Biology subjects

Autheman, D.

Publications and source records attributed to Autheman, D..

3 recordsLinked to original sources

bioRxiv2025

Cure of experimental Trypanosoma vivax infection with a single dose of an unmodified antibody-based drug targeting the invariant flagellum cell surface protein IFX

Animal African trypanosomiasis (AAT) is an infectious wasting disease of economically important livestock caused by Trypanosoma spp. parasites. The disease is primarily caused by two species: T. congolense and T. vivax which are endemic in many African countries. AAT is managed by therapeutic and prophylactic drugs; however, resistance is now widely reported and the development of new drugs has been impeded due to a chronic lack of investment. Recently, we identified an invariant flagellar-associated cell surface protein (IFX) that could elicit protective immune responses when used as a vaccine against T. vivax. We showed that a complement-recruiting anti-IFX monoclonal antibody can prevent infection when used prophylactically. Here, we show that this same unmodified antibody can be used to cure T. vivax infections in a murine experimental model. Importantly, we show that infections can be treated with a single dose and demonstrate full cure by the lack of detectable parasites in peripheral tissues even after immunosuppression. Using structural modelling and site-directed mutagenesis, we localise the protective antibody epitope thereby identifying targetable regions on IFX to improve vaccine design. Together, these findings validate IFX as both a prophylactic and curative drug target that could be useful in the management of AAT. ImportanceTrypanosoma vivax is a parasite that causes animal African trypanosomiasis (AAT), a chronic wasting disease that infects economically-important livestock animals which is a particular problem in African countries south of the Sahara. The impact of this disease is significant: it is responsible for over 3 million cattle deaths and an estimated $4.5 billion of annual lost productivity. There is a desperate need to develop new control measures because resistance is now widely reported to the drugs commonly used to treat this infection. We show here that a single dose of an unmodified monoclonal antibody that recognises IFX - a parasite cell surface protein localised to the flagellum - is sufficient to cure an established T. vivax infection with no parasite reservoirs detectable in peripheral tissues. Our finding validates IFX as a new drug target and provides a rationale route to the development of new drugs to target AAT.

microbiology↗

bioRxiv2022

Vivaxin genes encode highly immunogenic non-variant antigens unique to the Trypanosoma vivax cell-surface

Trypanosoma vivax is a unicellular hemoparasite, and a principal cause of animal African trypanosomiasis (AAT), a vector-borne and potentially fatal disease of livestock across sub-Saharan Africa. Previously, we identified diverse T. vivax-specific genes that were predicted to encode cell surface proteins. Here, we examine the immune responses of naturally and experimentally infected hosts to many of these unique parasite antigens, to identify immunogens that could become vaccine candidates. Immunoprofiling of host serum showed that one particular family (Fam34) elicits a consistent IgG antibody response. This gene family, which we now call Vivaxin, encodes at least 124 transmembrane glycoproteins that display quite distinct expression profiles and patterns of genetic variation. We focused on one gene (viv-{beta}8) that is among the most immunogenic and highly expressed but displays minimal polymorphism. VIV{beta}8 was localized across the cell body and flagellar membrane, suggesting that vivaxin is substantial family of novel surface proteins. Although vaccination of mice with VIV{beta}8 adjuvanted with Quil-A elicits a strong, balanced immune response and delays parasite proliferation in some animals, ultimately, it does not prevent disease. However, our phylogenetic analysis shows vivaxin includes other antigens shown to induce immunity against T. vivax. Thus, the introduction of vivaxin represents an important advance in our understanding of the T. vivax cell surface. Besides being a source of proven and promising vaccine antigens, the gene family is clearly an important component of the parasite glycocalyx, with potential to influence the host-parasite interaction. Author summaryAnimal African trypanosomiasis (AAT) is an important livestock disease throughout sub-Saharan Africa and beyond. AAT is caused by Trypanosoma vivax, among other species, a unicellular parasite that is spread by biting tsetse flies and multiplies in the bloodstream and other tissues, leading to often fatal neurological conditions if untreated. Although concerted drug treatment and vector eradication programmes have succeeded in controlling Human African trypanosomiasis, AAT continues to adversely affect animal health and impede efficient food production and economic development in many less-developed countries. In this study, we attempted to identify parasite surface proteins that stimulated the strongest immune responses in naturally infected animals, as the basis for a vaccine. We describe the discovery of a new, species-specific protein family in T. vivax, which we call vivaxin. We show that one vivaxin protein (VIV{beta}8) is surface expressed and retards parasite proliferation when used to immunize mice, but does not prevent infection. However, we also reveal that vivaxin includes another protein previously shown to induce protective immunity (IFX/VIV{beta}1). Besides its great potential for novel approaches to AAT control, vivaxin is revealed as a significant component of the T. vivax cell surface and may have important, species-specific roles in host interactions.

microbiology↗

bioRxiv2021

An invariant Trypanosoma vivax vaccine antigen inducing protective immunity

Trypanosomes are protozoan parasites that cause infectious diseases including human African trypanosomiasis (sleeping sickness), and nagana in economically-important livestock animals1,2. An effective vaccine against trypanosomes would be an important control tool, but the parasite has evolved sophisticated immunoprotective mechanisms including antigenic variation3 that present an apparently insurmountable barrier to vaccination. Here we show using a systematic genome-led vaccinology approach4 and a murine model of Trypanosoma vivax infection5 that protective invariant subunit vaccine antigens can be identified. Vaccination with a single recombinant protein comprising the extracellular region of a conserved cell surface protein localised to the flagellum membrane termed "invariant flagellum antigen from T. vivax" (IFX) induced long-lasting protection. Immunity was passively transferred with immune serum, and recombinant monoclonal antibodies to IFX could induce sterile protection and revealed multiple mechanisms of antibody-mediated immunity, including a major role for complement. Our discovery identifies a vaccine candidate for an important parasitic disease that has constrained the socioeconomic development of sub-Saharan African countries6 and challenges long-held views that vaccinating against trypanosome infections cannot be achieved.

microbiology↗