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Abstract：
Gonorrhea, caused by the bacterium Neisseria gonorrhoeae (Gc), is characterized by neutrophilic influx to infection sites. Gc has developed mechanisms to resist killing by neutrophils that include modifications to its surface lipooligosaccharide (LOS). One such LOS modification is sialylation: Gc sialylates its terminal LOS sugars with cytidine-5\'-monophosphate-N-acetylneuraminic acid, which is scavenged from the host using LOS sialyltransferase (Lst) since Gc cannot make its sialic acid. Sialylation enables sensitive strains of Gc to resist complement-mediated killing in a serum-dependent manner. However, little is known about the contribution of sialylation to complement-independent, direct Gc-neutrophil interactions. In the absence of complement, we found sialylated Gc expressing opacity-associated (Opa) proteins decreased the oxidative burst and granule exocytosis from primary human neutrophils. In addition, sialylated Opa+ Gc survived better than vehicle treated or Δlst Gc when challenged with neutrophils. However, Gc sialylation did not significantly affect Opa-dependent association with or internalization of Gc by neutrophils. Previous studies have implicated sialic acid-binding immunoglobulin-type lectins (Siglecs) in modulating neutrophil interactions with sialylated Gc. Blocking neutrophil Siglecs with antibodies that bind to their extracellular domains eliminated the ability of sialylated Opa+ Gc to suppress the oxidative burst and resist neutrophil killing. These findings highlight a new role for sialylation in Gc evasion of human innate immunity, with implications for the development of vaccines and therapeutics for gonorrhea.
OBJECTIVE: Neisseria gonorrhoeae, the bacterium that causes gonorrhea, is an urgent global health concern due to increasing infection rates, widespread antibiotic resistance, and its ability to thwart protective immune responses. The mechanisms by which Gc subverts protective immune responses remain poorly characterized. One way N. gonorrhoeae evades human immunity is by adding sialic acid that is scavenged from the host onto its lipooligosaccharide, using the sialyltransferase Lst. Here, we found that sialylation enhances N. gonorrhoeae survival from neutrophil assault and inhibits neutrophil activation, independently of the complement system. Our results implicate bacterial binding of sialic acid-binding lectins (Siglecs) on the neutrophil surface, which dampens neutrophil antimicrobial responses. This work identifies a new role for sialylation in protecting N. gonorrhoeae from cellular innate immunity, which can be targeted to enhance the human immune response in gonorrhea.
OBJECTIVE: Neisseria gonorrhoeae, the bacterium that causes gonorrhea, is an urgent global health concern due to increasing infection rates, widespread antibiotic resistance, and its ability to thwart protective immune responses. The mechanisms by which Gc subverts protective immune responses remain poorly characterized. One way N. gonorrhoeae evades human immunity is by adding sialic acid that is scavenged from the host onto its lipooligosaccharide, using the sialyltransferase Lst. Here, we found that sialylation enhances N. gonorrhoeae survival from neutrophil assault and inhibits neutrophil activation, independently of the complement system. Our results implicate bacterial binding of sialic acid-binding lectins (Siglecs) on the neutrophil surface, which dampens neutrophil antimicrobial responses. This work identifies a new role for sialylation in protecting N. gonorrhoeae from cellular innate immunity, which can be targeted to enhance the human immune response in gonorrhea.
摘要：
淋病,由淋病奈瑟菌（Gc）引起，以嗜中性粒细胞流入感染部位为特征。Gc已开发出抵抗嗜中性粒细胞杀伤的机制，包括对其表面脂寡糖（LOS）的修饰。一种这样的LOS修饰是唾液酸化：Gc用胞苷-5'-单磷酸-N-乙酰神经氨酸将其末端LOS糖唾液酸化，使用LOS唾液酸转移酶（Lst）从宿主中清除，因为Gc不能产生唾液酸。唾液酸化使得敏感的Gc菌株能够以血清依赖性方式抵抗补体介导的杀伤。然而,关于唾液酸化对补体独立的贡献知之甚少，直接的Gc-中性粒细胞相互作用。如果没有补语,我们发现,唾液酸化的Gc表达不透明相关(Opa)蛋白降低了原发性人类中性粒细胞的氧化爆发和颗粒胞吐作用.此外,当用嗜中性粒细胞攻击时，唾液酸化的OpaGc比媒介物处理或ΔlstGc存活更好。然而,Gc唾液酸化没有显着影响嗜中性粒细胞与Gc的Opa依赖性关联或内化。先前的研究涉及唾液酸结合免疫球蛋白型凝集素（Siglecs）在调节嗜中性粒细胞与唾液酸化Gc的相互作用中。用与它们的胞外结构域结合的抗体阻断嗜中性粒细胞Siglecs消除了唾液酸化的Opa+Gc抑制氧化爆发和抵抗嗜中性粒细胞杀伤的能力。这些发现强调了唾液酸化在人类先天免疫Gc逃避中的新作用，对淋病疫苗和疗法的开发具有重要意义。
目的：淋病奈瑟菌，导致淋病的细菌，由于感染率上升，这是一个紧迫的全球健康问题，广泛的抗生素耐药性，以及它阻止保护性免疫反应的能力。Gc颠覆保护性免疫反应的机制仍然缺乏表征。淋病奈瑟菌逃避人体免疫力的一种方法是将从宿主中清除的唾液酸添加到其脂寡糖中，使用唾液酸转移酶Lst.这里,我们发现唾液酸化增强淋病奈瑟菌从中性粒细胞攻击中存活并抑制中性粒细胞活化,独立于互补系统。我们的结果暗示唾液酸结合凝集素（Siglecs）在中性粒细胞表面的细菌结合，抑制中性粒细胞抗菌反应。这项工作确定了唾液酸化在保护淋病奈瑟菌免受细胞先天免疫的新作用，可以有针对性地增强淋病中的人体免疫反应。
目的：淋病奈瑟菌，导致淋病的细菌，由于感染率上升，这是一个紧迫的全球健康问题，广泛的抗生素耐药性，以及它阻止保护性免疫反应的能力。Gc颠覆保护性免疫反应的机制仍然缺乏表征。淋病奈瑟菌逃避人体免疫力的一种方法是将从宿主中清除的唾液酸添加到其脂寡糖中，使用唾液酸转移酶Lst.这里,我们发现唾液酸化增强淋病奈瑟菌从中性粒细胞攻击中存活并抑制中性粒细胞活化,独立于互补系统。我们的结果暗示唾液酸结合凝集素（Siglecs）在中性粒细胞表面的细菌结合，抑制中性粒细胞抗菌反应。这项工作确定了唾液酸化在保护淋病奈瑟菌免受细胞先天免疫的新作用，可以有针对性地增强淋病中的人体免疫反应。
