Phylogenetic analysis of the origin and spread of plague in Madagascar

Abstract

Background Plague is a zoonotic disease caused by the bacterium Yersinia pestis, highly prevalent in the Central Highlands, a mountainous region in the center of Madagascar. After a plague-free period of over 60 years in the northwestern coast city of Mahajanga, the disease reappeared in 1991 and caused several outbreaks until 1999. Previous research indicates that the disease was reintroduced to the city of Mahajanga from the Central Highlands instead of reemerging from a local reservoir. However, it is not clear how many reintroductions occurred and when they took place. Methodology/Principal findings In this study we applied a Bayesian phylogeographic model to detect and date migrations of Y. pestis between the two locations that could be linked to the re-emergence of plague in Mahajanga. Genome sequences of 300 Y. pestis strains sampled between 1964 and 2012 were analyzed. Four migrations from the Central Highlands to Mahajanga were detected. Two resulted in persistent transmission in humans, one was responsible for most of the human cases recorded between 1995 and 1999, while the other produced plague cases in 1991 and 1992. We dated the emergence of the Y. pestis sub-branch 1.ORI3, which is only present in Madagascar and Turkey, to the beginning of the 20th century, using a Bayesian molecular dating analysis. The split between 1.ORI3 and its ancestor lineage 1.ORI2 was dated to the second half of the 19th century. Conclusions/Significance Our results indicate that two independent migrations from the Central Highlands caused the plague outbreaks in Mahajanga during the 1990s, with both introductions occurring during the early 1980s. They happened over a decade before the detection of human cases, thus the pathogen likely survived in wild reservoirs until the spillover to humans was possible. This study demonstrates the value of Bayesian phylogenetics in elucidating the re-emergence of infectious diseases.

Review of genotyping methods for Yersinia pestis in Madagascar

“…In Madagascar, WGS has been used mainly to identify genetic markers of evolution, such as single-nucleotide polymorphisms (SNPs), in order to use them to genotype strains that have not been sequenced [ 3 , 39 , 40 ]. Increasingly, all the strains in a study are sequenced, with the resulting whole genome sequences used to directly call SNPs and to infer the phylogeny [ 41 , 42 ]. In that case, the genotyping process is more exhaustive because it captures the diversity of the entire genome sequence of all the strains studied.…”

“…pestis means that genetic typing can be used to identify rare transfer events, such as multiple introductions of Y . pestis from the Central Highlands to the coastal city of Madagascar, where it persisted for some years before eventually dying out [ 40 , 41 ]. Finally, Ambositra was among the most diverse districts in terms of Y .…”

“…Recent studies have focused on dating phylogenetic trees of Y . pestis to determine the divergence times of the different clades [ 39 , 41 ]. The authors studied the transmission events between Madagascar and other countries (from India to Madagascar, from Madagascar to Turkey) and inside Madagascar (between the Central Highlands and Mahajanga) [ 41 ].…”

Genomic diversity of Yersinia pestis from Yunnan Province, China, implies a potential common ancestor as the source of two plague epidemics

“…Epidemic-silent cycles of plague have been reported in other countries, with the plague in Mahajanga, a northwestern coastal city in Madagascar, being well-studied 29 . Plague reemerged in Mahajanga from 1991 to 1999 after a silent period lasting over six decades since 1928 10 , 30 . Several studies suggest that the outbreaks in the 1990s were caused by the reintroduction of new Y. pestis populations from the Central Highlands, rather than a latent strain preserved in local wildlife or the environment 10 , 29 , 30 .…”

“…Plague reemerged in Mahajanga from 1991 to 1999 after a silent period lasting over six decades since 1928 10 , 30 . Several studies suggest that the outbreaks in the 1990s were caused by the reintroduction of new Y. pestis populations from the Central Highlands, rather than a latent strain preserved in local wildlife or the environment 10 , 29 , 30 . This supports Hypothesis2 and rejects Hypothesis1, which is consistent with our speculation regarding the two cycles of Yunnan plague.…”