Deciphering the immune-modulating effect of Staphylococcus aureus protein A (SpA) on the functional antibody response

解读金黄色葡萄球菌蛋白 A (SpA) 对功能性抗体反应的免疫调节作用

• 批准号: 2594575
• 金额: --
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2594575
• 关键词: Deciphering; immune; modulating; effect; Staphylococcus

While Staphylococcus aureus is commonly found as part of the human commensal flora it is also a major opportunistic pathogen causing significant illness and burden on healthcare systems. The increasing incidence of antimicrobial resistant infection including methicillin-resistant Staphylococcus aureus (MRSA) and the failure of effective prevention approaches means that it remains a high-priority target for the development of new therapeutics and vaccines [1].Human immune responses to S. aureus often appear dysregulated due to an array of immune-modulator bacterial virulence factors. These factors block immune cell chemotaxis, complement activation, phagocytic uptake and oxidative killing, and facilitate pathogen replication. This results in disruption of normal B and T cell function, preventing the establishment of otherwise protective immune responses [2]. Central to the disruption of B cell survival and function is S. aureus protein A (SpA), an immunoglobulin (Ig)-binding virulence factor, which subsequently impairs the humoral response. As a cell wall-associated protein, SpA is either expressed on the bacterial surface or secreted. By sequestering immunoglobulin through the Fc portion, SpA causes disruption of opsonophagocytosis resulting in bacterial persistence. Another key function of SpA is to impair the B cell response by binding the Fab region of VH3-type B cell receptor and acting as a superantigen. In mice, B cells targeted by this superantigen initially undergo massive activation, followed by apoptosis and cell death [3]. SpA is also associated with the transient extrafollicular expansion of short-lived VH3-biased B cells followed by reduction of protective secondary anti-S. aureus antibody response and of the pool of bone marrow-resident long-lived antigen-specific plasma cells [4]. Moreover, analysis of human B cells revealed a similar VH3-dominant response both during natural infection and in the memory compartment of healthy individuals [5, 6]. It is currently unknown to what extent these effects are relevant to the functional human response to infection and what is the impact of this biased antibody response to the establishment of protective defenses. The aim of this PhD project is to understand the immune-modulating effect of S. aureus protein A on the functional response to infection in humans. Using clinical samples obtained from healthy donors, individuals recovering from S. aureus infection and other sources, you will characterize the mechanisms underlying SpA-mediated evasion of a functional antibody response. Understanding this mechanism will be vital to deciphering the virulence of S. aureus and other microorganisms.

虽然金黄色葡萄球菌通常被发现是人类肠道植物群的一部分，但它也是一种主要的机会致病菌，导致严重的疾病和医疗保健系统的负担。包括耐甲氧西林金黄色葡萄球菌（MRSA）在内的抗微生物药物耐药性感染的发病率不断增加，以及有效预防方法的失败意味着它仍然是开发新疗法和疫苗的高度优先目标[1]。金黄色葡萄球菌通常由于一系列免疫调节细菌毒力因子而出现失调。这些因子阻断免疫细胞趋化性、补体激活、吞噬细胞摄取和氧化杀伤，并促进病原体复制。这导致正常B和T细胞功能的破坏，阻止了保护性免疫应答的建立[2]。破坏B细胞存活和功能的核心是S。金黄色葡萄球菌蛋白A（SpA），一种免疫球蛋白（IG）结合毒力因子，其随后损害体液应答。作为一种细胞壁相关蛋白，SpA在细菌表面表达或分泌。通过Fc部分隔离免疫球蛋白，SpA引起调理吞噬作用的破坏，导致细菌持续存在。SpA的另一个关键功能是通过结合VH 3型B细胞受体的Fab B区并作为超抗原来削弱B细胞应答。在小鼠中，这种超抗原靶向的B细胞最初经历大量活化，随后发生凋亡和细胞死亡[3]。SpA还与短寿命VH3偏置B细胞的短暂滤泡外扩增相关，随后是保护性次级抗S抗体的减少。金黄色葡萄球菌抗体应答和骨髓驻留的长寿命抗原特异性浆细胞池[4]。此外，对人B细胞的分析揭示了在自然感染期间和在健康个体的记忆隔室中的类似VH 3显性应答[5，6]。目前尚不清楚这些效应在多大程度上与人类对感染的功能性反应相关，以及这种偏倚的抗体反应对建立保护性防御的影响。本博士项目的目的是了解S.金黄色葡萄球菌蛋白A对人类感染功能反应的影响。使用从健康供体获得的临床样品，从S.金黄色葡萄球菌感染和其他来源，您将表征SpA介导的功能性抗体应答逃避的机制。了解这一机制将是至关重要的破译的毒力S。金黄色葡萄球菌和其他微生物。