Biology subjects

McCaw, J.

Publications and source records attributed to McCaw, J..

3 recordsLinked to original sources

bioRxiv2023

Characterisation of Plasmodium vivax lactate dehydrogenase dynamics in P. vivax infections

Plasmodium vivax lactate dehydrogenase (PvLDH) is an essential enzyme in the glycolytic pathway of Plasmodium vivax. It can also be used as a diagnostic biomarker. Quantitation of plasma PvLDH has been used as a measure of P. vivax biomass in clinical studies of uncomplicated and severe vivax malaria. With the increasing importance of PvLDH in studying P. vivax diagnosis and infection, improved characterisation of the dynamics of this biomarker is important. In this study, we developed mathematical models that capture parasite and matrix PvLDH dynamics in ex vivo culture and the human host. We estimated the biological parameters using ex vivo and in vivo longitudinal data of parasitemia and PvLDH concentration collected from P. vivax-infected humans using Bayesian hierarchical inference. We found that the ex vivo and in vivo estimates of PvLDH in a parasitized red blood cell differed significantly across the asexual life cycle, with in vivo estimates at least ten-fold higher than ex vivo estimates (for example, the median estimate of intraerythrocytic PvLDH mass at the end of the life cycle was 9.4x10-3 ng in vivo vs. 5.1x10-4 ng ex vivo). We also estimated the ex vivo PvLDH half-life to be 65.3 h (95% credible interval: 60.8--70.7 h), which is approximately three times longer than the median estimate of the in vivo PvLDH half-life, 21.9 h (16.7--29.9 h). Our findings provide an important foundation to further improve quantitative understanding of P. vivax biology and facilitate the development of PvLDH-based diagnostic tools.

biophysics↗

bioRxiv2022

Choice of spatial discretisation influences the progression of viral infection within multicellular tissues

There has been an increasing recognition of the utility of models of the spatial dynamics of viral spread within tissues. Multicellular models, where cells are represented as discrete regions of space coupled to a virus density surface, are a popular approach to capture these dynamics. Conventionally, such models are simulated by discretising the viral surface and depending on the rate of viral diffusion and other considerations, a finer or coarser discretisation may be used. The impact that this choice may have on the behaviour of the system has not been studied. Here we demonstrate that, if rates of viral diffusion are small, then the choice of spatial discretisation of the viral surface can have quantitative and even qualitative influence on model outputs. We investigate in detail the mechanisms driving these phenomena and discuss the constraints on the design and implementation of multicellular viral dynamics models for different parameter configurations. Author summaryHere we analyse the impact that the resolution of spatial discretisation has on the behaviour of spatial models of viral dynamics. We show that the extent of this influence depends on the size of the diffusion coefficient, and that, if the diffusion coefficient is sufficiently small - for example, small enough to describe tight plaque-forming dynamics - the choice of discretisation of the viral surface relative to the cell grid can appreciably change key predictions of the model. We show that the resolution of spatial discretisation modulates the timescale of infection, and identify the mechanisms by which this occurs. This work provides theory to inform the development of multicellular models of viral dynamics, which is in short supply in the literature.

immunology↗

bioRxiv2018

Investigating the efficacy of triple artemisinin-based combination therapies (TACTs) for treating Plasmodium falciparum malaria patients using mathematical modelling

The first line treatment for uncomplicated falciparum malaria is artemisinin-based combination therapy (ACT), which consists of an artemisinin derivative co-administered with a longer acting partner drug. However, the spread of Plasmodium falciparum resistant to both artemisinin and its partner drugs poses a major global threat to malaria control activities. Novel strategies are needed to retard and reverse the spread of these resistant parasites. One such strategy is triple artemisinin-based combination therapy (TACT). We developed a mechanistic within-host mathematical model to investigate the efficacy of a TACT (dihydroartemisinin-piperaquine-mefloquine - DHA-PQ-MQ), for use in South-East Asia, where DHA and PQ resistance are now increasingly prevalent. Comprehensive model simulations were used to explore the degree to which the underlying resistance influences the parasitological outcomes. The effect of MQ dosing on the efficacy of TACT was quantified at varying degrees of DHA and PQ resistance. To incorporate interactions between drugs, a novel model is presented for the combined effect of DHA-PQ-MQ, which illustrates how the interactions can influence treatment efficacy. When combined with a standard regimen of DHA and PQ, the administration of three 8.3 mg/kg doses of MQ was sufficient to achieve parasitological efficacy greater than that currently recommended by WHO guidelines.

pharmacology and toxicology↗