Schwarz Flavio, Landig Corinna S, Siddiqui Shoib, Secundino Ismael, Olson Joshua, Varki Nissi, Nizet Victor, Varki Ajit
Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA, USA.
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
EMBO J. 2017 Mar 15;36(6):751-760. doi: 10.15252/embj.201695581. Epub 2017 Jan 18.
Paired immune receptors display near-identical extracellular ligand-binding regions but have intracellular sequences with opposing signaling functions. While inhibitory receptors dampen cellular activation by recognizing self-associated molecules, the functions of activating counterparts are less clear. Here, we studied the inhibitory receptor Siglec-11 that shows uniquely human expression in brain microglia and engages endogenous polysialic acid to suppress inflammation. We demonstrated that the human-specific pathogen K1 uses its polysialic acid capsule as a molecular mimic to engage Siglec-11 and escape killing. In contrast, engagement of the activating counterpart Siglec-16 increases elimination of bacteria. Since mice do not have paired Siglec receptors, we generated a model by replacing the inhibitory domain of mouse Siglec-E with the activating module of Siglec-16. Siglec-E16 enhanced proinflammatory cytokine expression and bacterial killing in macrophages and boosted protection against intravenous bacterial challenge. These data elucidate uniquely human interactions of a pathogen with Siglecs and support the long-standing hypothesis that activating counterparts of paired immune receptors evolved as a response to pathogen molecular mimicry of host ligands for inhibitory receptors.
配对免疫受体具有几乎相同的细胞外配体结合区域，但细胞内序列具有相反的信号传导功能。抑制性受体通过识别自身相关分子来抑制细胞活化，而活化性受体的功能则不太清楚。在这里，我们研究了抑制性受体唾液酸结合免疫球蛋白样凝集素11（Siglec-11），它在脑小胶质细胞中呈现独特的人类表达，并与内源性多唾液酸结合以抑制炎症。我们证明，人类特异性病原体K1利用其多唾液酸荚膜作为分子模拟物来结合Siglec-11并逃避杀伤。相比之下，活化性受体Siglec-16的结合增加了细菌的清除。由于小鼠没有配对的Siglec受体，我们通过用Siglec-16的活化模块替换小鼠Siglec-E的抑制结构域构建了一个模型。Siglec-E16增强了巨噬细胞中促炎细胞因子的表达和细菌杀伤能力，并增强了对静脉内细菌攻击的保护作用。这些数据阐明了病原体与Siglec的独特人类相互作用，并支持了一个长期存在的假设，即配对免疫受体的活化性受体是作为对病原体对宿主配体进行分子模拟以结合抑制性受体的反应而进化的。
