Novartis Vaccines and Diagnostics Srl, Siena, Italy.
mBio. 2013 Jul 23;4(4):e00206-13. doi: 10.1128/mBio.00206-13.
In this study, we have characterized the functional properties of a novel Escherichia coli antigen named EsiB (E. coli secretory immunoglobulin A-binding protein), recently reported to protect mice from sepsis. Gene distribution analysis of a panel of 267 strains representative of different E. coli pathotypes revealed that esiB is preferentially associated with extraintestinal strains, while the gene is rarely found in either intestinal or nonpathogenic strains. These findings were supported by the presence of anti-EsiB antibodies in the sera of patients affected by urinary tract infections (UTIs). By solving its crystal structure, we observed that EsiB adopts a superhelical fold composed of Sel1-like repeats (SLRs), a feature often associated with bacterial proteins possessing immunomodulatory functions. Indeed, we found that EsiB interacts with secretory immunoglobulin A (SIgA) through a specific motif identified by an immunocapturing approach. Functional assays showed that EsiB binding to SIgA is likely to interfere with productive FcαRI signaling, by inhibiting both SIgA-induced neutrophil chemotaxis and respiratory burst. Indeed, EsiB hampers SIgA-mediated signaling events by reducing the phosphorylation status of key signal-transducer cytosolic proteins, including mitogen-activated kinases. We propose that the interference with such immune events could contribute to the capacity of the bacterium to avoid clearance by neutrophils, as well as reducing the recruitment of immune cells to the infection site.
Pathogenic Escherichia coli infections have recently been exacerbated by increasing antibiotic resistance and the number of recurrent contagions. Attempts to develop preventive strategies against E. coli have not been successful, mainly due to the large antigenic and genetic variability of virulence factors, but also due to the complexity of the mechanisms used by the pathogen to evade the immune system. In this work, we elucidated the function of a recently discovered protective antigen, named EsiB, and described its capacity to interact with secretory immunoglobulin A (SIgA) and impair effector functions. This work unravels a novel strategy used by E. coli to subvert the host immune response and avoid neutrophil-dependent clearance.
在这项研究中，我们描述了一种新型大肠杆菌抗原 EsiB（大肠杆菌分泌型免疫球蛋白 A 结合蛋白）的功能特性，该抗原最近被报道可保护小鼠免受败血症的影响。对 267 株不同大肠杆菌病原体代表菌株的基因分布分析表明，esiB 优先与肠外菌株相关联，而该基因在肠道或非致病性菌株中很少发现。这些发现得到了受尿路感染（UTI）影响的患者血清中存在抗 EsiB 抗体的支持。通过解决其晶体结构，我们观察到 EsiB 采用由 Sel1 样重复（SLRs）组成的超螺旋折叠，这一特征通常与具有免疫调节功能的细菌蛋白相关。事实上，我们发现 EsiB 通过免疫捕获方法鉴定的特定基序与分泌型免疫球蛋白 A（SIgA）相互作用。功能测定表明，EsiB 与 SIgA 的结合可能通过抑制 SIgA 诱导的中性粒细胞趋化和呼吸爆发来干扰有效的 FcαRI 信号转导。事实上，EsiB 通过降低包括丝裂原激活的蛋白激酶在内的关键信号转导细胞内蛋白的磷酸化状态，来阻碍 SIgA 介导的信号事件。我们提出，这种免疫事件的干扰可能有助于细菌逃避中性粒细胞的清除，同时减少免疫细胞向感染部位的募集。
最近，大肠杆菌感染的抗生素耐药性和反复感染的增加加剧了致病性大肠杆菌感染。尝试开发针对大肠杆菌的预防策略尚未成功，这主要是由于毒力因子的抗原和遗传变异性大，但也由于病原体逃避免疫系统的机制复杂。在这项工作中，我们阐明了一种新发现的保护性抗原 EsiB 的功能，并描述了它与分泌型免疫球蛋白 A（SIgA）相互作用并损害效应功能的能力。这项工作揭示了大肠杆菌用来颠覆宿主免疫反应并避免中性粒细胞依赖清除的新策略。
