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Trypanosoma spp.
Published in Peter M. Lydyard, Michael F. Cole, John Holton, William L. Irving, Nino Porakishvili, Pradhib Venkatesan, Katherine N. Ward, Case Studies in Infectious Disease, 2010
Peter M. Lydyard, Michael F. Cole, John Holton, William L. Irving, Nino Porakishvili, Pradhib Venkatesan, Katherine N. Ward
There are innate and adaptive host responses to trypanosomal infection. Humans may be exposed to nonpathogenic species of trypanosomes. However, in normal human serum, apolipoprotein L-1 binds to the trypanosome surface and is endocytosed. Within the trypanosomal cytoplasm, apoliprotein L-1 reaches and forms pores in lysosomes. Release of lysosomal contents causes trypanosomal killing. Species of trypanosomes that are usually nonpathogenic may only cause infection in humans with apolipoprotein L-1 deficiency. The pathogenic species T. brucei rhodesiense possesses a serum resistance-associated protein (SRA), which strongly binds to apolipoprotein L-1, inhibiting its toxic action. The other pathogenic species, T. brucei gambiense, does not possess SRA and how it might resist the action of apolipoprotein L-1 is not clear.
Evolutionary Biology of Parasitism
Published in Eric S. Loker, Bruce V. Hofkin, Parasitology, 2023
Eric S. Loker, Bruce V. Hofkin
Although clear enough conceptually, examples of parasite–host arms races in which a selective sweep in one partner is followed by a selective sweep in the other as shown in Figure 7.10 are hard to come by, especially for eukaryotic parasites. Consider this example involving the association of humans with African trypanosomes (see also Chapter 2). Humans are resistant to trypanosomes of cattle such as Trypanosoma brucei brucei because they possess a serum factor called apolipoprotein L-1 (APOL1) that lyses the membranes of such trypanosomes (Figure 7.11). It seems reasonable to imagine a strong evolutionary response of humans to the threat posed by trypanosomes in Africa to account for the presence of APOL1. However, as we well know, some trypanosomes such as T. brucei gambiense and T. brucei rhodesiense have evolved means to overcome the lytic activity of APOL1, enabling them to establish long-term infections in people. For T. b. gambiense, which causes 97% of the cases of human African trypanosomiasis, there seem to be at least three different mechanisms for overcoming the adverse effects of APOL1. These involve the expression of a protein that stiffens trypanosome membranes and makes them less vulnerable to APOL1 lysis, an alteration in the membrane receptor involved in taking up APOL1 in the first place, and changes in biochemistry of trypanosome lysosomes to make it less likely for APOL1 to intercalate into parasite membranes. T. b. rhodesiense by contrast has evolved a serum resistance associated protein (SRA), which alone can prevent APOL1 lysis by binding to it and preventing its insertion into parasite membranes. All these mechanisms can be viewed as countermeasures that the human trypanosomes have taken in response to the APOL1 defense put up by humans. Variant forms of human APO1 are also known, one of which, G2, is not inactivated by SRA, can lyse T. b. rhodesiense and confer on its hosts a five-fold reduction in risk of infection with this species in East Africa. Another APO1 variant, G1, does not prevent infections with T. b. gambiense in West Africa, but the infections are more likely to be asymptomatic. Interestingly, the presence of these variant forms of APOL1 is associated with kidney disease, suggesting that intense selection as caused by an arms race with parasites can come at the risk of significant collateral damage.
Immunotoxins and nanobody-based immunotoxins: review and update
Published in Journal of Drug Targeting, 2021
Mohammad Reza Khirehgesh, Jafar Sharifi, Fatemeh Safari, Bahman Akbari
African protozoan parasite Trypanosoma brucei causes African trypanosomiasis or sleeping sickness. Apolipoprotein L-I (apoL-I) lysis the African trypanosomes except for resistant forms such as Trypanosoma brucei rhodesiense because of expression of a protein known as apoL-I neutralising serum resistance-associated (SRA). Tr-apoL-I, a modified format of apoL-I without the SRA-interacting domain, can overcome this resistance. The cell surface of Trypanosoma brucei rhodesiense is covered by a variant surface glycoprotein (VSG). As a result, many anti-VSG nanobodies are developed. For example, NbAn33, a non-trypanolytic Nb, can access the preserved cryptic epitopes of the VSG. Conjugation of NbAn33 to the Tr-apoL-I led to the generation of recombinant IT (NbAn33–Tr-apoL-I). The IT recognised and lysed the resistant Trypanosoma strains in the in vitro study in a dose-dependent manner. Also, in vivo studies in mouse models showed that the IT leads to complete parasite clearance and did not show any adverse symptoms [155].
Heme metabolism as a therapeutic target against protozoan parasites
Published in Journal of Drug Targeting, 2019
Guilherme Curty Lechuga, Mirian C. S. Pereira, Saulo C. Bourguignon
In human serum, the glycoprotein, haptoglobin, binds to hemoglobin with high affinity, and is an important mechanism of heme scavenging during hemolysis [28]. The T. brucei bloodstream stage has a haptoglobin-hemoglobin receptor (TbHpHbr) that mediates heme uptake and is also implicated in the host innate immune response [29]. The knockout of the TbHpHbr gene, as expected, affects parasite growth, since parasites are auxotrophic for heme (Figure 1). However, the parasite is tricked by the same receptor since it also recognises the trypanosome lytic factor 1 (TLF1), which harbours apolipoprotein L-1 (ApoL-1) and forms pores in lysosomal membrane leading to parasite lysis [30]. Unfortunately, T. brucei has mechanisms to avoid and neutralise this trypanolytic factor in human blood [31]. Despite low heme requirements in bloodstream forms, due to glycolysis as the only source of energy, this molecule is still vital. A recent report demonstrated the expression of the hemeprotein, CYP51, in T. brucei and highlighted this protein as a possible drug target [32].