scholarly journals Modelling the population dynamics of Plasmodium falciparum gametocytes in humans during malaria infection

2019 ◽  
Author(s):  
Pengxing Cao ◽  
Katharine A. Collins ◽  
Sophie Zaloumis ◽  
Thanaporn Wattanakul ◽  
Joel Tarning ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Plasmodium Falciparum ◽  
Population Dynamics ◽  
Malaria Infection ◽  
Credible Interval ◽  
The Novel ◽  
Reliable Prediction ◽  
Bayesian Hierarchical ◽  
Kinetics Of

AbstractEvery year over two hundred million people are infected with the malaria parasite. Renewed efforts to eliminate malaria has highlighted the potential to interrupt transmission from humans to mosquitoes which is mediated through the gametocytes. Reliable prediction of transmission requires an improved understanding of in vivo kinetics of gametocytes. Here we study the population dynamics of Plasmodium falciparum gametocytes in human hosts by establishing a framework which incorporates improved measurements of parasitaemia in humans, a novel mathematical model of gametocyte dynamics, and model validation using a Bayesian hierarchical inference method. We found that the novel mathematical model provides an excellent fit to the available clinical data from 17 volunteers infected with P. falciparum, and reliably predicts observed gametocyte levels. We estimated the P. falciparum’s sexual commitment rate and gametocyte sequestration time in humans to be 0.54% (95% credible interval: 0.30-1.00) per life cycle and 8.39 (6.54-10.59) days respectively. Furthermore, we used the data-calibrated model to predict the effects of those gametocyte dynamics parameters on human-to-mosquito transmissibility, providing a method to link within-human host kinetics of malaria infection to epidemiological-scale infection and transmission patterns.

scholarly journals Modeling the dynamics of Plasmodium falciparum gametocytes in humans during malaria infection

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Pengxing Cao ◽  
Katharine A Collins ◽  
Sophie Zaloumis ◽  
Thanaporn Wattanakul ◽  
Joel Tarning ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Clinical Data ◽  
Malaria Infection ◽  
Model Fitting ◽  
Credible Interval ◽  
Dynamics Model ◽  
Bayesian Hierarchical ◽  
Human Host ◽  
Host Infection

Renewed efforts to eliminate malaria have highlighted the potential to interrupt human-to-mosquito transmission — a process mediated by gametocyte kinetics in human hosts. Here we study the in vivo dynamics of Plasmodium falciparum gametocytes by establishing a framework which incorporates improved measurements of parasitemia, a novel gametocyte dynamics model and model fitting using Bayesian hierarchical inference. We found that the model provides an excellent fit to the clinical data from 17 volunteers infected with P. falciparum (3D7 strain) and reliably predicts observed gametocytemia. We estimated the sexual commitment rate and gametocyte sequestration time to be 0.54% (95% credible interval: 0.30–1.00%) per asexual replication cycle and 8.39 (6.54–10.59) days respectively. We used the data-calibrated model to investigate human-to-mosquito transmissibility, providing a method to link within-human host infection kinetics to epidemiological-scale infection and transmission patterns.

scholarly journals In Vivo Hemozoin Kinetics after Clearance of Plasmodium berghei Infection in Mice

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Rosangela Frita ◽  
Daniel Carapau ◽  
Maria M. Mota ◽  
Thomas Hänscheid
Keyword(s):  
Plasmodium Berghei ◽  
Blood Cells ◽  
Malaria Infection ◽  
Blood Stream ◽  
Biologically Active ◽  
Immune Functions ◽  
Parasite Replication ◽  
Kinetics Of

