抗性的分子基础。这些研究将有助于确定新的机制，C逃避Nm的信息，将促进理解脑膜炎球菌的发病机制，并改善正在进行的努力，以开发有效的蛋白质为基础的疫苗。