Multiple Introductions and Recent Spread of the Emerging Human Pathogen Mycobacterium ulcerans across Africa

Abstract

Buruli ulcer (BU) is an insidious neglected tropical disease. Cases are reported around the world but the rural regions of West and Central Africa are most affected. How BU is transmitted and spreads has remained a mystery, even though the causative agent, Mycobacterium ulcerans, has been known for more than 70 years. Here, using the tools of population genomics, we reconstruct the evolutionary history of M. ulcerans by comparing 165 isolates spanning 48 years and representing 11 endemic countries across Africa. The genetic diversity of African M. ulcerans was found to be restricted due to the bacterium's slow substitution rate coupled with its relatively recent origin. We identified two specific M. ulcerans lineages within the African continent, and inferred that M. ulcerans lineage Mu_A1 existed in Africa for several hundreds of years, unlike lineage Mu_A2, which was introduced much more recently, approximately during the 19th century. Additionally, we observed that specific M. ulcerans epidemic Mu_A1 clones were introduced during the same time period in the three hydrological basins that were well covered in our panel. The estimated time span of the introduction events coincides with the Neo-imperialism period, during which time the European colonial powers divided the African continent among themselves. Using this temporal association, and in the absence of a known BU reservoir or-vector on the continent, we postulate that the so-called "Scramble for Africa" played a significant role in the spread of the disease across the continent.

Keywords: bacterial pathogen transmission; microbial population genomics; molecular evolution; phylogeography.

Fig. 1.—

Bayesian maximum clade credibility phylogeny for African M. ulcerans. The tree was visualized and colored in Figtree v1.4.2 (Rambaut 2015). Branches are color coded according to their branch specific substitution rate (legend at top). Branches defining major lineages are annotated on the tree. Tip labels are color coded according to their respective BAPS-clusters (the best visited BAPS partitioning scheme of our sample yielded a natural log marginal likelihood of − 95,857). Divergence dates (mean estimates and their respective 95% HDP) are indicated in green for major nodes. Note 95% HDP intervals grow larger closer to the root of the tree as increasingly less timing calibration information is available the further one goes back in time. Geographically localized clonal expansions associated with four particular hydrological basins (Congo, Kouffo, Oueme, and Nyong) are highlighted with boxes and their corresponding t(MRCA) & 95% HDP are specified in green.

Fig. 2.—

Geospatial distribution of African M. ulcerans through time. A Bayesian maximum clade credibility phylogeny is drawn for lineage Mu_A1 with branches color coded according to their most likely location state (legend at top). Pie charts indicate location state posterior probability distributions of major nodes. The amount of location states was limited to five by merging the disease isolates of certain neighboring countries. The genetically distinct Ugandan singleton node (which represents its own BAPS-cluster) was omitted from the analysis as multiple isolates are required per cluster. Divergence dates (mean estimates and their respective 95% HDP) are indicated in green for nodes that fall outside of the time scale. A number of oversampled localized clonal expansions are collapsed in the tree with the size of their representing cartoon proportional to the amount of collapsed taxa. The tips of the tree are connected to the location of residence of patients from whom the isolate was grown.