Hemozoin (Hz) is released into the blood stream after rupture of infected red blood cells (iRBCs) at the end of each parasite replication cycle. This free Hz is ingested by circulating and resident phagocytes. The presence of Hz in tissues after clearance of infection has been previously reported. Still, little is known about the kinetics of Hz in vivo, during and after Plasmodium infection. It is particularly important to understand Hz kinetics after malaria infections as it has been reported that Hz is associated with impairment of immune functions, including possible consequences for coinfections. Indeed, if Hz remains biologically active for prolonged periods of time inside immunocompetent cells, the potential consequences of such accumulation and presence to the immune system should be clarified. Here, using several independent methods to assess the presence of Hz, we report the long-term in vivo kinetics of Hz in diverse organs in a murine model of malaria infection.

scholarly journals In vivo imaging of the kinetics of microglial self-renewal and maturation in the adult visual cortex

2020 ◽  
Author(s):  
Monique S. Mendes ◽  
Jason Atlas ◽  
Zachary Brehm ◽  
Antonio Ladron-de-Guevara ◽  
Matthew N. McCall ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Visual Cortex ◽  
Adult Brain ◽  
Self Renewal ◽  
Two Photon ◽  
And Migration ◽  
The Mathematical Model ◽  
Kinetics Of ◽  
The Brain

AbstractMicroglia are the resident immune cells in the brain with the capacity to autonomously self-renew. Under basal conditions, microglial self-renewal appears to be slow and stochastic, although microglia have the ability to proliferate very rapidly following depletion or in response to injury. Because microglial self-renewal has largely been studied using static tools, the mechanisms and kinetics by which microglia renew and acquire mature characteristics in the adult brain are not well understood. Using chronic in vivo two-photon imaging in awake mice and PLX5622 (Colony stimulating factor 1 receptor (CSF1R) inhibitor) to deplete microglia, we set out to understand the dynamic self-organization and maturation of microglia following depletion in the visual cortex. We confirm that under basal conditions, cortical microglia show limited turnover and migration. Following depletion, however, microglial repopulation is remarkably rapid and is sustained by the dynamic division of the remaining microglia in a manner that is largely independent of signaling through the P2Y12 receptor. Mathematical modeling of microglial division demonstrates that the observed division rates can account for the rapid repopulation observed in vivo. Additionally, newly-born microglia resemble mature microglia, in terms of their morphology, dynamics and ability to respond to injury, within days of repopulation. Our work suggests that microglia rapidly self-renew locally, without the involvement of a special progenitor cell, and that newly born microglia do not recapitulate a slow developmental maturation but instead quickly take on mature roles in the nervous system.Graphical Abstract(a) Microglial dynamics during control condition. Cartoon depiction of the heterogenous microglia in the visual cortex equally spaced. (b) During the early stages of repopulation, microglia are irregularly spaced and sparse. (c) During the later stages of repopulation, the number of microglia and the spatial distribution return to baseline. (d-f) We then created and ran a mathematical model that sampled the number of microglia, (d) the persistent doublets, (e) the rapid divisions of microglia and (f) the secondary divisions of microglia during the peak of repopulation day 2-day 3. The mathematical model suggested that residual microglia can account for the rapid repopulation we observed in vivo.

scholarly journals Calibration, Selection and Identifiability Analysis of a Mathematical Model of the in vitro Erythropoiesis in Normal and Perturbed Contexts

2018 ◽  
Author(s):  
Ronan Duchesne ◽  
Anissa Guillemin ◽  
Fabien Crauste ◽  
Olivier Gandrillon
Keyword(s):  
Mathematical Model ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Identifiability Analysis ◽  
The Past ◽  
Parameter Variations ◽  
Linear Ode ◽  
Kinetics Of

AbstractThe in vivo erythropoiesis, which is the generation of mature red blood cells in the bone marrow of whole organisms, has been described by a variety of mathematical models in the past decades. However, the in vitro erythropoiesis, which produces red blood cells in cultures, has received much less attention from the modelling community. In this paper, we propose the first mathematical model of in vitro erythropoiesis. We start by formulating different models and select the best one at fitting experimental data of in vitro erythropoietic differentiation. It is based on a set of linear ODE, describing 3 hypothetical populations of cells at different stages of differentiation. We then compute confidence intervals for all of its parameters estimates, and conclude that our model is fully identifiable. Finally, we use this model to compute the effect of a chemical drug called Rapamycin, which affects all states of differentiation in the culture, and relate these effects to specific parameter variations. We provide the first model for the kinetics of in vitro cellular differentiation which is proven to be identifiable. It will serve as a basis for a model which will better account for the variability which is inherent to experimental protocol used for the model calibration.

