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Evasion of host immunity by the M protein

M蛋白逃避宿主免疫

基本信息

批准号：
10798688
负责人：
PARTHO GHOSH
金额：
$ 3.33万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
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/10798688
关键词：
3-Dimensional Acute Amino Acid Sequence Amino Acids Antibodies Antigenic Variation Antigens Attenuated Autoimmune Bacteria Binding Binding Proteins Blood Cell Wall Collaborations Complement 3b Complement Factor H Complex Consensus Crystallography Deposition Development Disease Fibrinogen Goals Hand Human Immune Immune system Immunity Infection Inflammatory Knowledge Life Microbiology Morbidity - disease rate Nature Opsonin Pattern Phagocytes Prevention strategy Productivity 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 success uptake

项目摘要

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，化脓性链球菌)仍然是一种主要的公共卫生威胁。这种广为流传的革兰氏- 阳性细菌病原体会导致急性侵袭性疾病，并会导致严重的自身免疫后遗症，并对全球范围内的发病率和死亡率负责。气体的一种基本毒力因素，即抗原性可变的M蛋白，使细菌能够逃避免疫对吞噬细胞的杀伤系统。M蛋白通过招募特定的可溶性细胞来赋予吞噬细胞抵抗这一不可或缺的功能人类蛋白质到气体表面，阻止主要调色素C3b以及抗原的沉积- 特异性调理抗体--即C4b结合蛋白(C4BP)、H因子(FH)和纤维蛋白原(Fg)。在……里面在某些GAS菌株中，一种类似M的蛋白具有这一功能。已知的类型超过220M，而大多数M 蛋白质类型结合C4BP、FH或FG，或这些结合的组合，在M和除了最近由于我们的突破而获得的C4BP以外的所有这些人类蛋白的类M蛋白。这是因为招募这些反调理人类蛋白的M蛋白的暴露部分是序列变量。虽然抑制这些相互作用已被证明使气体对免疫敏感杀戮，缺乏共识的结合基序阻碍了以这些为靶点的治疗目标互动。布法罗等人报道的我们最近的突破为这个问题提供了解决方案。实际上，我们发现在许多M蛋白的可变区中隐藏着一个三维(3D)模式，该模式与C4BP结合是保守的。M蛋白中的这种3D C4BP结合模式是分散的(或隐藏的) 在可变氨基酸的海洋中，这使得3D模式几乎不可能通过初级识别单独的序列。然而，利用手中的结构知识作为指导模板，3D图案变成在许多M类型的主序列中很容易识别。我们假设，就像C4BP一样，在M蛋白和类M蛋白的可变区中隐藏着保守的3D模式结合FH和FG。我们建议通过以下方式来测试隐藏在可变性中的这个新兴的保护主题揭示M蛋白和类M蛋白中潜在保守的FH和FG结合的3D模式。我们还建议完成我们在C4BP上的工作，作为我们在Buffalo等人上发现并发布的3D模式。仅解释与C4BP结合有关的M蛋白约有一半。我们建议通过X光来实现这一点结晶学。我们在M蛋白的结晶学研究方面取得了广泛的成功记录，并且已经获得了与C4BP、FH和FG结合的M蛋白的初步共晶体。在每种情况下，我们都会采取利用我们的结构研究提供的高度详细的信息来确定准确的通过与我们的长期合作，这些相互作用中的每一种对毒力的功能性贡献联合调查员维克多·尼泽(UCSD)。我们的研究结果将为设计提供必要的指导抗毒力策略，并可能在广泛中和气体疫苗的开发中应用。