Salivarian Trypanosomosis: A Review of Parasites Involved, Their Global Distribution and Their Interaction With the Innate and Adaptive Mammalian Host Immune System

Abstract

Salivarian trypanosomes are single cell extracellular parasites that cause infections in a wide range of hosts. Most pathogenic infections worldwide are caused by one of four major species of trypanosomes including (i) Trypanosoma brucei and the human infective subspecies T. b. gambiense and T. b. rhodesiense, (ii) Trypanosoma evansi and T. equiperdum, (iii) Trypanosoma congolense and (iv) Trypanosoma vivax. Infections with these parasites are marked by excessive immune dysfunction and immunopathology, both related to prolonged inflammatory host immune responses. Here we review the classification and global distribution of these parasites, highlight the adaptation of human infective trypanosomes that allow them to survive innate defense molecules unique to man, gorilla, and baboon serum and refer to the discovery of sexual reproduction of trypanosomes in the tsetse vector. With respect to the immunology of mammalian host-parasite interactions, the review highlights recent findings with respect to the B cell destruction capacity of trypanosomes and the role of T cells in the governance of infection control. Understanding infection-associated dysfunction and regulation of both these immune compartments is crucial to explain the continued failures of anti-trypanosome vaccine developments as well as the lack of any field-applicable vaccine based anti-trypanosomosis intervention strategy. Finally, the link between infection-associated inflammation and trypanosomosis induced anemia is covered in the context of both livestock and human infections.

Keywords: anemia; immunology; pathology; transmission; trypanosomosis.

Figure 1

Geographic distribution of salivarian trypanosomosis. Salivarian trypanosomosis is a worldwide problem caused in large by Trypanosoma evansi, Trypanosoma brucei (including the human infective subspecies T. b. gambiense and T. b. rhodesiense), Trypanosoma vivax and Trypanosoma congolense. T. brucei, and T. congolense infections are limited to the sub-Saharan tsetse belt. In contrast, as T. vivax and T. evansi can be mechanically transmitted, these parasites have migrate beyond the tsetse belt, out of Africa and into South America and Asia [adapted from (–22)].

Figure 2

Cyclic transmission of salivarian trypanosomes mediated by tsetse and other biting flies. Most lifecycle data of African Trypanosomes is based on the T. brucei cycle involving the tsetse (52). Here, short stumpy form parasite are taken up by the fly, progress through the body of the insect vector passing via the midgut, proventiculus and salivary gland, to be re-injected though the proboscis as infective metacyclic trypomastigotes into a new target. In the bloodstream, differentiation to long slender forms occurs followed by binary fission proliferation. Differentiation back to short stumpy forms will complete the cycle. While T. congolense and T. vivax can follow a similar cyclic transmission mode, the latter also is known to be spread through mechanical transmission (53, 54), as is the case for T. evansi (1). T. equiperdum spreads through sexual transmission only (37). Sexual reproduction of trypanosomes itself has been reported to take part in the teste, and has been reported for both T. brucei and T. congolense (5).

Figure 3

Antigenic variation and host immune destruction are closely linked. Antigenic variation of the trypanosome VSG surface coat enables trypanosomes to escape specific antibody-mediated destruction, resulting in immunologicaly distinct parasites occurring at regular intervals (upper panel). To prevent total eradication, trypanosomes undermine the immune system by ablation of the B cell compartment. In mice, this results in abrogation of an efficient antibody mediated immune defense system, allowing different parasite variants to occur simultaneously (schematically represented as the week 3 situation). Despite to co-occurrence of several variants, later-stage parasitaemia peaks usually have a reduced magnitude in terms of actual parasite numbers as various non-B cell defense systems aid in parasiteamia control [upper panel, adapted from (134)]. The lower panel schematically represent the finding that onset of infection is followed by a rapid depletion of the MZ B cell compartment (purple), followed by a gradual destruction of the FoB cell compartment (red) (116, 119). While the initially host immune response generates effector Plasma B cells, later waves of newly arising parasite variants fail to be efficiently depleted due to the impaired capacity of the host to deliver a renewed Plasma B cell response (green). Overall immunopathology is initiated by excessive production of IFNγ during the first week of infection, involving mainly CD8⁺ T cells, NK cells, and NKT cells. By 7 days post infection, IFNγ production is taken over by CD4⁺ T cells, while activated macrophages now produce excessive amounts of TNF that contribute to pathology (135, 136). Later-on in infection, production of IL-10 has been documented to counteract the initial inflammation (137).

Figure 4

Trypanosomosis-induced B cell destruction results in prolonged B cell dysfunction. Experimental infections in mice have shown that trypanosomes can destroy non-related DTPa induced vaccine responses (upper panel). Vaccinated mice that have been confronted with trypanosomes fail to clear diphtheria bacteria from their lungs, even when the bacterial challenge is performed after the trypanosome infection has been cleared by drug treatment [adapted from (119)]. Indeed is was shown that while the commercial vaccine Boostrix® provides significant protection against a B. pertussis challenge (green bar: vaccinated, blue bar: non-vaccinated), exposure to trypanosomes abrogated vaccine-induced protection (red bar). In humans (lower panel), trypanosome infections were shown to suppress vaccine induced anti-measles antibodies. Serum antibody titers in vaccinated T. gambiense HAT patients (blue bar) were shown to be significantly lower as compared to vaccinated control individuals (green bar), and specific antibody titers did not recover after curative anti-HAT treatment (red bar) (121).