New approaches to a livestock trypanosomiasis vaccine: targeting the bite-site by immunization with novel metacyclic-stage parasite antigens

点击翻译按钮获取中文摘要

We will express recombinant forms of newly-discovered, parasite proteins that are specific to the surface of infective-stage cells, and examine their ability to protect vaccinated mice against infection by African trypanosomes.African animal trypanosomiasis (AAT) is a livestock disease caused by vector-borne, blood parasites (Trypanosoma congolense and T. vivax), and endemic in 37 sub-Saharan countries. AAT causes chronic anaemia and muscle wastage, resulting in death if untreated. The UN FAO considers AAT to "lie at the heart of Africa's struggle against poverty" with 50 million cattle at risk and billions of dollars lost in agricultural productivity annually. Resolving AAT is an enormous challenge because trypanocidal drugs frequently solicit parasite resistance, vector control is typically unsustainable, while vaccines are unavailable because the trypanosome surface is enveloped by a variable surface glycoprotein (VSG) coat. Serial replacement of the active VSG through antigenic variation allows the parasite population to evade host immunity indefinitely. Antigenic variation is the common thread linking the physiology and epidemiology of AAT, and key to understanding and preventing disease.Nevertheless, a vaccine remains the most sustainable solution to AAT, and thus, discovering invariant parasite antigens that elicit protective immunity is a priority. A decade of trypanosome genomics and gene expression analysis has revolutionized our understanding of the antigenic landscape. Our work has identified parasite-specific proteins expressed uniquely during the metacyclic life stage in the fly mouthparts. We have shown that metacyclic protein architecture is distinct, and unlike the VSG-dominated surface of bloodstream form trypanosomes. These stage-specific proteins are typically invariant and produce strong immune responses. Our hypothesis is that immunizing with these metacyclic antigens can provide the host immune system with a 'standing-start' in fighting infection, producing antibodies that neutralize metacyclics before they migrate into the bloodstream and, critically, before they become antigenically variant. We aim to test this by evaluating a panel of novel antigens for their protective properties and correlates of protection.Our motivation is to translate this knowledge into an effective vaccination strategy. In this project, our approach has several innovations. First, we examine host-parasite interactions at the bite site, where the immunological response initiates. Second, we focus on the metacyclic stage of the trypanosome life cycle prior to the onset of antigenic variation. Third, we use a natural challenge model that produces an authentic initiation to infection. We have four specific objectives. 1) Recombinant protein expression in a range of combinations. 2) Vaccinate mice using different antigen formulations. 3) Infect mice via infected tsetse bite and compare the infection in vaccinated and control animals. 4) Profile gene expression around the bite site using transcriptomics of mouse leucocytes and parasites to identify correlates of protection, while providing the first global analysis of host-parasite interactions during the first days of infection.This project will identify antigens for an experimental multivalent vaccine against metacyclic T. congolense and T. vivax, while establishing the immunological correlates of protection. Besides the immediate application of this new knowledge to efficacy trials of an AAT vaccine, it will also transform our understanding of host-parasite interactions at the bite site. The potential commercial application of AAT vaccines is enormous, and the likely positive effect on animal health and livestock productivity across the world would be profound. As one of the world's foremost veterinary diseases, a sustainable solution to AAT would be a seminal breakthrough leading to improved health and wealth in the world's poorest countries.