scholarly journals Controlled Human Malaria Infection in Semi-Immune Kenyan Adults (CHMI-SIKA): a study protocol to investigate in vivo Plasmodium falciparum malaria parasite growth in the context of pre-existing immunity

2018 ◽  
Vol 3 ◽  
pp. 155 ◽  
Author(s):  
Melissa C. Kapulu ◽  
Patricia Njuguna ◽  
Mainga M. Hamaluba ◽  
Keyword(s):  
Plasmodium Falciparum ◽  
Immune Responses ◽  
Malaria Infection ◽  
Malaria Vaccine ◽  
Parasite Growth ◽  
Host Immunity ◽  
Human Malaria ◽  
Controlled Human Malaria Infection ◽  
Adult Volunteers

Malaria remains a major public health burden despite approval for implementation of a partially effective pre-erythrocytic malaria vaccine. There is an urgent need to accelerate development of a more effective multi-stage vaccine. Adults in malaria endemic areas may have substantial immunity provided by responses to the blood stages of malaria parasites, but field trials conducted on several blood-stage vaccines have not shown high levels of efficacy.  We will use controlled human malaria infection (CHMI) studies with malaria-exposed volunteers to identify correlations between immune responses and parasite growth rates in vivo.  Immune responses more strongly associated with control of parasite growth should be prioritized to accelerate malaria vaccine development. We aim to recruit up to 200 healthy adult volunteers from areas of differing malaria transmission in Kenya, and after confirming their health status through clinical examination and routine haematology and biochemistry, we will comprehensively characterize immunity to malaria using >100 blood-stage antigens. We will administer 3,200 aseptic, purified, cryopreserved Plasmodium falciparum sporozoites (PfSPZ Challenge) by direct venous inoculation. Serial quantitative polymerase chain reaction to measure parasite growth rate in vivo will be undertaken. Clinical and laboratory monitoring will be undertaken to ensure volunteer safety. In addition, we will also explore the perceptions and experiences of volunteers and other stakeholders in participating in a malaria volunteer infection study. Serum, plasma, peripheral blood mononuclear cells and extracted DNA will be stored to allow a comprehensive assessment of adaptive and innate host immunity. We will use CHMI in semi-immune adult volunteers to relate parasite growth outcomes with antibody responses and other markers of host immunity. Registration: ClinicalTrials.gov identifier NCT02739763.

scholarly journals Phosphorylation of SNAP-23 by the Novel Kinase SNAK Regulates t-SNARE Complex Assembly

1999 ◽  
Vol 10 (12) ◽  
pp. 4033-4041 ◽  
Author(s):  
J.-P. Cabaniols ◽  
V. Ravichandran ◽  
P.A. Roche
Keyword(s):  
Snare Complex ◽  
Snare Proteins ◽  
Eukaryotic Cells ◽  
The Novel ◽  
Complex Assembly ◽  
Human Kinase ◽  
Target Membrane ◽  
The Stability ◽  
Kinetics Of

The docking and fusion of cargo-containing vesicles with target membranes of eukaryotic cells is mediated by the interaction of SNARE proteins present on both vesicle and target membranes. In many cases, the target membrane SNARE, or t-SNARE, exists as a complex of syntaxin with a member of the SNAP-25 family of palmitoylated proteins. We have identified a novel human kinase SNAK (SNARE kinase) that specifically phosphorylates the nonneuronal t-SNARE SNAP-23 in vivo. Interestingly, only SNAP-23 that is not assembled into t-SNARE complexes is phosphorylated by SNAK, and phosphorylated SNAP-23 resides exclusively in the cytosol. Coexpression with SNAK significantly enhances the stability of unassembled SNAP-23, and as a consequence, the assembly of newly synthesized SNAP-23 with syntaxin is augmented. These data demonstrate that phosphorylation of SNAP-23 by SNAK enhances the kinetics of t-SNARE assembly in vivo.

