Modeling Barrier Properties of Intestinal Mucus Reinforced with IgG and Secretory IgA against Motile Bacteria
Modeling Barrier Properties of Intestinal Mucus Reinforced with IgG and Secretory IgA against Motile Bacteria
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DOI：
10.1021/acsinfecdis.9b00109
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发表时间：
2019-09-01
影响因子：
5.3
通讯作者：
Lai，Samuel K.
中科院分区：
文献类型：
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作者：
Xu，Feifei;Newby，Jay M.;Lai，Samuel K.
胃肠道(GI)内有一层粘弹性粘液凝胶层，其特征是由缠绕和交联的粘蛋白以及丰富的抗体(Ab)组成的致密网络。分泌型免疫球蛋白A(SIgA)是胃肠道中的主要抗体亚型，是一种具有4个抗原结合域的二聚体分子，能够诱导细菌的有效聚集或凝集。免疫球蛋白是另一种常见的粘膜表面抗体，它可以通过免疫球蛋白抗体Fc和粘蛋白之间的多个弱键将单个病毒与粘蛋白网络进行交联，这一过程被称为粘液捕获。凝集作用与粘液捕集作用在阻止可移动细菌通过粘液渗透方面的相对作用尚不清楚。在这里，我们建立了一个数学模型，该模型考虑了与生理相关的空间维度和时间尺度，抗体与细菌之间以及抗体与粘蛋白之间的结合和解结率，抗体的扩散率，以及活性细菌的滚动运动。我们的模型预测，SIgA和IgG都可以足够的数量和速度在单个细菌的表面积累，以便在单个细菌穿透粘液层之前将它们捕获在粘蛋白中。此外，我们的模型预测，凝集只会适度提高抗体阻止细菌通过粘液渗透的能力。这些结果表明，虽然SIgA在阻止细菌穿透方面是最有效的抗体亚型，但免疫球蛋白G可能是一种实用的粘膜预防和治疗选择。我们的工作提高了对抗体增强粘液屏障属性的机理的理解，并强调了捕获粘液抗体保护粘膜表面运动性病原体的能力。
The gastrointestinal (GI) tract is lined with a layer of viscoelastic mucus gel, characterized by a dense network of entangled and cross-linked mucins together with an abundance of antibodies (Ab). Secretory IgA (sIgA), the predominant Ab isotype in the GI tract, is a dimeric molecule with 4 antigen-binding domains capable of inducing efficient clumping of bacteria, or agglutination. IgG, another common Ab at mucosal surfaces, can cross-link individual viruses to the mucin mesh through multiple weak bonds between IgG-Fc and mucins, a process termed muco-trapping. Relative contributions by agglutination versus muco-trapping in blocking permeation of motile bacteria through mucus remain poorly understood. Here, we developed a mathematical model that takes into account physiologically relevant spatial dimensions and time scales, binding and unbinding rates between Ab and bacteria as well as between Ab and mucins, the diffusivities of Ab, and run-tumble motion of active bacteria. Our model predicts both sIgA and IgG can accumulate on the surface of individual bacteria at sufficient quantities and rates to enable trapping individual bacteria in mucins before they penetrate the mucus layer. Furthermore, our model predicts that agglutination only modestly improves the ability for antibodies to block bacteria permeation through mucus. These results suggest that while sIgA is the most potent Ab isotype overall at stopping bacterial penetration, IgG may represent a practical alternative for mucosal prophylaxis and therapy. Our work improves the mechanistic understanding of Ab-enhanced barrier properties of mucus and highlights the ability for muco-trapping Ab to protect against motile pathogens at mucosal surfaces.