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Evaluating paratransgenesis as a potential control strategy for African trypanosomiasis.

ABSTRACT: Genetic-modification strategies are currently being developed to reduce the transmission of vector-borne diseases, including African trypanosomiasis. For tsetse, the vector of African trypanosomiasis, a paratransgenic strategy is being considered: this approach involves modification of the commensal symbiotic bacteria Sodalis to express trypanosome-resistance-conferring products. Modified Sodalis can then be driven into the tsetse population by cytoplasmic incompatibility (CI) from Wolbachia bacteria. To evaluate the effectiveness of this paratransgenic strategy in controlling African trypanosomiasis, we developed a three-species mathematical model of trypanosomiasis transmission among tsetse, humans, and animal reservoir hosts. Using empirical estimates of CI parameters, we found that paratransgenic tsetse have the potential to eliminate trypanosomiasis, provided that any extra mortality caused by Wolbachia colonization is low, that the paratransgene is effective at protecting against trypanosome transmission, and that the target tsetse species comprises a large majority of the tsetse population in the release location.

SUBMITTER: Medlock J

PROVIDER: S-EPMC3744416 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Evaluating paratransgenesis as a potential control strategy for African trypanosomiasis.

Medlock Jan J Atkins Katherine E KE Thomas David N DN Aksoy Serap S Galvani Alison P AP

PLoS neglected tropical diseases 20130815 8

Genetic-modification strategies are currently being developed to reduce the transmission of vector-borne diseases, including African trypanosomiasis. For tsetse, the vector of African trypanosomiasis, a paratransgenic strategy is being considered: this approach involves modification of the commensal symbiotic bacteria Sodalis to express trypanosome-resistance-conferring products. Modified Sodalis can then be driven into the tsetse population by cytoplasmic incompatibility (CI) from Wolbachia bac ...[more]

PMID: 23967363

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Project description:Human African trypanosomiasis (HAT), transmitted by tsetse flies, has historically infected hundreds of thousands of individuals annually in sub-Saharan Africa. Over the last decade, concerted control efforts have reduced reported cases to below 10,000 annually, bringing complete elimination within reach. A potential technology to eliminate HAT involves rendering the flies resistant to trypanosome infection. This approach can be achieved through the introduction of transgenic Sodalis symbiotic bacteria that have been modified to produce a trypanocide, and propagated via Wolbachia symbionts, which confer a reproductive advantage to the paratransgenic tsetse. However, the population dynamics of these symbionts within tsetse flies have not yet been evaluated. Specifically, the key factors that determine the effectiveness of paratransgenesis have yet to be quantified. To identify the impact of these determinants on T.b. gambiense and T.b. rhodesiense transmission, we developed a mathematical model of trypanosome transmission that incorporates tsetse and symbiont population dynamics. We found that fecundity and mortality penalties associated with Wolbachia or recombinant Sodalis colonization, probabilities of vertical transmission, and tsetse migration rates are fundamental to the feasibility of HAT elimination. For example, we determined that HAT elimination could be sustained over 25 years when Wolbachia colonization minimally impacted fecundity or mortality, and when the probability of recombinant Sodalis vertical transmission exceeded 99.9%. We also found that for a narrow range of recombinant Sodalis vertical transmission probability (99.9-90.6% for T.b. gambiense and 99.9-85.8% for T.b. rhodesiense), cumulative HAT incidence was reduced between 30% and 1% for T.b. gambiense and between 21% and 3% for T.b. rhodesiense, although elimination was not predicted. Our findings indicate that fitness and mortality penalties associated with paratransgenic symbionts, as well as tsetse migration rates, are instrumental to HAT elimination, and should be a key focus in the development of paratransgenic symbionts.

Project description:BackgroundHuman African Trypanosomiasis is one of the Neglected Tropical Diseases that is targeted for elimination by the World Health Organization. Strong health delivery system in endemic countries is required for a control program to eliminate this disease. In Zambia, Human African Trypanosomiasis is lowly endemic in the northeastern part of the country.FindingsWe conducted a cross-sectional survey of health institutions in Mpika district in Northern Province of Zambia from 9th to 23rd November 2011. The aim of this study was to assess current health delivery system in the management of Human African Trypanosomiasis cases in Mpika district, Northern Province of Zambia. Ten health institutions were covered in the survey. Two structured questionnaires targeting health workers were used to collect the data on general knowledge on HAT and state of health care facilities in relation to HAT management from the surveyed health institution.Only 46% of the 28 respondents scored more than 50% from the questionnaire on general knowledge about Human African Trypanosomiasis disease. None of the respondents knew how to differentiate the two clinical stages of Human African Trypanosomiasis disease. There were only three medical doctors to attend to all Human African Trypanosomiasis cases and other diseases at the only diagnostic and treatment hospital in Mpika district. The supply of antitrypanosomal drugs to the only treatment centre was erratic. Only one refresher course on Human African Trypanosomiasis case diagnosis and management for health staff in the district had been organized by the Ministry of Health in conjunction with the World Health Organization in the district in 2009. The referral system for suspected Human African Trypanosomiasis cases from Rural Health Centres (RHCs) to the diagnostic/treatment centre was inefficient.ConclusionsThere are a number of challenges that have been identified and need to be addressed if Human African Trypanosomiasis is to be eliminated in a lowly endemic country such as Zambia. These include shortage of trained health workers, inadequate diagnostic and treatment centres, lack of more sensitive laboratory diagnostic techniques, shortage of trypanosomicides among others discussed in detail here.

Dataset Information

Evaluating paratransgenesis as a potential control strategy for African trypanosomiasis.

Publications

Evaluating paratransgenesis as a potential control strategy for African trypanosomiasis.

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