Evasion of host immunity by the M protein

M蛋白逃避宿主免疫

• 批准号: 10438582
• 负责人: PARTHO GHOSH
• 金额: $ 61.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10438582
• 关键词: 3-Dimensional; Acute; Amino Acid Sequence; Amino Acids; Antibodies; Antigens; Attenuated; Autoimmune; Bacteria; Binding; Binding Proteins; Blood; Buffaloes; Cell Wall; Collaborations; Complement 3b; Complement Factor H; Complex; Consensus; Crystallization; Deposition; Development; Disease; Fibrinogen; Goals; Hand; Human; Immune; Immune system; Immunity; Infection; Knowledge; Lead; Life; Microbiology; Morbidity - disease rate; Nature; Opsonin; Pattern; Phagocytes; Prevention strategy; Property; Proteins; Public Health; Publishing; Reporting; Research Personnel; Resistance; Role; Sea; Streptococcus pyogenes; Surface; Testing; Therapeutic; Vaccine Design; Vaccines; Variant; Virulence; Virulence Factors; Work; X-Ray Crystallography; complement 4b-binding protein; design; mortality; multiple myeloma M Protein; neutralizing antibody; novel; novel therapeutics; pathogenic bacteria; protein complex; recruit; streptococcal M protein; success; uptake

Group A Streptococcus (GAS, S. pyogenes) remains a major public health threat. This widespread Gram- positive bacterial pathogen causes acute invasive diseases and gives rise to severe autoimmune sequelae, and is responsible for morbidity and mortality on a global scale. An essential virulence factor of GAS, the antigenically variable M protein, enables the bacterium to evade opsonophagocytic killing by the immune system. The M protein confers this indispensable function of phagocyte resistance by recruiting specific soluble human proteins to the GAS surface that block the deposition of the major opsonin C3b as well as antigen- specific opsonic antibodies — namely, C4b-binding protein (C4BP), factor H (FH), and fibrinogen (Fg). In some GAS strains, an M-like protein serves this function. More than 220 M types are known, and while most M protein types bind C4BP, FH, or Fg, or a combination of these, no consensus binding motif is evident in M and M-like proteins for any of these human proteins, except most recently for C4BP due to our breakthrough. This is because the exposed portion of the M protein that recruits these anti-opsonic human proteins is sequence variable. While inhibition of these interactions has been shown to render GAS sensitive to immune killing, the lack of consensus binding motifs has hindered the therapeutic goal of targeting these interactions. Our recent breakthrough, reported in Buffalo et al., offers a solution to this problem. In effect, we found that hidden within the variable region of many M proteins is a three-dimensional (3D) pattern that is conserved for binding C4BP. This 3D C4BP-binding pattern in the M protein is dispersed (or hidden) within a sea of variable amino acids, which makes the 3D pattern nearly impossible to identify by primary sequence alone. However with structural knowledge in hand as a guiding template, the 3D pattern becomes easily recognizable within the primary sequence of many M types. We hypothesize that just as with C4BP, hidden within the variable regions of M and M-like proteins are 3D patterns that are conserved for binding FH and Fg. We propose to test this emerging theme of conservation hidden within variability by unveiling potentially conserved FH- and Fg-binding 3D patterns in M and M-like proteins. We also propose to complete our work on C4BP, as the 3D pattern we discovered and published in Buffalo et al. explains only about a half of the set of M proteins implicated in C4BP binding. We propose to carry this out through X-ray crystallography. We have an extensive record of success with crystallographic studies of the M protein, and have obtained initial co-crystals of M proteins bound to C4BP, FH, and Fg. In each case, we will take advantage of the highly detailed level of information provided by our structural studies to determine the precise functional contributions of each of these interactions to virulence through our long-standing collaboration with co-Investigator Victor Nizet (UCSD). The results from our studies will provide essential guidance in designing anti-virulence strategies, and may have applications in the development of a broadly neutralizing GAS vaccine.

A组链球菌（Gas，S。pyogenes）仍然是主要的公共卫生威胁。这个宽度的革兰氏 阳性细菌病原体会引起急性浸润性疾病，并引起严重的自身免疫性后遗症， 并负责全球范围内的发病率和死亡率。气体的基本病毒因素， 抗原可变的M蛋白质，使细菌能够通过免疫逃避op子杀虫剂 系统。 M蛋白通过募集特定的可溶性来承认吞噬细胞耐药性不可或缺的功能 人类蛋白质到阻塞主要opsonin c3b的沉积以及抗原的沉积的气表面 特定的Opsonic抗体 - 即C4b结合蛋白（C4BP），因子H（FH）和纤维蛋白原（FG）。 某些气体菌株，一种M样蛋白质可起到此功能。已知超过220 m的类型，而大多数M 蛋白质类型结合C4BP，FH或FG或这些组合，没有共识结合基序是M和 这些人类蛋白质中的任何一种，除了最近，由于我们的突破，最近C4BP的M样蛋白质。这 是因为募集这些抗偶然人蛋白的M蛋白的暴露部分是 序列变量。虽然抑制这些相互作用已显示出对免疫敏感的气体 杀人，缺乏共识约束的图案阻碍了针对这些目标的治疗目标 互动。我们最近在Buffalo等人的突破提供了解决此问题的解决方案。实际上，我们 发现隐藏在许多M蛋白的变量区域内是一种三维（3D）模式 保守用于结合C4BP。 M蛋白中的这种3D C4BP结合模式被分散（或隐藏） 在可变氨基酸的海洋中，这使得3D模式几乎无法通过初级识别 单独的序列。但是，由于手头的结构知识是指导模板，3D模式变为 在许多M类型的主要序列中易于识别。我们假设这与C4BP一样 隐藏在M和M样蛋白的可变区域内是3D模式，可保守 结合FH和FG。我们建议通过通过 在M和M样蛋白中揭示潜在保守的FH和FG结合3D模式。我们还建议 完成了我们在Buffalo等人发现和出版的3D模式上完成我们在C4BP上的工作。仅解释 在C4BP结合中实现的一组M蛋白的一半。我们建议通过X射线执行此操作 晶体学。通过M蛋白的晶体学研究，我们有广泛的记录，以及 已经获得了与C4BP，FH和FG结合的M蛋白的初始共结晶。在每种情况下，我们都会接受 我们的结构研究提供的高度详细信息水平的优势来确定精度 通过我们与我们长期合作，这些相互作用对病毒的功能贡献 共同投资者Victor Nizet（UCSD）。我们研究的结果将为设计提供基本的指导 反病毒策略，可能在开发广泛中和气体疫苗方面有应用。