Center for Microbial Genetics and Genomics, Northern Arizona University, Flagstaff, Arizona, USA.
mBio. 2013 Feb 12;4(1):e00623-12. doi: 10.1128/mBio.00623-12.
A cluster of human plague cases occurred in the seaport city of Mahajanga, Madagascar, from 1991 to 1999 following 62 years with no evidence of plague, which offered insights into plague pathogen dynamics in an urban environment. We analyzed a set of 44 Mahajanga isolates from this 9-year outbreak, as well as an additional 218 Malagasy isolates from the highland foci. We sequenced the genomes of four Mahajanga strains, performed whole-genome sequence single-nucleotide polymorphism (SNP) discovery on those strains, screened the discovered SNPs, and performed a high-resolution 43-locus multilocus variable-number tandem-repeat analysis of the isolate panel. Twenty-two new SNPs were identified and defined a new phylogenetic lineage among the Malagasy isolates. Phylogeographic analysis suggests that the Mahajanga lineage likely originated in the Ambositra district in the highlands, spread throughout the northern central highlands, and was then introduced into and became transiently established in Mahajanga. Although multiple transfers between the central highlands and Mahajanga occurred, there was a locally differentiating and dominant subpopulation that was primarily responsible for the 1991-to-1999 Mahajanga outbreaks. Phylotemporal analysis of this Mahajanga subpopulation revealed a cycling pattern of diversity generation and loss that occurred during and after each outbreak. This pattern is consistent with severe interseasonal genetic bottlenecks along with large seasonal population expansions. The ultimate extinction of plague pathogens in Mahajanga suggests that, in this environment, the plague pathogen niche is tenuous at best. However, the temporary large pathogen population expansion provides the means for plague pathogens to disperse and become ecologically established in more suitable nonurban environments.
Maritime spread of plague led to the global dissemination of this disease and affected the course of human history. Multiple historical plague waves resulted in massive human mortalities in three classical plague pandemics: Justinian (6th and 7th centuries), Middle Ages (14th to 17th centuries), and third (mid-1800s to the present). Key to these events was the pathogen's entry into new lands by "plague ships" via seaport cities. Although initial disease outbreaks in ports were common, they were almost never sustained for long and plague pathogens survived only if they could become established in ecologically suitable habitats. Although plague pathogens' ability to invade port cities has been essential for intercontinental spread, these regions have not proven to be a suitable long-term niche. The disease dynamics in port cities such as Mahajanga are thus critical to plague pathogen amplification and dispersal into new suitable ecological niches for the observed global long-term maintenance of plague pathogens.
1991 年至 1999 年，马达加斯加海港城市马任加出现了一组人间鼠疫病例，此前 62 年均无鼠疫证据，这为城市环境中的鼠疫病原体动态提供了深入了解。我们分析了来自这 9 年暴发的 44 株马任加分离株，以及来自高地焦点的另外 218 株马达加斯加分离株。我们对 4 株马任加菌株进行了基因组测序，对这些菌株进行了全基因组序列单核苷酸多态性（SNP）发现，筛选发现的 SNP，并对分离株进行了高分辨率的 43 个基因座多位点可变数串联重复分析。确定了 22 个新的 SNP，并在马达加斯加分离株中定义了一个新的系统发育谱系。系统地理分析表明，马任加谱系可能起源于高地的安布希特拉地区，传播到北部中央高地，然后传入并在马任加短暂建立。尽管中央高地和马任加之间发生了多次转移，但存在一个局部分化和占主导地位的亚群，主要负责 1991 年至 1999 年的马任加暴发。对该马任加亚群的系统发育时间分析表明，多样性的产生和丧失存在周期性模式，发生在每次暴发期间和之后。这种模式与季节性严重遗传瓶颈以及大规模季节性种群扩张一致。鼠疫病原体在马任加的最终灭绝表明，在这种环境下，鼠疫病原体的生态位充其量也是脆弱的。然而，暂时的大型病原体种群扩张为鼠疫病原体在更适宜的非城市环境中传播和生态建立提供了手段。
海上传播导致了这种疾病的全球传播，并影响了人类历史的进程。三次经典的鼠疫大流行（6 世纪和 7 世纪、中世纪（14 世纪至 17 世纪）和第三次（19 世纪中叶至今））导致了大规模的人类死亡。这些事件的关键是病原体通过“鼠疫船”进入新土地进入海港城市。虽然港口最初的疾病暴发很常见，但它们几乎从未持续很长时间，只有当鼠疫病原体能够在生态适宜的栖息地中建立时，它们才能存活。虽然鼠疫病原体进入港口城市的能力对于洲际传播至关重要，但这些地区并不是一个合适的长期生态位。因此，像马任加这样的港口城市的疾病动态对于鼠疫病原体的扩增和传播到新的适宜生态位至关重要，这是观察到鼠疫病原体在全球范围内长期维持的原因。