Quantification of Cerebral A1 Adenosine Receptors in Humans using [18F]CPFPX and PET

2004 ◽  
Vol 24 (3) ◽  
pp. 323-333 ◽  
Author(s):  
Philipp T Meyer ◽  
Dirk Bier ◽  
Marcus H Holschbach ◽  
Christian Boy ◽  
Ray A Olsson ◽  
...  
Keyword(s):  
Compartment Model ◽  
Graphical Analysis ◽  
Attractive Alternative ◽  
The Novel ◽  
Tissue Compartment ◽  
Arterial Blood ◽  
Positron Emission ◽  
Pet Scanning ◽  
Kinetics Of

Adenosine is an important neuromodulator. Basic cerebral effects of adenosine are exerted by the A1 adenosine receptor (A1AR), which is accessible in vivo by the novel ligand [18F]8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine ([18F]CPFPX) and positron emission tomography (PET). The present study investigates the applicability of kinetic models to describe the cerebral kinetics of [18F]CPFPX in order to quantify A1AR density in vivo. Six healthy volunteers underwent dynamic PET scanning and arterial blood sampling after bolus injection of [18F]CPFPX. For quantitative analysis, a standard two-tissue compartment model (2TCM) was compared with a one-tissue compartment model (1TCM) and Logan's graphical analysis (GA). The 2TCM described the cerebral kinetics of [18F]CPFPX significantly better than the 1TCM (in all regions and subjects examined). The estimated values of the regional total distribution volumes ( DVt) correlated strongly between the 2TCM and GA (linear regression r2 = 0.99, slope: 1.007). The DVt correlation between the 2TCM and the 1TCM was comparably high, but there was a significant bias towards lower DVt estimates given by the 1TCM (r2: 0.99, slope: 0.929). It is concluded that a 2TCM satisfactorily accounts for the cerebral kinetics of [18F]CPFPX. GA represents an attractive alternative method of analysis.

scholarly journals The P. falciparum CSP repeat region contains three distinct epitopes required for protection by antibodies in vivo

2021 ◽  
Vol 17 (11) ◽  
pp. e1010042
Author(s):  
Yevel Flores-Garcia ◽  
Lawrence T. Wang ◽  
Minah Park ◽  
Beejan Asady ◽  
Azza H. Idris ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Monoclonal Antibodies ◽  
Malaria Infection ◽  
Vaccine Development ◽  
Circumsporozoite Protein ◽  
Repeat Region ◽  
Human Mabs ◽  
Necessary And Sufficient

Rare and potent monoclonal antibodies (mAbs) against the Plasmodium falciparum (Pf) circumsporozoite protein (CSP) on infective sporozoites (SPZ) preferentially bind the PfCSP junctional tetrapeptide NPDP or NVDP minor repeats while cross-reacting with NANP major repeats in vitro. The extent to which each of these epitopes is required for protection in vivo is unknown. Here, we assessed whether junction-, minor repeat- and major repeat-preferring human mAbs (CIS43, L9 and 317 respectively) bound and protected against in vivo challenge with transgenic P. berghei (Pb) SPZ expressing either PfCSP with the junction and minor repeats knocked out (KO), or PbCSP with the junction and minor repeats knocked in (KI). In vivo protection studies showed that the junction and minor repeats are necessary and sufficient for CIS43 and L9 to neutralize KO and KI SPZ, respectively. In contrast, 317 required major repeats for in vivo protection. These data establish that human mAbs can prevent malaria infection by targeting three different protective epitopes (NPDP, NVDP, NANP) in the PfCSP repeat region. This report will inform vaccine development and the use of mAbs to passively prevent malaria.

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