Accounting for red blood cell accessibility reveals distinct invasion strategies in Plasmodium falciparum strains

Cai, Francisco Y.; DeSimone, Tiffany M.; Hansen, Elsa; Jennings, Cameron V.; Bei, Amy K.; Ahouidi, Ambroise D.; Mboup, Souleymane; Duraisingh, Manoj T.; Buckee, Caroline O.

doi:10.1371/journal.pcbi.1007702

Cited by 3 publications

(1 citation statement)

References 57 publications

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“…RBC availability might also constrain successful invasion of RBCs and thus affect the effective replication of the parasite. Recent in vitro studies highlighted distinct RBC invasion strategies of P. falciparum strains, with parasites that favour RBCs of different age [ 41 ], and different parasite strains either invading a larger fraction of RBCs at lower rates or invading smaller fraction of RBCs at a higher rates [ 41 ]. In addition to potential age-dependent differences in RBC availability, it is known that certain RBC polymorphisms, for example sickle cell traits and blood groups [ 42 ] impact the invasion of RBCs.…”

Section: Discussionmentioning

confidence: 99%

Mechanistic within-host models of the asexual Plasmodium falciparum infection: a review and analytical assessment

Lee

Russell

Burgert

et al. 2021

Malar J

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Background Malaria blood-stage infection length and intensity are important drivers of disease and transmission; however, the underlying mechanisms of parasite growth and the host’s immune response during infection remain largely unknown. Over the last 30 years, several mechanistic mathematical models of malaria parasite within-host dynamics have been published and used in malaria transmission models. Methods Mechanistic within-host models of parasite dynamics were identified through a review of published literature. For a subset of these, model code was reproduced and descriptive statistics compared between the models using fitted data. Through simulation and model analysis, key features of the models were compared, including assumptions on growth, immune response components, variant switching mechanisms, and inter-individual variability. Results The assessed within-host malaria models generally replicate infection dynamics in malaria-naïve individuals. However, there are substantial differences between the model dynamics after disease onset, and models do not always reproduce late infection parasitaemia data used for calibration of the within host infections. Models have attempted to capture the considerable variability in parasite dynamics between individuals by including stochastic parasite multiplication rates; variant switching dynamics leading to immune escape; variable effects of the host immune responses; or via probabilistic events. For models that capture realistic length of infections, model representations of innate immunity explain early peaks in infection density that cause clinical symptoms, and model representations of antibody immune responses control the length of infection. Models differed in their assumptions concerning variant switching dynamics, reflecting uncertainty in the underlying mechanisms of variant switching revealed by recent clinical data during early infection. Overall, given the scarce availability of the biological evidence there is limited support for complex models. Conclusions This study suggests that much of the inter-individual variability observed in clinical malaria infections has traditionally been attributed in models to random variability, rather than mechanistic disease dynamics. Thus, it is proposed that newly developed models should assume simple immune dynamics that minimally capture mechanistic understandings and avoid over-parameterization and large stochasticity which inaccurately represent unknown disease mechanisms.

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Section: Discussionmentioning

confidence: 99%

Mechanistic within-host models of the asexual Plasmodium falciparum infection: a review and analytical assessment

Lee

Russell

Burgert

et al. 2021

Malar J

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Deconstructing the parasite multiplication rate of Plasmodium falciparum

Gnangnon

Duraisingh

Buckee

2021

Trends in Parasitology

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Growing Malaria Parasites at a Critical Shaking Speed Mimicking Physiological Flow Reveals New Phenotypes for Invasion Ligands

Kals,

Cicuta

et al. 2024

Preprint

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Malaria kills over 600,000 people annually, with all the clinical symptoms being caused by the blood stage of the infection. Malaria parasites invade red blood cells (RBCs), where they grow and multiply until daughter parasites egress to invade new RBCs. This cycle happens primarily in the blood circulation, bone marrow, and spleen, where parasites and RBCs are exposed to flow-generated forces. However, most in vitro growth assays are carried out in static conditions, which are a poor mimic for growth in the body. Previously, more dynamic growth conditions were created using orbital shaking platforms, but exploration of the impact of shaking has been limited, and no attempt has been made to understand the forces generated by the resultant fluid motion. For several strains of the deadliest malaria species, Plasmodium falciparum, we show that growth under shaking is strongly impacted by shaking speed, vessel geometry and haematocrit. Strikingly, for any given vessel, there is a critical shaking speed at which growth rates are reduced, corresponding to when the RBCs start to aggregate in the centre of the well, at which point the forces that RBCs and parasites are exposed to are comparable to the forces in the microvasculature. By contrast, the growth rate is increased in more turbulent conditions generated by higher shaking speeds. Using a panel of P. falciparum lines in which known invasion proteins were disrupted, we show that the critical shaking speed can reveal new growth phenotypes, showing several ligands have greater importance in high wall shear stress conditions.

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Accounting for red blood cell accessibility reveals distinct invasion strategies in Plasmodium falciparum strains

Cited by 3 publications

References 57 publications

Mechanistic within-host models of the asexual Plasmodium falciparum infection: a review and analytical assessment

Mechanistic within-host models of the asexual Plasmodium falciparum infection: a review and analytical assessment

Deconstructing the parasite multiplication rate of Plasmodium falciparum

Growing Malaria Parasites at a Critical Shaking Speed Mimicking Physiological Flow Reveals New Phenotypes for Invasion Ligands

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