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.作为一种烈性腹泻疾病，霍乱的流行与大流行自19世纪早期便已出现，相关疫情浪潮至今仍未停歇。霍乱的流行由霍乱弧菌（Vibrio cholerae）的单一遗传单型谱系引发：自1961年起在全球蔓延的当前第七次大流行，与埃尔托生物型（biotype El Tor）的L2谱系密切相关。此前针对第七次大流行流行病学开展的基因组学研究，已在L2谱系中鉴定出三个连续的亚谱系，被命名为第1至3波疫情，这些亚谱系曾多次从孟加拉湾向外实现全球扩散。然而，此类研究未纳入中国的相关样本——近数十年来，中国也曾多次暴发霍乱疫情。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株菌株进行了基因组测序，并将其与181个已发表的基因组序列进行了比对分析。分析结果显示，1960年至1990年间中国的霍乱暴发与第1波疫情相关，而1990年后的霍乱暴发则与第2波疫情相关。但此前定义的疫情波在时间维度上存在重叠，无法充分反映全球基因谱系的演化结构。因此，本研究建议用一系列严格界定的进化枝（clades）替代原有的疫情波划分体系。1960年至1990年间，多个此类进化枝被引入中国，在当地发生进一步的微观演化后，又传播至其他国家。因此，在霍乱弧菌的大流行传播过程中，中国既是疫菌的接收汇点也是输出源点，在重建霍乱全球传播模式的研究中，必须将中国纳入考量范围。