Whole genome sequencing shows sleeping sickness relapse is due to parasite regrowth and not reinfection

Abstract

The trypanosome Trypanosoma brucei gambiense (Tbg) is a cause of human African trypanosomiasis (HAT) endemic to many parts of sub‐Saharan Africa. The disease is almost invariably fatal if untreated and there is no vaccine, which makes monitoring and managing drug resistance highly relevant. A recent study of HAT cases from the Democratic Republic of the Congo reported a high incidence of relapses in patients treated with melarsoprol. Of the 19 Tbg strains isolated from patients enrolled in this study, four pairs were obtained from the same patient before treatment and after relapse. We used whole genome sequencing to investigate whether these patients were infected with a new strain, or if the original strain had regrown to pathogenic levels. Clustering analysis of 5938 single nucleotide polymorphisms supports the hypothesis of regrowth of the original strain, as we found that strains isolated before and after treatment from the same patient were more similar to each other than to other isolates. We also identified 23 novel genes that could affect melarsoprol sensitivity, representing a promising new set of targets for future functional studies. This work exemplifies the utility of using evolutionary approaches to provide novel insights and tools for disease control.

Trypanosoma brucei Parasites Occupy and Functionally Adapt to the Adipose Tissue in Mice

“…HIV takes advantage of the fat as a viral reservoir during the chronic stage of infection, and persistence on this reservoir is an obstacle for treatment ( Chun et al., 2015 ). It is possible that persistence of T. brucei in the fat may also account for some of the treatment failures in humans ( Richardson et al., 2016 ).…”

Adipose Tissue: A Safe Haven for Parasites?

“…Trindade et al have shown, using transplantation experiments, that parasites can egress from AT and repopulate the blood [20]. Thus, it is possible that AT contributes to the relapses also observed in the treatment of African trypanosomiasis, which are typically less than 5–10% after treatment [56,57]. …”

Genomic analyses of African Trypanozoon strains to assess evolutionary relationships and identify markers for strain identification

“…First, we provide a large comparative genomic analysis of African trypanosomes of the sub-genus Trypanozoon by analyzing whole genome data from 83 strains from across sub-Saharan Africa, representing a range of human and animal infective types ( S1 Table ), and comprising 21 Tbb , 21 Tbg-1 , 1 Tbg-2 , 35 Tbr and 4 Tev strains (4 Type A and 1 type B). Nineteen of the Tbg-1 strains were isolated from a hospital in the Democratic Republic of the Congo in response to a sleeping sickness outbreak [ 18 ]. Eleven of the newly sequenced strains, and 24 in total, are from Uganda, the only country where both Tbr and Tbg-1 co-occur and where methods of strain discovery can be extremely useful [ 17 ].…”