Prospects for vaccination against pathogenic African trypanosomes

Black, Samuel J.; Mansfield, John M.

doi:10.1111/pim.12387

Cited by 37 publications

(40 citation statements)

References 67 publications

(102 reference statements)

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“…This would negatively affect the fitness of the trypanosome. Hence, while such negative selective pressure would favor the acquisition of non-immunogenic conserved regions, the artificial induction of T cell responses against these epitopes prior to infection might tip the balance in favor of the host, in a way that trypanosomes have not been evolutionary prepared for (4).…”

Section: T Cells Contribute To the Maintenance Of An Anti-trypanosomementioning

confidence: 99%

“…This is not a hostile environment, this is where they "live." One way to possibly circumvent these issues is to focus on T cell epitope vaccination rather than B cell epitope targeting (4). Indeed, while the latter is "anticipated" by the parasite and has driven the evolutionary development, triggering T cell memory prior to infection might be a way to boost the immunological "help" in a way that so far has not been part of the immunological pressure that drives the trypanosome genetic drift.…”

Section: Introductionmentioning

confidence: 99%

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Infections With Extracellular Trypanosomes Require Control by Efficient Innate Immune Mechanisms and Can Result in the Destruction of the Mammalian Humoral Immune System

et al. 2020

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Salivarian trypanosomes are extracellular parasites that affect humans, livestock, and game animals around the world. Through co-evolution with the mammalian immune system, trypanosomes have developed defense mechanisms that allow them to thrive in blood, lymphoid vessels, and tissue environments such as the brain, the fat tissue, and testes. Trypanosomes have developed ways to circumvent antibody-mediated killing and block the activation of the lytic arm of the complement pathway. Hence, this makes the innate immune control of the infection a crucial part of the host-parasite interaction, determining infection susceptibility, and parasitemia control. Indeed, trypanosomes use a combination of several independent mechanisms to avoid clearance by the humoral immune system. First, perpetuated antigenic variation of the surface coat allows to escape antibody-mediated elimination. Secondly, when antibodies bind to the coat, they are efficiently transported toward the endocytosis pathway, where they are removed from the coat proteins. Finally, trypanosomes engage in the active destruction of the mammalian humoral immune response. This provides them with a rescue solution in case antigenic variation does not confer total immunological invisibility. Both antigenic variation and B cell destruction pose significant hurdles for the development of anti-trypanosome vaccine strategies. However, developing total immune escape capacity and unlimited growth capabilities within a mammalian host is not beneficial for any parasite, as it will result in the accelerated death of the host itself. Hence, trypanosomes have acquired a system of quorum sensing that results in density-dependent population growth arrest in order to prevent overpopulating the host. The same system could possibly sense the infection-associated host tissue damage resulting from inflammatory innate immune responses, in which case the quorum sensing serves to prevent excessive immunopathology and as such also promotes host survival. In order to put these concepts together, this review summarizes current knowledge on the interaction between Magez et al.Trypanosomosis and Innate Immune Control trypanosomes and the mammalian innate immune system, the mechanisms involved in population growth regulation, antigenic variation and the immuno-destructive effect of trypanosomes on the humoral immune system. Vaccine trials and a discussion on the role of innate immune modulation in these trials are discussed at the end.

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Section: T Cells Contribute To the Maintenance Of An Anti-trypanosomementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Infections With Extracellular Trypanosomes Require Control by Efficient Innate Immune Mechanisms and Can Result in the Destruction of the Mammalian Humoral Immune System

et al. 2020

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“…Nevertheless, they all thrive in mammalian reservoirs free-living in their bloodstream and manage to persist there causing chronic infections. In livestock, these infections produce anemia, poor condition and reproduction, and death, which leads to huge economic losses [2]. In Africa, AAT exerts a devastating toll and it is considered the most important disease driven limitation to livestock production [3].…”

Section: Introductionmentioning

confidence: 99%

“…Antigen name and annotation are those reported in the parasite proteome of origin from TriTrypDB[12] 2. Subcellular localization of antigens predicted with TargetP1.1[21]: M, mitochondrial; S, secreted; number in brackets stands for the prediction "Reliability class" (RC), which ranges from 1 to 5 where 1 indicates the strongest prediction 3.…”

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confidence: 99%

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Design of an Epitope-Based Vaccine Ensemble for Animal Trypanosomiasis by Computational Methods

et al. 2020

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African animal trypanosomiasis is caused by vector-transmitted parasites of the genus Trypanosoma. T. congolense and T. brucei brucei are predominant in Africa; T. evansi and T. vivax in America and Asia. They have in common an extracellular lifestyle and livestock tropism, which provokes huge economic losses in regions where vectors are endemic. There are licensed drugs to treat the infections, but adherence to treatment is poor and appearance of resistances common. Therefore, the availability of a prophylactic vaccine would represent a major breakthrough towards the management and control of the disease. Selection of the most appropriate antigens for its development is a bottleneck step, especially considering the limited resources allocated. Herein we propose a vaccine strategy based on multiple epitopes from multiple antigens to counteract the parasites´ biological complexity. Epitopes were identified by computer-assisted genome-wide screenings, considering sequence conservation criteria, antigens annotation and sub-cellular localization, high binding affinity to antigen presenting molecules, and lack of cross-reactivity to proteins in cattle and other breeding species. We ultimately provide 31 B-cell, 8 CD4 T-cell, and 15 CD8 T-cell epitope sequences from 30 distinct antigens for the prospective design of a genetic ensemble vaccine against the four trypanosome species responsible for African animal trypanosomiasis.

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Drug Discovery and Development for Kinetoplastid Diseases

Caffrey

Steverding

Ferreira

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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In this article, we review the disease, biology, and biochemistry of kinetoplastids, as well as the new drugs and drug candidates that have entered the clinic in the last decade. We also describe examples of the preclinical exploration of small molecules against various protein targets (e.g. cysteine proteases, the proteasome, and tubulin), as well as cutting‐edge molecular and computational strategies and technologies being brought to bear to discover and develop new antitrypanosomal drugs. For comprehensive descriptions of the disease, biology, and drug therapies prior to 2011, the reader is encouraged to review the article by P.M. Woster that appeared in 2010 in the seventh edition of Burger's Medicinal Chemistry, Drug Discovery, and Development, entitled Antiprotozoal/Antiparasitic Agents.

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Prospects for vaccination against pathogenic African trypanosomes

Abstract: SummaryAfrican trypanosomes cause human and animal African trypanosomiases, which are chronic, debilitating and often fatal diseases of people and livestock in sub-Saharan Africa. The extracellular protozoan parasites are exemplars of antigenic variation.

Cited by 37 publications

References 67 publications

Infections With Extracellular Trypanosomes Require Control by Efficient Innate Immune Mechanisms and Can Result in the Destruction of the Mammalian Humoral Immune System

Infections With Extracellular Trypanosomes Require Control by Efficient Innate Immune Mechanisms and Can Result in the Destruction of the Mammalian Humoral Immune System

Design of an Epitope-Based Vaccine Ensemble for Animal Trypanosomiasis by Computational Methods

Drug Discovery and Development for Kinetoplastid Diseases

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