Immunology, molecular biology and control of flaviviruses (Dengue and Zika)

黄病毒登革热和寨卡是世界上大部分热带和亚热带地区的地方病。一项估计表明，登革热由伊蚊传播，每年感染3.9亿人，其中9600万人临床表现（疾病严重程度）。另一项关于登革热流行的研究估计，128个国家的39亿人面临感染登革热病毒的风险。虽然寨卡病毒于20世纪50年代首次被发现，但2015年在南美洲爆发的一次疫情引起了全球关注，在这次疫情期间，出生缺陷儿童的病例显著增加。在新加坡等地，可以看到登革热传播的效率，在这些地方，这些蚊子的数量非常少（伊蚊场所指数不到1%，几乎没有发现受感染的蚊子），但发病率很高（通常每年每10万居民报告200多例病例），2013年有23,000多人住院（人口为550万）。尽管登革病毒是研究最多的病毒之一，但流行病学动态的一些关键成分尚不清楚。例如;蚊子在其两周（和两个进食期）的生命周期中通常只飞行150米，登革热感染患者通常仅在3至6天（发烧期间）被蚊子传染。最近广泛的研究集中在解释蚊子数量与天气变量的关系，并将其与疾病发病率联系起来，但将这些知识与病毒分子流行病学相结合的进一步工作可能会揭示疾病如何在人与人之间传播的更精确细节。下一代测序技术可以对病毒爆发进行系统发育分析，可以揭示爆发的途径，还可以检测可能与新疾病表型相关或影响分子诊断的突变。因此，这些可以用来推断传播动力学。该项目将利用一个来自越南的全面监测队列，实时跟踪登革热疫情、家庭聚集性病例，并获取可用于分子分型的血液样本以及血清学数据。综合起来，这些数据将使数学模型测试和改进；同时也启动了一个现场站点，以后可以用于干预。我将首先专注于开发和使用分子检测技术来诊断和排序病毒。由此产生的数据将用于推断传播途径以及病毒如何对免疫压力作出反应。

The flaviviruses Dengue and Zika are endemic to much of the tropical and sub-tropical areas of the world. Spread by Aedes mosquitos, one estimate indicates 390 million dengue infections per year, of which 96 million manifest clinically (with any severity of disease). Another study, of the prevalence of dengue, estimates that 3.9 billion people, in 128 countries, are at risk of infection with dengue viruses. Although Zika virus was first identified in the 1950s it was an outbreak in 2015 in South America which brought it to global attention, during this outbreak there was a marked increase in cases of children born with birth defects. The efficiency of Dengue disease transmission can be seen in places such as Singapore, where very low numbers of these mosquitos can be found (Aedes premises index of less than 1% and virtually no infected mosquitos identified) and yet incidence rates are high (typically more than 200 cases notified per year per 100,000 residents) and in 2013 there were more than 23,000 hospitalizations (for a population of 5.5 million).Despite Dengue virus being one of the most studied viruses, some critical components of the epidemiology dynamics are unknown. For example; the mosquito typically only flies 150m in its life time of two weeks (and two feeding periods) and dengue infected patients are typically only contagious to the mosquito for 3 to 6 days (during the fever stage). Extensive recent research has concentrated on explaining mosquito numbers in relation to weather variables and correlating this to disease incidence, but further work integrating this knowledge with viral molecular epidemiology is likely to reveal more precise details of how the disease spreads from person to person.Next-generation sequencing technologies can allow phylogenetic analysis of viral outbreaks, can reveal the path of the outbreak and additionally can detect mutations that may be associated with new disease phenotypes or affect molecular diagnostics. These can be used to therefore infer transmission dynamics. This project will utilize a comprehensively monitored cohort from Vietnam to follow real time dengue outbreaks, household clusters of cases and obtain blood samples that will permit molecular typing, together with serological data. Taken together, this data will enable mathematical model testing and refinement; while also initiating a field site that could later be used for interventions.I will initially be focussing on developing and using molecular detection techniques to diagnose and sequence the virus. Data generated by this will then be used to infer routes of transmission as well as how the virus responds to immunological pressures.