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Host Defense and Parasite Evasion
Published in Eric S. Loker, Bruce V. Hofkin, Parasitology, 2023
Eric S. Loker, Bruce V. Hofkin
One of the most dramatic parasite evasion strategies is the antigenic variation employed by African trypanosomes. The blood-borne stage in vertebrates, the trypomastigote, regularly changes the composition of its surface coat. Antibodies generated against the previous coat become ineffective against the new coat. By changing its single coat protein, the variant surface glycoprotein (VSG), to antigenically distinct forms, the parasite in effect remains one jump ahead of the immune response, which must constantly initiate new antibody responses against the new antigens (Figure 4.27). The result is a chronic infection characterized by waves of increased parasitemia, each followed by a decrease in parasite numbers as the lagging immune response struggles to catch up.
Host Defenses Against Prototypical Intracellular Protozoans, the Leishmania
Published in Peter D. Walzer, Robert M. Genta, Parasitic Infections in the Compromised Host, 2020
Richard D. Pearson, Mary E. Wilson
A marmose-containing ligand from promastigotes, which is involved in promastigote attachment, has subsequently been isolated from L. mexicana mexicana and other Leishmania species (82-85). Initial examination of promastigote surface proteins by radiolabeling and two-dimensional polyacrylamide gel electrophoresis revealed an abundant polypeptide of molecular weight 63 kD (gp63). Lectin-binding studies indicated that it was a glycoprotein that contained mannose, N-acetyiglucosamine, and N-acetylgalactosamine residues. The gp63 was found to be distributed over the entire promastigote plasmalemma, and anti-gp63 antibodies reduced promastigote binding to macrophages by 65-70% (84). Additional evidence for the involvement of gp63 in parasitemacrophage interactions was provided by studies in which gp63 was incorporated into proteoliposomes. Liposomes containing gp63 were phagocytosed by macrophages, and uptake was inhibited by more than 90% by both anti-gp63 F(ab) fragments and mannan. These results suggest that the abundant gp63 is a ligand for the macrophage mannose/fucose receptor (Fig. 6). Recent studies indicate that this major integral membrane protein is a protease (83). A water-soluble form of the protease is obtained following digestion with the phospholipase C responsible for the release of variant surface glycoprotein from Trypanosoma brucei (83).
Saccharomyces cerevisiae
Published in Dongyou Liu, Handbook of Foodborne Diseases, 2018
Brunella Posteraro, Gianluigi Quaranta, Patrizia Posteraro, Maurizio Sanguinetti
S. cerevisiae is primarily unicellular, although capable of polarized growth (resembling hyphae), by which the cell can grow toward an environmental cue source.17 Its cells come in three types, called a, α, and a/α, and these cell types differ at the mating-type locus that specifies cell type. The two haploid cell types of yeast (a and α) are able to interconvert through a reversible, programmed DNA-rearrangement process known as mating-type switching.18 This process—that could also be called cell-type switching—is indispensable for unicellular organisms such as yeasts that do not contain distinct germline and somatic DNA, and it is reminiscent of the reversible rearrangements that include the shuffling of variant surface glycoprotein genes in kinetoplastids19 and phase variation in Salmonella20—both are microbial strategies to evade the host immune system. Similarly to as in S. pombe, the switching mechanism in S. cerevisiae requires the haploid genome to have one active and two silent copies of the mating-type locus (a three cassette structure). During switching, the active locus is cleaved, and a synthesis-dependent strand annealing process allows it to be replaced with a copy of a silent locus encoding the opposite mating-type information. Consequently, a haploid a cell can become a haploid α cell, or vice versa, by changing its genotype at the mating-type locus.18
Emerging compounds and therapeutic strategies to treat infections from Trypanosoma brucei: an overhaul of the last 5-years patents
Published in Expert Opinion on Therapeutic Patents, 2023
Francesco Melfi, Simone Carradori, Cristina Campestre, Entela Haloci, Alessandra Ammazzalorso, Rossella Grande, Ilaria D’Agostino
Rhodesian (TbrCATL) belongs to the family of cathepsin L (CATL)-like proteases usually found in the parasite lysosomes and is important for survival, infectivity, and CNS penetration. It possesses a conserved catalytic triad (Cys/His/Asn) within its single chain of 215 peptidic residues [83], able to degrade both protozoan and host proteins, among which the variant surface glycoproteins (VSGs) of the parasite coat and protective immunoglobulins to escape the host immune system [84–86]. Antigenic variation in these VSGs is the main pathogenetic mechanism in T. brucei mediated by regular switching to maintain prolonged infections by bloodstream trypomastigotes [87]. Moreover, proteins involved in DNA recombination include RAD51, which mediates strand invasion in homologous recombination, RAD51-3, and BRCA2 that facilitate VSG switching, and proteins involved in DNA metabolism suppressing VSG switching. TRF and RAP1 are two telomere proteins with unique nucleic acid-binding activities, vital for T. brucei. In addition, TRF and RAP1 play crucial roles in antigenic variation; indeed, several telomere proteins have been identified in T. brucei. TbTRF is the duplex TTAGGG repeat binding factor and a TRF homolog; it associates with the telomere throughout the cell cycle, thus indicating the importance of TRF for the terminal telomere structure and cell proliferation [88]; defects in telomere integrity maintenance allow more VSG switching. TbRAP1 is a homolog of yeast and mammalian RAP1s.
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].
Membrane insertion and intercellular transfer of glycosylphosphatidylinositol-anchored proteins: potential therapeutic applications
Published in Archives of Physiology and Biochemistry, 2020
Certain proteins in eukaryotic cells are modified with a specific glycolipid species, the GPI anchor, which becomes embedded in the outer phospholipid layer of plasma membranes thereby mediating attachment of the protein moiety to the cell surface as so-called GPI-AP (Orlean and Menon 2007). Variant surface glycoprotein (VSG), merozoite surface antigen and promastigote surface protease from the protozoan parasites Trypanosoma brucei (Ferguson et al. 1985, 1988), Plasmodium falciparum (Haldar et al. 1985) and Leishmania major (Schneider et al. 1990), respectively, represent the first GPI-AP for which the structure of their anchor was elucidated by a combination of (bio)chemical cleavage and subsequent two-dimensional NMR. During the following decades GPI-AP have been detected in eukaryotic organisms ranging from yeast (Saccharomyces cerevisiae: Nuoffer et al. 1991, Müller et al. 1992), plants (Pyrus communis: Oxley and Bacic 1999) and mammals (Low and Zilversmit 1980, Ikezawa and Taguchi 1981, Medof et al. 1986, Webb and Todd 1988). Meanwhile, databases relying on algorithms for the in silico prediction of GPI anchorage argue for 1–2% of the translated proteins in mammals representing GPI-AP (Eisenhaber et al. 2001, Poisson et al. 2007). So far, the state-of-the-art (bio)chemical generation of GPI anchor fragments and their mass spectroscopic MS/MS analysis have revealed the GPI modification of more than 150 proteins in mammalian cells including receptors, enzymes and adhesion molecules (Paulick and Bertozzi 2008).