Feng Chiguang, Li Jihong, Snyder Greg, Huang Wei, Goldblum Simeon E, Chen Wilbur H, Wang Lai-Xi, McClane Bruce A, Cross Alan S
Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
mBio. 2017 Jun 27;8(3):e00078-17. doi: 10.1128/mBio.00078-17.
Neuraminidases (NAs) are critical virulence factors for several microbial pathogens. With a highly conserved catalytic domain, a microbial NA "superfamily" has been proposed. We previously reported that murine polymorphonuclear leukocyte (PMN) sialidase activity was important in leukocyte trafficking to inflamed sites and that antibodies to NA recognized a cell surface molecule(s), presumed to be a sialidase of eukaryotic origin on interleukin-8-stimulated human and murine PMNs. These antibodies also inhibited cell sialidase activity both and, in the latter instance, We therefore hypothesized that mammalian sialidases share structural homology and epitopes with microbial NAs. We now report that antibodies to one of the isoforms of NA, as well as anti-influenza virus NA serum, recognize human NEU3 but not NEU1 and that antibodies to NA inhibit NEU3 enzymatic activity. We conclude that the previously described microbial NA superfamily extends to human sialidases. Strategies designed to therapeutically inhibit microbial NA may need to consider potential compromising effects on human sialidases, particularly those expressed in cells of the immune system. We previously reported that sialidase activity of human neutrophils plays a critical role in the host inflammatory response. Since the catalytic domains of microbial neuraminidases are highly conserved, we hypothesized that antibodies against neuraminidase might inhibit mammalian sialidase activity. Before the recognition of four mammalian sialidase () isoforms, we demonstrated that anti- neuraminidase antibodies inhibited human and murine sialidase activity and We now show that the antibodies to microbial neuraminidase ( and influenza virus) recognize human NEU3, which is important for neural development and cell signaling. Since many microbes that infect mucosal surfaces express neuraminidase, it is possible that the use of sialidase inhibitors (e.g., zanamivir), might also compromise human sialidase activity critical to the human immune response. Alternatively, sialidase inhibitors may prove useful in the treatment of hyperinflammatory conditions.
神经氨酸酶（NAs）是几种微生物病原体的关键毒力因子。由于具有高度保守的催化结构域，有人提出了一个微生物NA“超家族”。我们之前报道过，小鼠多形核白细胞（PMN）的唾液酸酶活性在白细胞向炎症部位的迁移中很重要，并且针对NA的抗体识别一种细胞表面分子，推测该分子是白细胞介素-8刺激的人和小鼠PMN上真核来源的唾液酸酶。这些抗体还抑制细胞唾液酸酶活性，在后者的情况下，我们因此推测哺乳动物唾液酸酶与微生物NAs具有结构同源性和表位。我们现在报道，针对NA一种同工型的抗体以及抗流感病毒NA血清识别人类NEU3而非NEU1，并且针对NA的抗体抑制NEU3酶活性。我们得出结论，先前描述的微生物NA超家族延伸至人类唾液酸酶。旨在治疗性抑制微生物NA的策略可能需要考虑对人类唾液酸酶的潜在不利影响，特别是那些在免疫系统细胞中表达的唾液酸酶。我们之前报道过人类中性粒细胞的唾液酸酶活性在宿主炎症反应中起关键作用。由于微生物神经氨酸酶的催化结构域高度保守，我们推测针对神经氨酸酶的抗体可能抑制哺乳动物唾液酸酶活性。在识别出四种哺乳动物唾液酸酶（）同工型之前，我们证明抗神经氨酸酶抗体抑制人和小鼠唾液酸酶活性，并且我们现在表明针对微生物神经氨酸酶（和流感病毒）的抗体识别对神经发育和细胞信号传导很重要的人类NEU3。由于许多感染粘膜表面的微生物表达神经氨酸酶，使用唾液酸酶抑制剂（例如扎那米韦）也可能损害对人类免疫反应至关重要的人类唾液酸酶活性。或者，唾液酸酶抑制剂可能被证明对治疗过度炎症状态有用。
