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

虽然金黄色葡萄球菌通常是人类共生菌群的一部分，但它也是一种主要的机会性病原体，可引起重大疾病并给卫生保健系统带来负担。包括耐甲氧西林金黄色葡萄球菌（MRSA）在内的抗菌素耐药性感染的发病率不断上升，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[10]。由于一系列免疫调节细菌毒力因子，人类对金黄色葡萄球菌的免疫反应经常出现失调。这些因子阻断免疫细胞趋化、补体活化、吞噬摄取和氧化杀伤，促进病原体复制。这导致正常的B细胞和T细胞功能的破坏，阻止了原本保护性免疫反应[2]的建立。破坏B细胞存活和功能的核心是金黄色葡萄球菌蛋白A (SpA)，这是一种免疫球蛋白（Ig）结合的毒力因子，随后会损害体液反应。作为细胞壁相关蛋白，SpA可在细菌表面表达或分泌。通过Fc部分隔离免疫球蛋白，SpA导致调理吞噬作用的破坏，从而导致细菌的持续存在。SpA的另一个关键功能是通过结合vh3型B细胞受体Fab区并作为超抗原来破坏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。SpA还与短命的vh3偏置B细胞的瞬时滤泡外扩张有关，随后是保护性次级抗- s的减少。金黄色葡萄球菌抗体反应和骨髓驻留的长寿抗原特异性浆细胞池[4]。此外，对人类B细胞的分析显示，在自然感染和健康个体的记忆区中，vh3都有类似的优势反应[5,6]。目前尚不清楚这些影响在多大程度上与人类对感染的功能性反应有关，以及这种有偏见的抗体反应对保护性防御的建立有何影响。本博士项目的目的是了解金黄色葡萄球菌蛋白A对人类感染功能反应的免疫调节作用。使用从健康供体、金黄色葡萄球菌感染恢复个体和其他来源获得的临床样本，您将描述spa介导的逃避功能性抗体反应的机制。了解这一机制对于破译金黄色葡萄球菌和其他微生物的毒力至关重要。

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.