Study of Neisseria gonorrhoeae adaptability to impact microbial survival and host response inside human neutrophil phagosomes

淋病奈瑟菌(Ng)是一种细胞内和人类特有的病原体，可引起性行为 传播疾病淋病。淋病的一个特征是继发于 人多形核白细胞(HPMN)募集。正常情况下，hPMN摄取和 杀死hPMN吞噬体内的入侵微生物，然后经过吞噬诱导的hPMN细胞 死亡(PICD)作为炎症程序分解的一部分(1，2)。作为一种成功的病原体，Ng Not 不仅能在hPMN吞噬体内存活和复制，还能延缓hPMN(3，4)的PICD。如何Ng 通过存活hPMN杀伤和延迟hPMN HAS的PICD来破坏正常的hPMN介导的宿主防御 还没有得到澄清。 候选人的目标是了解Ng在hPMN中的适应性的机制 吞噬小体。候选人的假设是：(1)乙酰化是翻译后的一种 对Ng存活和(2)Ng从吞噬小体中逃逸至关重要的新序列蛋白的修饰 HPMN信号通路的修饰延缓了正常情况下hPMN的程序性细胞死亡 吞噬作用。为了检验这些假设，候选人设定了两个具体目标： 目的1：确定Ne-赖氨酸乙酰化作为Ng存活的调节决定因素的作用 在hPMN吞噬体内。 目的2：研究NGAG00012对hPMN吞噬小体的影响及对hPMN后续细胞命运的影响 喂了Ng。 这一建议是创新的，因为候选人使用了有偏见的(诱变和质谱分析)和 无偏(转录组分析)方法阐明hPMN吞噬体内的Ng生物学 与临床相关的背景。Ng对抗生素耐药性的增加使淋病得到了有效的治疗 这几乎是不可能的，因此必须了解Ng在hPMN中的行为。这项建议是 重要的是，它的发现将提供更好的理解Ng如何在hPMN吞噬小体中 存活下来，因此是淋病新的治疗干预措施的理性选择。

Neisseria gonorrhoeae (Ng) is an intracellular and exclusively human pathogen that causes the sexually transmitted disease gonorrhea. A hallmark of gonorrhea is the exuberant inflammation secondary to recruitment of human polymorphonuclear leukocytes (hPMN). Under normal circumstances, hPMN ingest and kill invading microbes inside hPMN phagosomes, after which spent hPMN undergo phagocytosis-induced cell death (PICD) as part of the programmed resolution of inflammation (1, 2). As a successful pathogen, Ng not only survives and replicates inside hPMN phagosomes, but also delay PICD of hPMN (3, 4). How Ng undermines normal hPMN-mediated host defense by surviving hPMN killing and delaying PICD of hPMN has not been elucidated. The candidate’s objective is to understand the mechanisms underpinning the adaptability of Ng inside hPMN phagosomes. The candidate’s hypotheses are that (1) that acetylation is one of the post-translational modifications of neisserial proteins that is critical to Ng survival and (2) that the Ng escape from phagosomes and modification of hPMN signaling pathways delay programmed cell death of hPMN that normally follows phagocytosis. To test these hypotheses, the candidate has created two specific aims: Aim 1: To determine the role of Ne-lysine acetylation as a regulatory determinant for the survival of Ng inside hPMN phagosomes. Aim 2: To determine the effect of NGAG00012 on hPMN phagosomes and subsequent cell fate of hPMN fed Ng. This proposal is innovative because the candidate uses biased (mutagenesis and mass spectrometry) and unbiased (transcriptome analysis) approach to elucidate Ng biology within the phagosomes of hPMN, a clinically relevant context. The rise in resistance of Ng to antibiotics has made effective treatment for gonorrhea nearly impossible, thus making it imperative to understand Ng’s behavior inside hPMN. This proposal is significant in that its discoveries will provide better understanding of how Ng inside hPMN phagosomes survives and thus a rational for novel therapeutic intervention for gonorrhea.