Trypanosome Transmission Biology in Tsetse

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This application is on Human African Trypanosomiases (HAT), one of the most neglected diseases of sub- Saharan Africa. Despite the anticipated elimination of the gambiense disease by 2030, control in conflict-ridden and remote areas where HAT typically occurs remains challenging. Interruption of the rhodesiense disease is not yet envisioned at this time due to the presence of wild and domestic animal reservoirs. Because related tsetse- transmitted parasites also cause devastating wasting diseases in domestic animals, our studies stand to also improve nutrient availability and agricultural productivity on the continent. While considerable progress has been recently made on therapeutics to cure patients, the tool box for disease prevention remains inadequate. Recent discoveries on the mammalian bite site biology opened up a new frontier for the development of novel methods to prevent transmission early in the infection in the mammal when very few parasites are introduced in saliva. Here, we will develop the foundation on the molecular and immunological dialogues and the influential factors that ultimately shape disease progression at the bite site. This information will help evaluate the feasibility of a transmission blocking vaccine (TBV) strategy that target metacyclic parasites transmitted in tsetse saliva. Aim 1. Understand the mechanistic basis of the tsetse-trypanosome dialogue in salivary glands (SG). Our data indicate that trypanosome infections modify tsetse SG gene expression and saliva components (sialome). To understand the parasite-SG molecular dialogue, we will: 1) characterize the miRNA populations in normal and infected SGs, 2) validate the functional involvement of candidate miRNAs in the regulation of products in the infectious inoculum, and 3) determine parasite infection mediated effects on SG physiology and saliva composition in natural tsetse populations. Aim 2. Characterize metacyclic trypanosome dissemination at the bite-site and elucidate vector-derived factors that orchestrate this process. Our data indicate that the different tissues of infected mammals harbor distinct populations of bloodstream form trypanosomes. To better understand the factors that mediate parasite infection dynamics in the mammalian host, we will determine: 1) the temporal and spatial host-parasite dialogue during dissemination from the bite site to blood and peripheral organs, and 2) the immunological dialogue at the bite site together with multiple factors transmitted in saliva (exosomes and saliva-borne symbionts). Aim 3. Investigate a family of surface proteins (Fam10) to block parasite development at the mammalian bite site. Our studies identified a family of proteins (Fam10) expressed on the surface of mMC cells and demonstrated that vaccination against one Fam10 member reduces parasitemia early in the infection. To evaluate the feasibility of TBV methods, we will: 1) investigate the diversity of Fam10 proteins in natural trypanosome populations, 2) screen for conserved immunogenic peptides, 3) test vaccine efficacy of peptide antibodies that target multiple conserved Fam10 antigens, and 4) identify the determinants of protective immunity at the bite site.