Wu Shang-Chuen, Ho Alex D, Kamili Nourine A, Wang Jianmei, Murdock Kaleb L, Cummings Richard D, Arthur Connie M, Stowell Sean R
Joint Program in Transfusion Medicine, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.
Center for Transfusion Medicine and Cellular Therapies, Emory University School of Medicine, Atlanta, GA, United States.
Front Microbiol. 2021 Oct 8;12:731026. doi: 10.3389/fmicb.2021.731026. eCollection 2021.
While adaptive immunity enables the recognition of a wide range of microbial antigens, immunological tolerance limits reactively toward self to reduce autoimmunity. Some bacteria decorate themselves with self-like antigens as a form of molecular mimicry to limit recognition by adaptive immunity. Recent studies suggest that galectin-4 (Gal-4) and galectin-8 (Gal-8) may provide a unique form of innate immunity against molecular mimicry by specifically targeting microbes that decorate themselves in self-like antigens. However, the binding specificity and antimicrobial activity of many human galectins remain incompletely explored. In this study, we defined the binding specificity of galectin-3 (Gal-3), the first galectin shown to engage microbial glycans. Gal-3 exhibited high binding toward mammalian blood group A, B, and αGal antigens in a glycan microarray format. In the absence of the N-terminal domain, the C-terminal domain of Gal-3 (Gal-3C) alone exhibited a similar overall binding pattern, but failed to display the same level of binding for glycans over a range of concentrations. Similar to the recognition of mammalian glycans, Gal-3 and Gal-3C also specifically engaged distinct microbial glycans isolated and printed in a microarray format, with Gal-3 exhibiting higher binding at lower concentrations toward microbial glycans than Gal-3C. Importantly, Gal-3 and Gal-3C interactions on the microbial microarray accurately predicted actual interactions toward intact microbes, with Gal-3 and Gal-3C displaying carbohydrate-dependent binding toward distinct strains of and that express mammalian-like antigens, while failing to recognize similar strains that express unrelated antigens. While both Gal-3 and Gal-3C recognized specific strains of and , only Gal-3 was able to exhibit antimicrobial activity even when evaluated at higher concentrations. These results demonstrate that while Gal-3 and Gal-3C specifically engage distinct mammalian and microbial glycans, Gal-3C alone does not possess antimicrobial activity.
虽然适应性免疫能够识别多种微生物抗原，但免疫耐受会限制对自身的反应性，以减少自身免疫。一些细菌会用类似自身的抗原装饰自己，作为一种分子模拟形式，以限制适应性免疫的识别。最近的研究表明，半乳糖凝集素-4（Gal-4）和半乳糖凝集素-8（Gal-8）可能通过特异性靶向那些用类似自身抗原装饰自己的微生物，提供一种独特的天然免疫形式来对抗分子模拟。然而，许多人类半乳糖凝集素的结合特异性和抗菌活性仍未得到充分探索。在本研究中，我们确定了半乳糖凝集素-3（Gal-3）的结合特异性，它是首个被证明能与微生物聚糖结合的半乳糖凝集素。Gal-3在聚糖微阵列中对哺乳动物A、B血型抗原和αGal抗原表现出高结合力。在没有N端结构域的情况下，单独的Gal-3的C端结构域（Gal-3C）表现出相似的总体结合模式，但在一系列浓度范围内对聚糖的结合水平未能达到相同程度。与对哺乳动物聚糖的识别类似，Gal-3和Gal-3C也特异性地与以微阵列形式分离和打印的不同微生物聚糖结合，Gal-3在较低浓度下对微生物聚糖的结合力高于Gal-3C。重要的是，Gal-3和Gal-3C在微生物微阵列上的相互作用准确预测了对完整微生物的实际相互作用，Gal-3和Gal-3C对表达类似哺乳动物抗原的不同菌株的 和 表现出碳水化合物依赖性结合，而无法识别表达无关抗原的类似菌株。虽然Gal-3和Gal-3C都能识别 和 的特定菌株，但即使在较高浓度下评估，只有Gal-3能够表现出抗菌活性。这些结果表明，虽然Gal-3和Gal-3C特异性地与不同的哺乳动物和微生物聚糖结合，但单独的Gal-3C不具有抗菌活性。
