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Ensemble modeling highlights importance of understanding parasite-host behavior in preclinical antimalarial drug development.

ABSTRACT: Emerging drug resistance and high-attrition rates in early and late stage drug development necessitate accelerated development of antimalarial compounds. However, systematic and meaningful translation of drug efficacy and host-parasite dynamics between preclinical testing stages is missing. We developed an ensemble of mathematical within-host parasite growth and antimalarial action models, fitted to extensive data from four antimalarials with different modes of action, to assess host-parasite interactions in two preclinical drug testing systems of murine parasite P. berghei in mice, and human parasite P. falciparum in immune-deficient mice. We find properties of the host-parasite system, namely resource availability, parasite maturation and virulence, drive P. berghei dynamics and drug efficacy, whereas experimental constraints primarily influence P. falciparum infection and drug efficacy. Furthermore, uninvestigated parasite behavior such as dormancy influences parasite recrudescence following non-curative treatment and requires further investigation. Taken together, host-parasite interactions should be considered for meaningful translation of pharmacodynamic properties between murine systems and for predicting human efficacious treatment.

SUBMITTER: Burgert L

PROVIDER: S-EPMC7064600 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Ensemble modeling highlights importance of understanding parasite-host behavior in preclinical antimalarial drug development.

Burgert Lydia L Rottmann Matthias M Wittlin Sergio S Gobeau Nathalie N Krause Andreas A Dingemanse Jasper J Möhrle Jörg J JJ Penny Melissa A MA

Scientific reports 20200310 1

Emerging drug resistance and high-attrition rates in early and late stage drug development necessitate accelerated development of antimalarial compounds. However, systematic and meaningful translation of drug efficacy and host-parasite dynamics between preclinical testing stages is missing. We developed an ensemble of mathematical within-host parasite growth and antimalarial action models, fitted to extensive data from four antimalarials with different modes of action, to assess host-parasite in ...[more]

PMID: 32157151

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Project description:The papillomaviruses (PVs) are a family of viruses infecting several mammalian and nonmammalian species that cause cervical cancer in humans. The evolutionary history of the PVs as it associated with a wide range of host species is not well understood. Incongruities between the phylogenetic trees of various viral genes as well as between these genes and the host phylogenies suggest historical viral recombination as well as violations of strict virus-host cospeciation. The extent of recombination events among PVs is uncertain, however, and there is little evidence to support a theory of PV spread via recent host transfers. We have investigated incongruence between PV genes and hence, the possibility of recombination, using Bayesian phylogenetic methods. We find significant evidence for phylogenetic incongruence among the six PV genes E1, E2, E6, E7, L1, and L2, indicating substantial recombination. Analysis of E1 and L1 phylogenies suggests ancestral recombination events. We also describe a new method for examining alternative host-parasite association mechanisms by applying importance sampling to Bayesian divergence time estimation. This new approach is not restricted by a fixed viral tree topology or knowledge of viral divergence times, multiple parasite taxa per host may be included, and it can distinguish between prior divergence of the virus before host speciation and host transfer of the virus following speciation. Using this method, we find prior divergence of PV lineages associated with the ancestral mammalian host resulting in at least 6 PV lineages prior to speciation of this host. These PV lineages have then followed paths of prior divergence and cospeciation to eventually become associated with the extant host species. Only one significant instance of host transfer is supported, the transfer of the ancestral L1 gene between a Primate and Hystricognathi host based on the divergence times between the upsilon human type 41 and porcupine PVs.

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Ensemble modeling highlights importance of understanding parasite-host behavior in preclinical antimalarial drug development.

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Ensemble modeling highlights importance of understanding parasite-host behavior in preclinical antimalarial drug development.

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