Adaptation of a Thai Multidrug-Resistant C2A Clone of Plasmodium falciparum to Aotus Monkeys and Its Preliminary in vivo Antimalarial Drug Efficacy-Resistance Profile

Obaldía, Nicanor; Milhous, Wilbur K.; Kyle, Dennis E.

doi:10.4269/ajtmh.2009.08-0445

Cited by 7 publications

(20 citation statements)

References 45 publications

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“…All P. falciparum strains tested so far have been supported, indicating that, in contrast to Aotus, Saimiri and previous mouse models, there is no requirement for preliminary adaptation of the parasite to this new host [11], [14], [23], [24], [25]. This was true for the 3 strains employed and for one clinical isolate of P. falciparum tested.…”

Section: Discussionmentioning

confidence: 59%

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Further Improvements of the P. falciparum Humanized Mouse Model

et al. 2011

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BackgroundIt has been shown previously that it is possible to obtain growth of Plasmodium falciparum in human erythrocytes grafted in mice lacking adaptive immune responses by controlling, to a certain extent, innate defences with liposomes containing clodronate (clo-lip). However, the reproducibility of those models is limited, with only a proportion of animals supporting longstanding parasitemia, due to strong inflammation induced by P. falciparum. Optimisation of the model is much needed for the study of new anti-malarial drugs, drug combinations, and candidate vaccines.Materials/MethodsWe investigated the possibility of improving previous models by employing the intravenous route (IV) for delivery of both human erythrocytes (huRBC) and P. falciparum, instead of the intraperitoneal route (IP), by testing various immunosuppressive drugs that might help to control innate mouse defences, and by exploring the potential benefits of using immunodeficient mice with additional genetic defects, such as those with IL-2Rγ deficiency (NSG mice).ResultsWe demonstrate here the role of aging, of inosine and of the IL-2 receptor γ mutation in controlling P. falciparum induced inflammation. IV delivery of huRBC and P. falciparum in clo-lip treated NSG mice led to successful infection in 100% of inoculated mice, rapid rise of parasitemia to high levels (up to 40%), long-lasting parasitemia, and consistent results from mouse-to-mouse. Characteristics were closer to human infection than in previous models, with evidence of synchronisation, partial sequestration, and receptivity to various P. falciparum strains without preliminary adaptation. However, results show that a major IL-12p70 inflammatory response remains prevalent.ConclusionThe combination of the NSG mouse, clodronate loaded liposomes, and IV delivery of huRBC has produced a reliable and more relevant model that better meets the needs of Malaria research.

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Section: Discussionmentioning

confidence: 59%

“…This is the only Malaria model that has ever demonstrated the phenomenon of synchronisation, which is not seen either in Aotus , Saimiri, or other immunodeficient mice [11], [14], [23], [24], [25]. Examination of slides is very impressive with over 95% of parasites seen being at the same stage.…”

Section: Discussionmentioning

confidence: 96%

Further Improvements of the P. falciparum Humanized Mouse Model

et al. 2011

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“…The day of clearance was defined as the first of three consecutive days in which the thick blood films were parasite negative. Suppression was defined as a transient decrease in parasite density post-treatment without clearance [ 17 ]. Animals that cleared parasitaemia were followed for recrudescence with daily blood sampling for parasite determinations until the end of the experiment on day 24 (first experiment) or daily blood sampling until day 32 then biweekly blood sampling until the end of the experiment on day 105 (second experiment).…”

Section: Methodsmentioning

confidence: 99%

Efficacy of intravenous methylene blue, intravenous artesunate, and their combination in preclinical models of malaria

