Infectious Diseases of Poverty. 2024, 13:43
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https://mp.weixin.qq.com/s/Do-Ft3dMg8w7OBEaRoRfpA
近 30 年来，登革热在全球的快速蔓延和病例数的持续上升，对全球公共卫生体系构成了严峻挑战。然而，我们对基于基因遗传尺度的登革病毒（DENV）流行，尤其是跨区域传播扩散模式的认知仍很有限。本研究旨在通过系统动态发育研究，以中国广东 DENV-1 的流行传播为例，融入病原体入侵-定殖-扩散致害进程的入侵生物学理论，揭示 DENV-1 在广东的入侵和扩散模式，重点阐释 DENV-1 跨区域流行传播规律，为登革热的防控提供新见解。
基于该研究团队前期建立的 DENV-1 全球统一基因分型框架，研究发现，在中国流行的 DENV-1 毒株分属 22 个基因亚型和 38 个基因分支。其中 7 个基因分支（1E1、1H4、1J7、1K1、1L1、1L2 和 5C1）所包含的毒株数量超过总数的 80%，被命名为“需重点关注基因分支”（Clades of Concern，COCs）。
1990—2019年，病例、基因分支、传播基因簇（transmission clusters）和序列的数量分析呈现一致的2～4年的周期性波动模式，峰值出现在2002、2004、2006、2010、2013、2017和2019，其中在2013年前后的增长趋势最为显著。
基于地点离散状态下贝叶斯随机搜索变量选择（Bayesian stochastic search variable selection，BSSVS）进行系统地理发生推断，结果显示，7个DENV-1 COCs传入中国的主要来源是湄公河流域、东南亚、南亚次大陆和大洋洲区域。其中，马来西亚、泰国和新加坡是最活跃的输入来源地。中国西南部的边境城市和东南沿海城市是主要的输入入境地，广州、佛山等广东省城市群是DENV-1在中国的流行传播中需要高度关注的地区。
基因组系统动态发育结合流行病学分析表明，2013—2015年DENV-1 5C1的一个传播基因簇5C1-CN4和2014—2015年1K1的一个传播基因簇1K1-CN6在广州地区存在明显的局部性连年传播进程。
以中国广东DENV-1流行传播为例，解析登革热从流行区逐渐向非流行区传播的流行格局，融合入侵生物学理论的病原体入侵-定殖-扩散致害的渐变进程，“在亚热带和温带地区跨年越冬的DENV本地传播链的存在”可视为DENV入侵传播过程中阶段划分的重要事件（图5）。
第一阶段 多点、多次的DENV连年传入。
第二阶段 定殖往往发生在DENV传入后的一段时间内，如发现跨年尤其是发生本地局部越冬传播链时，需高度预警输入性病原体已有定殖发生。
第三阶段 输入性病原体若成功实现定殖后，就可能引起进一步的本地扩散与传播，提示该地区的DENV流行模式转入复杂化，并呈现由简单的输入性“epidemic”向“epidemic”与“endemic”并行，并可能最终形成“endemic”即本土化的流行特征。
在该研究团队前期所建立的DENV-1全球统一基因分型框架的基础上，该研究进一步系统分析了DENV-1在中国大陆的入侵和扩散过程，揭示了在中国流行的DENV-1种群遗传多样性、输入源多源性及其流行的周期性动态，并基于病原体入侵-定殖-扩散致害进程的入侵生物学理论，重点阐释了DENV跨区域传播规律，为登革热的早期预警、预防控制以及遏制DENV在中国乃至全球的快速扩散提供了新见解。
The strong invasiveness and rapid expansion of dengue virus (DENV) pose a great challenge to global public health. However, dengue epidemic patterns and mechanisms at a genetic scale, particularly in term of crossborder transmissions, remain poorly understood. Importation is considered as the primary driver of dengue outbreaks in China, and since 1990 a frequent occurrence of large outbreaks has been triggered by the imported cases and subsequently spread to the western and northern parts of China. Therefore, this study aims to systematically reveal the invasion and difusion patterns of DENV-1 in Guangdong, China from 1990 to 2019.
These analyses were performed on 179 newly assembled genomes from indigenous dengue cases in Guangdong, China and 5152 E gene complete sequences recorded in Chinese mainland. The genetic population structure and epidemic patterns of DENV-1 circulating in Chinese mainland were characterized by phylogenetics, phylogeography, phylodynamics based on DENV-1 E-gene-based globally unifed genotyping framework.
Multiple serotypes of DENV were co-circulating in Chinese mainland, particularly in Guangdong and Yunnan provinces. A total of 189 transmission clusters in 38 clades belonging to 22 subgenotypes of genotype I, IV and V of DENV-1 were identifed, with 7 Clades of Concern (COCs) responsible for the large outbreaks since 1990.The epidemic periodicity was inferred from the data to be approximately 3 years. Dengue transmission events mainly occurred from Great Mekong Subregion-China (GMS-China), Southeast Asia (SEA), South Asia Subcontinent (SASC), and Oceania (OCE) to coastal and land border cities respectively in southeastern and southwestern China. Specially, Guangzhou was found to be the most dominant receipting hub, where DENV-1 difused to other cities within the province and even other parts of the country. Genome phylogeny combined with epidemiological investigation demonstrated a clear local consecutive transmission process of a 5C1 transmission cluster (5C1-CN4) of DENV-1 in Guangzhou from 2013 to 2015, while the two provinces of Guangdong and Yunnan played key roles in ongoing transition of dengue epidemic patterns. In contextualizing within Invasion Biology theories, we have proposed a derived three-stage model encompassing the stages of invasion, colonization, and dissemination, which is supposed to enhance our understanding of dengue spreading patterns.
This study demonstrates the invasion and difusion process of DENV-1 in Chinese mainland within a global genotyping framework, characterizing the genetic diversities of viral populations, multiple sources of importation, and periodic dynamics of the epidemic. These fndings highlight the potential ongoing transition trends from epidemic to endemic status ofering a valuable insight into early warning, prevention and control of rapid spreading of dengue both in China and worldwide.
