The Role of China in the Global Spread of the Current Cholera Pandemic

Epidemics and pandemics of cholera, a severe diarrheal disease, have occurred since the early 19th century and waves of epidemic disease continue today. Cholera epidemics are caused by individual, genetically monomorphic lineages of Vibrio cholerae: the ongoing seventh pandemic, which has spread globally since 1961, is associated with lineage L2 of biotype El Tor. Previous genomic studies of the epidemiology of the seventh pandemic identified three successive sub-lineages within L2, designated waves 1 to 3, which spread globally from the Bay of Bengal on multiple occasions. However, these studies did not include samples from China, which also experienced multiple epidemics of cholera in recent decades. We sequenced the genomes of 71 strains isolated in China between 1961 and 2010, as well as eight from other sources, and compared them with 181 published genomes. The results indicated that outbreaks in China between 1960 and 1990 were associated with wave 1 whereas later outbreaks were associated with wave 2. However, the previously defined waves overlapped temporally, and are an inadequate representation of the shape of the global genealogy. We therefore suggest replacing them by a series of tightly delineated clades. Between 1960 and 1990 multiple such clades were imported into China, underwent further microevolution there and then spread to other countries. China was thus both a sink and source during the pandemic spread of V. cholerae, and needs to be included in reconstructions of the global patterns of spread of cholera.

自19世纪早期以来，作为严重腹泻类疾病的霍乱已出现多次流行与大流行，且多波疫情至今仍在持续。霍乱流行由霍乱弧菌（Vibrio cholerae）单个基因单态谱系引发：1961年起在全球蔓延的当前第七次霍乱大流行，与埃尔托生物型（biotype El Tor）的L2谱系相关。此前针对第七次大流行流行病学开展的基因组研究，已在L2谱系中鉴定出三个连续亚谱系，分别命名为第1至第3波，它们多次从孟加拉湾向外实现全球扩散。但这些研究未纳入中国的菌株样本，而中国在近数十年间也经历了多起霍乱疫情。本研究对1961年至2010年间在中国分离得到的71株菌株，以及其他来源的8株菌株进行了全基因组测序，并与181株已发表的基因组序列开展比对分析。结果显示，1960年至1990年间中国的霍乱暴发疫情与第1波亚谱系相关，而后续暴发则与第2波亚谱系相关。然而，此前定义的这些波次在时间维度上存在重叠，无法准确反映全球霍乱弧菌基因谱系的演化结构。因此，本研究建议采用一系列界定清晰的进化枝（clade）来替代原有的波次划分体系。1960年至1990年间，多个此类进化枝被引入中国，在国内发生进一步的微演化后又传播至其他国家。由此可见，中国在霍乱弧菌的大流行传播过程中兼具“汇”与“源”的双重角色，因此霍乱全球传播模式的重建研究必须纳入中国的相关数据。