Beyond Tsetse – Implications for Research and Control of Human African Trypanosomiasis Epidemics

Welburn, Susan C.; Molyneux, David; Maudlin, I.

doi:10.1016/j.pt.2015.11.008

Cited by 65 publications

(49 citation statements)

References 82 publications

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“…Human African Trypanosomiasis (HAT) or African Sleeping Sickness is endemic to sub-Saharan Africa, with distribution restricted by the tsetse fly insect vector [1]. Most of the HAT disease burden (98%) is the chronic form of the disease caused by Trypanosoma brucei gambiense .…”

Section: Introductionmentioning

confidence: 99%

Selective inhibition of RNA polymerase I transcription as a potential approach to treat African trypanosomiasis

et al. 2017

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Trypanosoma brucei relies on an essential Variant Surface Glycoprotein (VSG) coat for survival in the mammalian bloodstream. High VSG expression within an expression site body (ESB) is mediated by RNA polymerase I (Pol I), which in other eukaryotes exclusively transcribes ribosomal RNA genes (rDNA). As T. brucei is reliant on Pol I for VSG transcription, we investigated Pol I transcription inhibitors for selective anti-trypanosomal activity. The Pol I inhibitors quarfloxin (CX-3543), CX-5461, and BMH-21 are currently under investigation for treating cancer, as rapidly dividing cancer cells are particularly dependent on high levels of Pol I transcription compared with nontransformed cells. In T. brucei all three Pol I inhibitors have IC50 concentrations for cell proliferation in the nanomolar range: quarfloxin (155 nM), CX-5461 (279 nM) or BMH-21 (134 nM) compared with IC50 concentrations in the MCF10A human breast epithelial cell line (4.44 μM, 6.89 μM or 460 nM, respectively). T. brucei was therefore 29-fold more sensitive to quarfloxin, 25-fold more sensitive to CX-5461 and 3.4-fold more sensitive to BMH-21. Cell death in T. brucei was due to rapid inhibition of Pol I transcription, as within 15 minutes treatment with the inhibitors rRNA precursor transcript was reduced 97-98% and VSG precursor transcript 91-94%. Incubation with Pol I transcription inhibitors also resulted in disintegration of the ESB as well as the nucleolus subnuclear structures, within one hour. Rapid ESB loss following the block in Pol I transcription argues that the ESB is a Pol I transcription nucleated structure, similar to the nucleolus. In addition to providing insight into Pol I transcription and ES control, Pol I transcription inhibitors potentially also provide new approaches to treat trypanosomiasis.

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Section: Introductionmentioning

confidence: 99%

Selective inhibition of RNA polymerase I transcription as a potential approach to treat African trypanosomiasis

et al. 2017

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“…, spread by tsetse fly vectors (genus Glossina ). The disease is endemic in foci in sub-Saharan Africa [1, 2]. After a peak of infection in the 1990s, the incidence of HAT has considerably declined in recent years [1].…”

Section: Introductionmentioning

confidence: 99%

Trypanosoma brucei Invasion and T-Cell Infiltration of the Brain Parenchyma in Experimental Sleeping Sickness: Timing and Correlation with Functional Changes

et al. 2016

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BackgroundThe timing of Trypanosoma brucei entry into the brain parenchyma to initiate the second, meningoencephalitic stage of human African trypanosomiasis or sleeping sickness is currently debated and even parasite invasion of the neuropil has been recently questioned. Furthermore, the relationship between neurological features and disease stage are unclear, despite the important diagnostic and therapeutic implications.MethodologyUsing a rat model of chronic Trypanosoma brucei brucei infection we determined the timing of parasite and T-cell neuropil infiltration and its correlation with functional changes. Parasite DNA was detected using trypanosome-specific PCR. Body weight and sleep structure alterations represented by sleep-onset rapid eye movement (SOREM) periods, reported in human and experimental African trypanosomiasis were monitored. The presence of parasites, as well as CD4+ and CD8+ T-cells in the neuropil was assessed over time in the brain of the same animals by immunocytochemistry and quantitative analyses.Principal findingsTrypanosome DNA was present in the brain at day 6 post-infection and increased more than 15-fold by day 21. Parasites and T-cells were observed in the parenchyma from day 9 onwards. Parasites traversing blood vessel walls were observed in the hypothalamus and other brain regions. Body weight gain was reduced from day 7 onwards. SOREM episodes started in most cases early after infection, with an increase in number and duration after parasite neuroinvasion.ConclusionThese findings demonstrate invasion of the neuropil over time, after an initial interval, by parasites and lymphocytes crossing the blood-brain barrier, and show that neurological features can precede this event. The data thus challenge the current clinical and cerebrospinal fluid criteria of disease staging.

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“…HAT epidemics display characteristic periodicity [9, 10]; cases are currently declining across sub-Saharan Africa, in part attributed to improved approaches to case finding and vector control [11]. HAT co-exists in natural ecosystems with a suite of trypanosomes that affect the health of domestic livestock.…”

Section: Introductionmentioning

confidence: 99%

A Multi-Host Agent-Based Model for a Zoonotic, Vector-Borne Disease. A Case Study on Trypanosomiasis in Eastern Province, Zambia

et al. 2016

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BackgroundThis paper presents a new agent-based model (ABM) for investigating T. b. rhodesiense human African trypanosomiasis (rHAT) disease dynamics, produced to aid a greater understanding of disease transmission, and essential for development of appropriate mitigation strategies.MethodsThe ABM was developed to model rHAT incidence at a fine spatial scale along a 75 km transect in the Luangwa Valley, Zambia. The method offers a complementary approach to traditional compartmentalised modelling techniques, permitting incorporation of fine scale demographic data such as ethnicity, age and gender into the simulation.ResultsThrough identification of possible spatial, demographic and behavioural characteristics which may have differing implications for rHAT risk in the region, the ABM produced output that could not be readily generated by other techniques. On average there were 1.99 (S.E. 0.245) human infections and 1.83 (S.E. 0.183) cattle infections per 6 month period. The model output identified that the approximate incidence rate (per 1000 person-years) was lower amongst cattle owning households (0.079, S.E. 0.017), than those without cattle (0.134, S.E. 0.017). Immigrant tribes (e.g. Bemba I.R. = 0.353, S.E.0.155) and school-age children (e.g. 5–10 year old I.R. = 0.239, S.E. 0.041) were the most at-risk for acquiring infection. These findings have the potential to aid the targeting of future mitigation strategies.ConclusionABMs provide an alternative way of thinking about HAT and NTDs more generally, offering a solution to the investigation of local-scale questions, and which generate results that can be easily disseminated to those affected. The ABM can be used as a tool for scenario testing at an appropriate spatial scale to allow the design of logistically feasible mitigation strategies suggested by model output. This is of particular importance where resources are limited and management strategies are often pushed to the local scale.

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Beyond Tsetse – Implications for Research and Control of Human African Trypanosomiasis Epidemics

Cited by 65 publications

References 82 publications

Selective inhibition of RNA polymerase I transcription as a potential approach to treat African trypanosomiasis

Selective inhibition of RNA polymerase I transcription as a potential approach to treat African trypanosomiasis

Trypanosoma brucei Invasion and T-Cell Infiltration of the Brain Parenchyma in Experimental Sleeping Sickness: Timing and Correlation with Functional Changes

A Multi-Host Agent-Based Model for a Zoonotic, Vector-Borne Disease. A Case Study on Trypanosomiasis in Eastern Province, Zambia

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