Ecopathogenomics of sexually transmitted infections (EPSTI)

描述（由申请人提供）：在感染部位的战场上，宿主细胞和微生物都采用复杂的信号传导机制和武器来破坏、中和或杀死对方。识别和理解这些感染和疾病的生物标志物是该合作研究中心（CRC）的短期和长期研究目标。预期的影响将是减少全世界人类性传播感染和疾病（STIs & STD）的发病率。这是一个大规模的挑战：在美国，沙眼衣原体（CT）生殖器感染是最常报告的细菌性传染病，估计每年有280万例。同样，每年估计有820，000例淋病奈瑟菌（GC）病例。由这两种病原体引起的感染和合并感染的后遗症是隐蔽的，并且占美国每年750，000例盆腔炎性疾病（PID）的大多数，这是危及生命的异位妊娠和女性输卵管因素不孕症（TFI）的前兆。因此，预防、控制和治疗这些性传播感染的研究将带来广泛的健康和经济效益。我们假设：a）受感染宿主的遗传变异、感染病原体的遗传多样性以及常驻微生物群的组成和功能直接影响STI的演变，并且可以是疾病严重程度或防止STI的生物标志物; B）由宿主、病原体表达或产生的基因、RNA和蛋白，和/或生殖器微生物群是特定类型STI或STD的生物标志物。因此，CRC的目的是确定STI的宿主、病原体和/或微生物群生物标志物，这些生物标志物可以揭示发病机制和治疗或诊断靶点，这些靶点可以用于开发对公共卫生有直接影响的转化性治疗或预防干预措施。为了验证这些假设并实现这些目标，该CRC，“性传播感染的生态病原体组学”（EPSTI），将建立在母CRC，“衣原体生殖道感染的生态病原体组学”，一个以衣原体为中心的计划，奠定了EPSTI的方法和概念基础所获得的数据。在EPSTI中，由多个性伴侣网络组成的STING（STI网络组）将被用来研究人类遗传变异，CT，GC感染和合并感染以及具有不同感染结果的伴侣之间的微生物群组成之间的三角关系。实验方法基本上是一种系统生物学策略，重点是鉴定生殖器/生殖感染和疾病的生物标志物，并且非常适合在临床和公共卫生中的转化应用。这些措施预计将包括根据个人的生物学和微生物组特征对性传播感染和性传播疾病风险最大的个人进行预测性诊断，开发敏感和特异性的即时诊断测试以及高度特异性的疫苗开发目标。

DESCRIPTION (provided by applicant): In the battleground of an infection site, both the host cells and the microbes employ complex signaling mechanisms and weaponry to destabilize, neutralize or kill the other. Identifying and understanding these biomarkers of infection and disease are the short and long-term research goals of this Cooperative Research Center (CRC). The anticipated impact will be to reduce the incidence of sexually transmitted infections and diseases (STIs & STDs) in humans worldwide. This is a large scale challenge: in the United States, Chlamydia trachomatis (CT) genital infections are the most frequently reported bacterial infectious disease with an estimated 2.8M cases yearly. Likewise there are an estimated 820,000 cases of Neisseria gonorrhoeae (GC) each year. The sequelae of infections and co-infections caused by these two pathogens are insidious and account for the majority of the 750,000 annual cases of pelvic inflammatory disease (PID) in the United States, a precursor to life-threatening ectopic pregnancy and tubal factor infertility (TFI) in women. Thus, research to prevent, control and treat these STIs will provide broad health and economic benefits. We hypothesize that: a) the genetic variance of the infected host, the genetic diversity of the infecting pathogen(s), and the composition and function of the resident microbiota directly impact the evolution of STIs and could be biomarkers of disease severity or protection from STIs; b) genes, RNAs and proteins that are expressed or produced by the host, the pathogens, and/or the genital microbiota in response to one another are biomarkers of a specific type of STI or STD. The aim of the CRC is therefore to identify host, pathogen and/or microbiota biomarkers of STIs that may reveal mechanisms of pathogenesis and therapeutic or diagnostic targets that can be exploited for the development of translational curative or prophylactic interventions that have a direct impact in public health. To test these hypotheses and realize these objectives, this CRC, "Eco-Pathogenomics of Sexually Transmitted Infections" (EPSTI), will build on data acquired by the parent CRC, "Eco-Pathogenomics of Chlamydial Reproductive Tract Infection", a Chlamydia-centric program that laid the methodological and conceptual foundations of EPSTI. Within EPSTI, STING (STI Network Groups), consisting of multiple networks of sexual partners, will be leveraged to examine the triangular relationship between human genetic variance, CT, GC infections and co-infections, and microbiota composition among partners with distinct infection outcomes. The experimental approach will essentially be a systems biology strategy focused on the identification of biomarkers of genital/reproductive infection and disease and are eminently amenable to translational applications in clinical and public health. These are expected to include predictive diagnosis for individuals at greatest risk of STI and STD based on their biological and microbiome characteristics, development of sensitive and specific point-of-care diagnostic tests and highly specific targets for vaccine development.