Ohrt

Obaldía

et al. 2014

Malar J

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BackgroundIntravenous artesunate (IV AS) is the present treatment of choice for severe malaria, but development of artemisinin resistance indicates that a further agent will be needed. Methylene blue (MB) is an approved human agent for IV and oral use, and is already being investigated for oral treatment of uncomplicated malaria. To initiate investigation of IV MB for severe malaria, the efficacy of IV MB was compared to IV AS and to their combination in rat and non-human primate malaria models.MethodsIV MB was compared to IV AS and to their combination in the Plasmodium berghei-infected rat, a self-curing model; the Plasmodium falciparum-infected Aotus monkey, a fatal model; and the Plasmodium cynomolgi-infected rhesus monkey, a fatal model. Key endpoints were clearance of all parasites from the blood and cure (clearance without recrudescence).ResultsIn rats, the minimal dose of individual drugs and their combination that cleared parasites from all animals was 20 mg IV MB/kg/day, 60 mg IV AS/kg/day and 10 mg IV MB/kg/day plus 30 mg IV AS/kg/day. In Aotus, 8 mg IV MB/kg/day and 8 mg IV AS/kg/day each cured two of three monkeys by one day after therapy, and the third monkey in each group was cured two days later. The combination of both drugs did not result in superior efficacy. In rhesus, 8 mg IV MB/kg/day and 8 mg IV AS/kg/day performed comparably: parasite clearance occurred by day 3 of therapy, although only one of four animals in each dose group cured. Eight mg/kg/day of both drugs in combination was 100% successful: all four of four animals cured.ConclusionsIn each of the three animal models, the efficacy of IV MB was approximately equal to that of standard of care IV AS. In the rat and rhesus models, the combination was more effective than either single agent. This preclinical data suggests that IV MB, alone or in combination with IV AS, is effective against Plasmodium spp. and can be evaluated in severe malaria models.

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“…We previously demonstrated treatment failures upon AS treatment with the multidrug resistant C2A in the Aotus monkey model 15 . Specifically, we observed recrudescence in monkey passage VII and suppression in passage VIII, in each case after treatment with AS at 20 mg/Kg i.v.…”

Section: Resultsmentioning

confidence: 99%

“…During the adaptation process of passaging the parasite in Aotus , we observed decreasing susceptibility of the parasites to oral MQ or i.v. AS alone or in combination 15 . To determine the basis for the altered drug sensitivity phenotype during Aotus adaptation, we tested the antimalarial drug efficacy to MQ and artemisinin derivatives in vivo and in vitro in C2A, and correlated these parameters with growth rates, genotypic changes and mutations in antimalarial drug resistance genes.…”

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confidence: 99%

Altered drug susceptibility during host adaptation of a Plasmodium falciparum strain in a non-human primate model

Obaldía

Dow

Gerena

et al. 2016

Sci Rep

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Infections with Plasmodium falciparum, the most pathogenic of the Plasmodium species affecting man, have been reduced in part due to artemisinin-based combination therapies. However, artemisinin resistant parasites have recently emerged in South-East Asia. Novel intervention strategies are therefore urgently needed to maintain the current momentum for control and elimination of this disease. In the present study we characterize the phenotypic and genetic properties of the multi drug resistant (MDR) P. falciparum Thai C2A parasite strain in the non-human Aotus primate model, and across multiple passages. Aotus infections with C2A failed to clear upon oral artesunate and mefloquine treatment alone or in combination, and ex vivo drug assays demonstrated reduction in drug susceptibility profiles in later Aotus passages. Further analysis revealed mutations in the pfcrt and pfdhfr loci and increased parasite multiplication rate (PMR) across passages, despite elevated pfmdr1 copy number. Altogether our experiments suggest alterations in parasite population structure and increased fitness during Aotus adaptation. We also present data of early treatment failures with an oral artemisinin combination therapy in a pre-artemisinin resistant P. falciparum Thai isolate in this animal model.

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Adaptation of a Thai Multidrug-Resistant C2A Clone of Plasmodium falciparum to Aotus Monkeys and Its Preliminary in vivo Antimalarial Drug Efficacy-Resistance Profile

Cited by 7 publications

References 45 publications

Further Improvements of the P. falciparum Humanized Mouse Model

Further Improvements of the P. falciparum Humanized Mouse Model

Efficacy of intravenous methylene blue, intravenous artesunate, and their combination in preclinical models of malaria

Altered drug susceptibility during host adaptation of a Plasmodium falciparum strain in a non-human primate model

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