The Influence of Recombinational Processes to Induce Dormancy in Trypanosoma cruzi

Resende, Bruno Carvalho; Oliveira, Anny Carolline Silva; Guañabens, Anna Carolina Paganini; Repolês, Bruno Marçal; Santana, Verônica de Fátima; Hiraiwa, Priscila Mazzocchi; Pena, Sérgio Danilo Junho; Franco, Glória Regina; Macedo, Andréa Mara; Tahara, Erich Birelli; Fragoso, Stênio Perdigão; Andrade, Luciana O.; Machado, Carlos Renato

doi:10.3389/fcimb.2020.00005

Cited by 23 publications

(25 citation statements)

References 34 publications

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“…This could be the case for those patients who showed an increase in parasite variability after Tx. On the other hand, dormancy would not be so relevant in TcI strains, at least compared to other DTUs, as reported by Resende et al (2020).…”

Section: Discussionmentioning

confidence: 82%

Characterization and Follow-Up of Trypanosoma cruzi Natural Populations Refractory to Etiological Chemotherapy in Oral Chagas Disease Patients

Muñoz-Calderón

Díaz-Bello

Noya

et al. 2021

Front. Cell. Infect. Microbiol.

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We aimed to characterize the genetic constitution of natural T. cruzi populations involved in an Oral Chagas Disease (OCD) outbreak at a rural school of the community of Chichiriviche de la Costa, Venezuela, which affected patients did not respond to the etiological treatment. Peripheral blood samples and/or hemocultures were obtained from twenty-nine OCD patients at time of diagnosis or along nine years of Post-treatment (Tx) follow-up. The IgG serology, T. cruzi discrete typing units (DTU), satellite DNA-qPCR parasitic loads, and minicircle signatures were determined at Pre-Tx and after Tx. The serological titles and parasitic loads changed after treatment, with a significant decrease of IgG titers (Spearman’s r value= -0.961) and median parasite loads from 2.869 [IQR = 2.113 to 3.720] to 0.105 [IQR = -1.147 to 1.761] log10 par eq. /mL at Pre-Tx and Post-Tx, respectively, suggesting infection evolution from acute to chronic phase, without seroconversion or parasitological eradication, which was indicative of treatment failure. All patients were infected with T. cruzi DTU I populations. At Pre-Tx their median Jaccard genetic distances were 0.775 [IQR = 0.708 to 0.882], decreasing in genetic variability towards the end of follow-up (Mann-Whitney U test p= 0.0031). Interestingly, no Post-Tx minicircle signature was identical to its Pre-Tx counterpart population in a same patient, revealing selection of parasite subpopulations between the primary infection and Post-Tx. The parasitic populations isolated from hemocultures showed a lower number of bands in the minicircle signatures with respect to the signatures obtained directly from the patients’ blood samples, demonstrating a process of parasitic selection and reduction of the population variability that initially infected the patients. Decrease of parasitic loads after treatment as well as Pre- and Post-Tx intra-TcI diversity might be a consequence of both, natural evolution of the acute infection to the chronic phase and persistence of refractory populations due to Tx selection.

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Section: Discussionmentioning

confidence: 82%

Characterization and Follow-Up of Trypanosoma cruzi Natural Populations Refractory to Etiological Chemotherapy in Oral Chagas Disease Patients

Muñoz-Calderón

Díaz-Bello

Noya

et al. 2021

Front. Cell. Infect. Microbiol.

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“…Individual non‐replicating amastigotes also occur spontaneously in vitro and are less susceptible to the anti‐parasitic drug benznidazole 21 . The frequency of 4‐day replication arrested in vitro amastigotes has been estimated to be approximately 0.1%‐6%, depending on the parasite strain 188 . The in vivo relevance of these phenomena remains almost completely unknown and will be hard to establish definitively, not least because neither amastigote DNA/kDNA replication, nor differentiation to constitutively non‐replicating trypomastigotes is synchronized 22 .…”

