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.

Genetic manipulation allows in vivo tracking of the life cycle of the son‐killer symbiont, Arsenophonus nasoniae, and reveals patterns of host invasion, tropism and pathology

“…These techniques would then enable research into the genetic systems underlying the development and maintenance of symbiotic lifestyles, and the mechanisms underlying symbiont impact on their hosts. The systems developed would additionally potentiate paratransgenic application (Gilbert et al, 2016).…”

Reciprocal interactions between Leishmania and their microenvironments during infection in the sand fly gut and human macrophages

“…As mentioned in Chapter I, it is important to understand the overall biology in the insect vectorparasitemicrobiome relationship, as manipulation in one of these entities can result in positive or negative outcomes in another depending on the disease model. Previous reports in other insect vectors of disease have shown the importance of the gut microbiome during parasite infection and altered vector competence [29,39,77,78,85,87,171,180,181]. Unlike the importance of the undisturbed native gut microbiome during parasite infection in sand flies as we have shown in Chapters II and III, other parasites within insect vectors can augment their overall burden when the gut microbiome is altered.…”

“…In both Old World and New World sand flies, low numbers of sequences from the symbiont Wolbachia have been identified [74][75][76]. However, it is not a heavily represented organism in the microbiome and there is no evidence that this bacterium plays a role in biological control of infection through cytoplasmic incompatibility (CI), as it has in other vector borne infections, particularly mosquitoes [70,[76][77][78][79][80].…”

“…Similarly, the native obligate symbiont Sodalis in tsetse flies can be engineered to secrete a trypanocide AMPs, which are effective against parasite infection. However, these engineered paratransgenic bacteria must be driven into the gut microbial population via Wolbachia infection and vertical transmission, which can lead to fly mortality [78,79].…”

“…Additionally, Wolbachia does not appear to alter the composition and diversity of the gut microbiome in adult Anopheles mosquitoes, further demonstrating its effectiveness as a viable biological control candidate in insect vectors and especially sand flies, where the highly diverse gut microbiome is important in resistance to Leishmania infection [39,77]. Although several Wolbachia strains have been identified in both Old and New World sand fly species, none have been able to be implemented as models of biological control similar to other insect vectors such as Anopheles mosquitoes and tsetse flies [70,[74][75][76][77][78]80].…”