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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
Two additional mechanisms of allelic variation involve expression of VSG genes that are not initially adjacent to promoters. Some of these genes remain unexpressed until a crossover event places one of them in an expression site. As the crossover occurs, the new VSG gene replaces the previously expressed VSG gene, which is then moved away from the promoter site. Finally, many VSG genes are pseuodogenes, arranged in long subtelomeric arrays (Figure 4.29). Because they are not adjacent to promoters, these genes cannot be directly expressed. Rather, they are first replicated and then the duplicate copy of the gene replaces the currently active VSG gene at the expression site. The pseudogene serving as a template remains in place. Thus, the pseudogenes are like a stored collection of genes that might be copied and subsequently expressed at any time. Both of these mechanisms occur following the transition to the blood-form trypomastigote, with the use of pseudogenes more likely to occur later, following the establishment of the chronic infection. This recombination appears to involve double-stranded breaks in the 70-base pair repeats, but the manner in which these breaks occur remains under investigation.
Orders Norzivirales and Timlovirales
Published in Paul Pumpens, Peter Pushko, Philippe Le Mercier, Virus-Like Particles, 2022
Paul Pumpens, Peter Pushko, Philippe Le Mercier
After putative vaccines using carbohydrate epitopes, the Qβ VLPs assisted in the elaboration of an excellent diagnostic tool of Chagas disease (Brito et al. 2016). Thus, the α-Gal antigen [Galα(1,3)Galβ(1,4)GlcNAcα] that was an immunodominant epitope displayed by infective trypomastigote forms of Trypanosoma cruzi, the causative agent of Chagas disease, was displayed on the Qβ VLPs by the CuAAC reaction. The Qβ VLPs displaying a high density of α-Gal were found to be a superior reagent for the ELISA-based serological diagnosis of Chagas disease and the assessment of treatment effectiveness. Next, such Qβ VLPs displaying approximately 540 α-Gal molecules were used to assess the protective effect of anti-α-Gal responses in falciparum malaria (Coelho et al. 2019).
Chimeric VLPs
Published in Paul Pumpens, Single-Stranded RNA Phages, 2020
After putative vaccines using carbohydrate epitopes, the Qβ VLPs assisted in the elaboration of an excellent diagnostic tool of Chagas disease (Brito et al. 2016). Thus, the α-Gal antigen [Galα(1,3)Galβ(1,4)GlcNAcα] that was an immunodominant epitope displayed by infective trypomastigote forms of Trypanosoma cruzi, the causative agent of Chagas disease, was displayed on the Qβ VLPs by the CuAAC reaction. The Qβ VLPs displaying a high density of α-Gal were found to be a superior reagent for the ELISA-based serological diagnosis of Chagas disease and the assessment of treatment effectiveness. A panel of sera from patients chronically infected with T. cruzi, both untreated and benznidazole-treated, was compared with sera from patients with leishmaniasis and from healthy donors. The nanoparticle-α-Gal construct allowed for perfect discrimination between Chagas patients and the others, avoiding false negative and false positive results obtained with current state-of-the-art reagents (Brito et al. 2016). Next, such Qβ VLPs displaying approximately 540 α-Gal molecules were used to assess the protective effect of anti-α-Gal responses in falciparum malaria (Coelho et al 2019).
Plant-made vaccines against parasites: bioinspired perspectives to fight against Chagas disease
Published in Expert Review of Vaccines, 2021
Abel Ramos-Vega, Elizabeth Monreal-Escalante, Eric Dumonteil, Bernardo Bañuelos-Hernández, Carlos Angulo
The antibody-mediated immune response is important for controlling acute T. cruzi infection, but the parasite is able to induce polyclonal activation of B lymphocytes, hypergammaglobulinemia, and block complement activation [33–35]. The antibody-lysis evasion allows trypomastigote spreading and the progression of the infection to the chronic phase of Chagas disease. Currently, the main players of adaptive immunity CD8+ cells through Th1 response have been proposed to fight against T. cruzi infection [36]. However, the cytotoxic T lymphocyte (CTL) response has been observed until two weeks after infection [37], which could be associated with slower intracellular growth cycle than that of intracellular bacteria or viruses. Overall, the development of a vaccine able to induce specific and long-lasting CTL response is of great importance for the prevention of Chagas disease.
Advances in preclinical approaches to Chagas disease drug discovery
Published in Expert Opinion on Drug Discovery, 2019
Fernando Villalta, Girish Rachakonda
Trypanosoma cruzi is the protozoan parasite that causes Chagas disease, also known as American trypanosomiasis. T. cruzi parasites are predominantly transmitted to humans as metacyclic trypomastigote forms (non-dividing) in the feces of infected hematophagous triatomine bugs at the bite site. Entry is either through the wound or transfer to neighboring mucosa. T. cruzi transmission can also occur congenitally, via organ transplantation, blood transfusion, or orally by ingestion of parasite-contaminated food and drink [1]. Infective trypomastigotes invade cells and differentiate into intracellular amastigotes, which multiply by binary fission to differentiate into trypomastigotes to further be released into the circulation as bloodstream trypomastigotes to infect cells again or to be ingested by another vector. The ingested blood trypomastigotes transform into epimastigotes in the vector’s midgut to multiply and then differentiate into infective metacyclic trypomastigotes. The infective trypomastigotes and intracellular replicative amastigotes are the clinically relevant life-cycle stages of the parasite that are targets for drug intervention.
Phenotypic screening approaches for Chagas disease drug discovery
Published in Expert Opinion on Drug Discovery, 2018
Eric Chatelain, Jean-Robert Ioset
Although whether an anti-T. cruzi compound should target all parasite stages is still open to debate, there is consensus within the scientific community on disregarding the vector epimastigote form of the parasite and prioritizing the intracellular amastigotes that persist in the chronic phase of the infection. The fact that azoles are not active against the non-replicative form of T. cruzi, i.e. the trypomastigote (which is not surprising given their mechanism of action) and failed in clinical trials, pointed to the possibility of having compounds targeting both the intracellular replicative amastigote and the non-replicative trypomastigote, highlighting the need for a trypomastigote assay. Unfortunately, neither tissue culture trypomastigote (TCT) nor blood trypomastigotes (BT) isolated from infected mice are particularly amenable to high-throughput assays. Moreover, recent data with a specific class of compound suggest that in vitro activity against the trypomastigote form of T. cruzi (in a given assay) is not essential for curative efficacy in vivo (personal communication).