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首页> 外文期刊>BMC Genomics >Murine host response to Neisseria gonorrhoeae upper genital tract infection reveals a common transcriptional signature, plus distinct inflammatory responses that vary between reproductive cycle phases
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Murine host response to Neisseria gonorrhoeae upper genital tract infection reveals a common transcriptional signature, plus distinct inflammatory responses that vary between reproductive cycle phases

机译：鼠宿主对淋病奈瑟氏球菌上生殖道感染的反应显示出共同的转录特征，以及在生殖周期各阶段之间不同的独特炎症反应

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The emergence of fully antimicrobial resistant Neisseria gonorrhoeae has led global public health agencies to identify a critical need for next generation anti-gonococcal pharmaceuticals. The development and success of these compounds will rely upon valid pre-clinical models of gonorrhoeae infection. We recently developed and reported the first model of upper genital tract gonococcal infection. During initial characterization, we observed significant reproductive cycle-based variation in infection outcome. When uterine infection occurred in the diestrus phase, there was significantly greater pathology than during estrus phase. The aim of this study was to evaluate transcriptional profiles of infected uterine tissue from mice in either estrus or diestrus phase in order to elucidate possible mechanisms for these differences. Genes and biological pathways with phase-independent induction during infection showed a chemokine dominant cytokine response to Neisseria gonorrhoeae. Despite general induction being phase-independent, this common anti-gonococcal response demonstrated greater induction during diestrus phase infection. Greater activity of granulocyte adhesion and diapedesis regulators during diestrus infection, particularly in chemokines and diapedesis regulators, was also shown. In addition to a greater induction of the common anti-gonococcal response, Gene Set Enrichment Analysis identified a diestrus-specific induction of type-1 interferon signaling pathways. This transcriptional analysis of murine uterine gonococcal infection during distinct points in the natural reproductive cycle provided evidence for a common anti-gonococcal response characterized by significant induction of granulocyte chemokine expression and high proinflammatory mediators. The basic biology of this host response to N. gonorrhoeae in estrus and diestrus is similar at the pathway level but varies drastically in magnitude. Overlaying this, we observed type-1 interferon induction specifically in diestrus infection where greater pathology is observed. This supports recent work suggesting this pathway has a significant, possibly host-detrimental, function in gonococcal infection. Together these findings lay the groundwork for further examination of the role of interferons in gonococcal infection. Additionally, this work enables the implementation of the diestrus uterine infection model using the newly characterized host response as a marker of pathology and its prevention as a correlate of candidate vaccine efficacy and ability to protect against the devastating consequences of N. gonorrhoeae-associated sequelae.
机译：完全耐药的淋病奈瑟氏球菌的出现促使全球公共卫生机构确定了下一代抗性淋球菌药物的关键需求。这些化合物的开发和成功将取决于淋病杆菌感染的有效临床前模型。我们最近开发并报告了上生殖道淋球菌感染的第一个模型。在初始表征期间，我们观察到感染结局中基于生殖周期的显着变化。当在二头肌期发生子宫感染时，与发情期相比，病理学明显变大。这项研究的目的是评估发情期或发情期小鼠感染的子宫组织的转录谱，以阐明产生这些差异的可能机制。在感染过程中具有阶段无关诱导的基因和生物学途径显示出对淋病奈瑟菌的趋化因子占主导的细胞因子反应。尽管一般诱导是不依赖于相的，但是这种常见的抗性淋球菌反应显示出在二头肌相感染期间的更大诱导。还显示出在二头肌感染期间，特别是在趋化因子和尿布分离调节剂中，粒细胞粘附和尿布分离调节剂的活性更高。除了更大程度地诱导常见的抗性淋球菌反应外，“基因集富集分析”还确定了一种1型干扰素信号传导途径的特定于雌蕊的诱导。小鼠子宫淋球菌感染在自然生殖周期中不同点的转录分析为常见的抗淋球菌反应提供了证据，其特征是明显诱导了粒细胞趋化因子的表达和高促炎介质。该寄主对发情期和双发性淋病奈瑟氏球菌的反应的基本生物学在途径水平上相似，但幅度变化很大。叠加这一点，我们观察到1型干扰素诱导特别是在二头肌感染中，在那里观察到更大的病理。这支持了最近的研究，表明该途径在淋球菌感染中具有重要的，可能对宿主有害的功能。这些发现共同为进一步检查干扰素在淋球菌感染中的作用奠定了基础。此外，这项工作使得能够使用新近表征的宿主反应作为病理学标志物来实施二头肌子宫感染模型，并将其预防与候选疫苗功效和预防淋病奈瑟氏球菌相关后遗症的严重后果相关联。

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