Antibodies Damage the Resilience of Fimbriae, Causing Them To Be Stiff and Tangled.
Antibodies Damage the Resilience of Fimbriae, Causing Them To Be Stiff and Tangled.
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抗体会损害菌毛的弹性，导致它们变得僵硬和缠结。
DOI：
10.1128/jb.00665-16
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发表时间：
2017
影响因子：
3.2
通讯作者：
Andersson,Magnus
中科院分区：
文献类型：
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作者：
Singh,Bhupender;Mortezaei,Narges;Savarino,StephenJ;Uhlin,BerntEric;Bullitt,Esther;Andersson,Magnus
由于粘附菌毛是许多致病性革兰氏阴性菌的主要毒力因子，因此它们也是抗体的潜在靶点。菌毛通常是启动导致疾病的定殖所需的，并且它们作为粘附细胞器的成功在于它们启动和维持细菌附着于上皮细胞的能力。伞的能力，以解开和重绕其螺旋丝大概减少其脱离组织表面的剪切力，伴随着显着的流体流动。因此，通过抑制这种弹性来破坏功能性菌毛应该具有很高的用作预防疾病的疫苗的潜力。在这项研究中，我们表明，菌毛弹性的两个特征的生物力学特征，即，延伸力和延伸长度，显着改变的菌毛抗体的结合。所研究的菌毛通常在肠源性大肠杆菌上表达，这是大肠杆菌病的主要原因。这种生物力学性质的改变在识别主要菌毛蛋白亚基的二价多克隆抗菌毛抗体中观察到，但在这些抗体的Fab片段中没有观察到。因此，我们提出，结合抗体破坏自然菌毛在力的作用下解旋的机制是通过将螺旋丝的层夹在一起，从而增加它们的刚度并降低它们在流体流动期间的弹性。此外，我们提出抗体通过二价结合缠结菌毛，即，通过与两个单独的菌毛结合并将它们连接在一起。使用抗体来破坏菌毛的物理性质通常可适用于大量依赖于这些表面粘附分子作为基本毒力因子的革兰氏阴性细菌。重要我们的研究表明，定植因子抗原I（CFA/I）和大肠杆菌表面抗原2（CS2）菌毛的弹性，它们是目前疫苗开发的靶点，在抗菌毛抗体的存在下会受到严重损害。目前尚不清楚在产肠毒素大肠杆菌（ETEC）附着到上皮表面后，体液免疫系统如何特异性地中断感染。我们的研究表明，免疫球蛋白，除了其在适应性免疫中的作用，可以机械损伤表面附着的ETEC的菌毛的弹性，从而揭示了一种新的作用模式。我们的数据表明，抗体涂层粘附和自由浮动的细菌，阻碍菌毛的弹性机制。进一步阐明这一可能的机制可能会为开发和完善ETEC腹泻预防性疫苗提供信息。
As adhesion fimbriae are a major virulence factor for many pathogenic Gram-negative bacteria, they are also potential targets for antibodies. Fimbriae are commonly required for initiating the colonization that leads to disease, and their success as adhesion organelles lies in their ability to both initiate and sustain bacterial attachment to epithelial cells. The ability of fimbriae to unwind and rewind their helical filaments presumably reduces their detachment from tissue surfaces with the shear forces that accompany significant fluid flow. Therefore, the disruption of functional fimbriae by inhibiting this resilience should have high potential for use as a vaccine to prevent disease. In this study, we show that two characteristic biomechanical features of fimbrial resilience, namely, the extension force and the extension length, are significantly altered by the binding of antibodies to fimbriae. The fimbriae that were studied are normally expressed on enterotoxigenic Escherichia coli, which are a major cause of diarrheal disease. This alteration in biomechanical properties was observed with bivalent polyclonal antifimbrial antibodies that recognize major pilin subunits but not with the Fab fragments of these antibodies. Thus, we propose that the mechanism by which bound antibodies disrupt the uncoiling of natural fimbria under force is by clamping together layers of the helical filament, thereby increasing their stiffness and reducing their resilience during fluid flow. In addition, we propose that antibodies tangle fimbriae via bivalent binding, i.e., by binding to two individual fimbriae and linking them together. Use of antibodies to disrupt physical properties of fimbriae may be generally applicable to the large number of Gram-negative bacteria that rely on these surface-adhesion molecules as an essential virulence factor.IMPORTANCEOur study shows that the resiliency of colonization factor antigen I (CFA/I) and coli surface antigen 2 (CS2) fimbriae, which are current targets for vaccine development, can be compromised significantly in the presence of antifimbrial antibodies. It is unclear how the humoral immune system specifically interrupts infection after the attachment of enterotoxigenic Escherichia coli (ETEC) to the epithelial surface. Our study indicates that immunoglobulins, in addition to their well-documented role in adaptive immunity, can mechanically damage the resilience of fimbriae of surface-attached ETEC, thereby revealing a new mode of action. Our data suggest a mechanism whereby antibodies coat adherent and free-floating bacteria to impede fimbrial resilience. Further elucidation of this possible mechanism is likely to inform the development and refinement of preventive vaccines against ETEC diarrhea.