Section: Stage 3: the 1% And The Chronic Host‐parasite Equilibriummentioning

confidence: 99%

Host‐parasite dynamics in Chagas disease from systemic to hyper‐local scales

Pérez‐Mazliah

Ward

Lewis

2020

Parasite Immunology

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Trypanosoma cruzi is a remarkably versatile parasite. It can parasitize almost any nucleated cell type and naturally infects hundreds of mammal species across much of the Americas. In humans, it is the cause of Chagas disease, a set of mainly chronic conditions predominantly affecting the heart and gastrointestinal tract, which can progress to become life threatening. Yet around two thirds of infected people are long‐term asymptomatic carriers. Clinical outcomes depend on many factors, but the central determinant is the nature of the host‐parasite interactions that play out over the years of chronic infection in diverse tissue environments. In this review, we aim to integrate recent developments in the understanding of the spatial and temporal dynamics of T. cruzi infections with established and emerging concepts in host immune responses in the corresponding phases and tissues.

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“…Although Posa at 10 mpk and the combo Posa 1.25 mpk + TH 3.75 mpk suppressed/highly reduced the parasitemia, neither therapeutic scheme was able to reach 100% animal survival and induce sterile cure. Thus, further studies will need to address the efficacy against dormant forms of T. cruzi as recent data suggest the existence of an adaptive difference between parasite strains to generate dormant cells, and that homologous recombination in T. cruzi may be important for dormancy stages ( Sánchez-Valdéz and Padilla, 2019 ; Resende et al., 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Combination With Tomatidine Improves the Potency of Posaconazole Against Trypanosoma cruzi

Rocha-Hasler

Oliveira

Gama

et al. 2021

Front. Cell. Infect. Microbiol.

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Azoles such as posaconazole (Posa) are highly potent against Trypanosoma cruzi. However, when tested in chronic Chagas disease patients, a high rate of relapse after Posa treatment was observed. It appears that inhibition of T. cruzi cytochrome CYP51, the target of azoles, does not deliver sterile cure in monotherapy. Looking for suitable combination partners of azoles, we have selected a set of inhibitors of sterol and sphingolipid biosynthetic enzymes. A small-scale phenotypic screening was conducted in vitro against the proliferative forms of T. cruzi, extracellular epimastigotes and intracellular amastigotes. Against the intracellular, clinically relevant forms, four out of 15 tested compounds presented higher or equal activity as benznidazole (Bz), with EC50 values ≤2.2 μM. Ro48-8071, an inhibitor of lanosterol synthase (ERG7), and the steroidal alkaloid tomatidine (TH), an inhibitor of C-24 sterol methyltransferase (ERG6), exhibited the highest potency and selectivity indices (SI = 12 and 115, respectively). Both were directed to combinatory assays using fixed-ratio protocols with Posa, Bz, and fexinidazole. The combination of TH with Posa displayed a synergistic profile against amastigotes, with a mean ΣFICI value of 0.2. In vivo assays using an acute mouse model of T. cruzi infection demonstrated lack of antiparasitic activity of TH alone in doses ranging from 0.5 to 5 mg/kg. As observed in vitro, the best combo proportion in vivo was the ratio 3 TH:1 Posa. The combination of Posa at 1.25 mpk plus TH at 3.75 mpk displayed suppression of peak parasitemia of 80% and a survival rate of 60% in the acute infection model, as compared to 20% survival for Posa at 1.25 mpk alone and 40% for Posa at 10 mpk alone. These initial results indicate a potential for the combination of posaconazole with tomatidine against T. cruzi.

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The Influence of Recombinational Processes to Induce Dormancy in Trypanosoma cruzi

Cited by 23 publications

References 34 publications

Characterization and Follow-Up of Trypanosoma cruzi Natural Populations Refractory to Etiological Chemotherapy in Oral Chagas Disease Patients

Characterization and Follow-Up of Trypanosoma cruzi Natural Populations Refractory to Etiological Chemotherapy in Oral Chagas Disease Patients

Host‐parasite dynamics in Chagas disease from systemic to hyper‐local scales

Combination With Tomatidine Improves the Potency of Posaconazole Against Trypanosoma cruzi

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