title: Determinants of Human African Trypanosomiasis Elimination via Paratransgenesis.
abstract: 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.
authors.affiliation: Center for Infectious Disease Modeling and Analysis, Yale School of Public Health, New Haven, Connecticut, United States of America.|Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut, United States of America.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Gilbert
authors.affiliation: Department of Biomedical Sciences, Oregon State University, Corvallis, Oregon, United States of America.
authors.forename: Jan
authors.initials: J
authors.lastname: Medlock
authors.affiliation: Department of Biostatistics, Yale University, New Haven, Connecticut, United States of America.|Department of Ecology and Evolutionary Biology, Yale University, New Haven, Connecticut, United States of America.|Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, United States of America.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Townsend
authors.affiliation: Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut, United States of America.
authors.forename: Serap
authors.initials: S
authors.lastname: Aksoy
authors.affiliation: Center for Infectious Disease Modeling and Analysis, Yale School of Public Health, New Haven, Connecticut, United States of America.|Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut, United States of America.
authors.forename: Martial
authors.initials: M
authors.lastname: Ndeffo Mbah
authors.affiliation: Center for Infectious Disease Modeling and Analysis, Yale School of Public Health, New Haven, Connecticut, United States of America.|Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut, United States of America.
authors.forename: Alison P
authors.initials: AP
authors.lastname: Galvani
mesh_terms: D017954:Africa South of the Sahara; D000818:Animals; D030801:Animals, Genetically Modified; D003140:Communicable Disease Control / Q000379:methods; D060740:Disease Eradication; D018562:Disease Transmission, Infectious / Q000517:prevention & control; D004755:Enterobacteriaceae / Q000235:genetics / Q000254:growth & development*; D004772:Entomology / Q000379:methods; D006801:Humans; D008962:Models, Theoretical; D011157:Population Dynamics; D013559:Symbiosis; D014346:Trypanosoma brucei brucei / Q000254:growth & development*; D014353:Trypanosomiasis, African / Q000453:epidemiology / Q000517:prevention & control* / Q000635:transmission; D014370:Tsetse Flies / Q000382:microbiology*; D020577:Wolbachia / Q000502:physiology*