SYNCHRONY-BREAKING HOPF BIFURCATION IN A MODEL OF ANTIGENIC VARIATION

2013 ◽  
Vol 23 (02) ◽  
pp. 1350021 ◽  
Author(s):  
BERNARD S. CHAN ◽  
PEI YU
Keyword(s):  
Plasmodium Falciparum ◽  
Hopf Bifurcation ◽  
Numerical Simulations ◽  
Antigenic Variation ◽  
Cross Reactivity ◽  
In Vivo Model ◽  
Main Attention ◽  
Cell Systems ◽  
Coupled Cell Systems

In this paper, we will analyze the bifurcation dynamics of an in vivo model of Plasmodium falciparum. The main attention of this model is focused on the dynamics of cross-reactivity from antigenic variation. We apply the techniques of coupled cell systems to study this model. It is shown that synchrony-breaking Hopf bifurcation occurs from a nontrivial synchronous equilibrium. In proving the existence of a Hopf bifurcation, we also discover the condition under which possible 2-color synchrony patterns arise from the bifurcation. The dynamics resulting from the bifurcation are qualitatively similar to known behavior of antigenic variation. These results are discussed and illustrated with specific examples and numerical simulations.

scholarly journals Optimization of an in vivo model to study immunity to Plasmodium falciparum pre-erythrocytic stages

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Yevel Flores-Garcia ◽  
Sonia M. Herrera ◽  
Hugo Jhun ◽  
Daniel W. Pérez-Ramos ◽  
C. Richter King ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Plasmodium Falciparum ◽  
Genetically Engineered ◽  
In Vivo Model ◽  
Protective Capacity ◽  
Liver Stage ◽  
In Vivo Bioluminescence Imaging ◽  
Bioluminescence Assay ◽  
Stage Infection

Abstract Background The circumsporozoite protein (CSP) of Plasmodium is a key surface antigen that induces antibodies and T-cells, conferring immune protection in animal models and humans. However, much of the work on CSP and immunity has been developed based on studies using rodent or non-human primate CSP antigens, which may not be entirely translatable to CSP expressed by human malaria parasites, especially considering the host specificity of the different species. Methods Using a genetically engineered strain of Plasmodium berghei that expresses luciferase, GFP and the Plasmodium falciparum orthologue of CSP, the effect of laboratory preparation, mosquito treatment and mouse factors on sporozoite infectivity was assessed using an in vivo bioluminescence assay on mice. This assay was compared with a PCR-based protection assay using an already described monoclonal antibody that can provide sterile protection against sporozoite challenge. Results Bioluminescence assay demonstrated similar detection levels of the quantity and kinetics of liver-stage infection, compared to PCR-based detection. This assay was used to evaluate treatment of sporozoite and delivery method on mouse infectivity, as well as the effects of age, sex and strain of mice. Finally, this assay was used to test the protective capacity of monoclonal antibody AB317; results strongly recapitulate the findings of previous work on this antibody. Conclusions The PbGFP-Luc line and in vivo bioluminescence imaging provide highly sensitive read-outs of liver-stage infection in mice, and this method can be useful to reliably evaluate potency of pre-erythrocytic interventions.

scholarly journals Metabolic Signature Profiling as a Diagnostic and Prognostic Tool in Pediatric Plasmodium falciparum Malaria

2015 ◽  
Vol 2 (2) ◽  
Author(s):  
Izabella Surowiec ◽  
Judy Orikiiriza ◽  
Elisabeth Karlsson ◽  
Maria Nelson ◽  
Mari Bonde ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Principal Component ◽  
Malaria Diagnosis ◽  
Plasmodium Falciparum Malaria ◽  
Metabolite Profile ◽  
Mass Spectrometry Analysis ◽  
Gas Chromatography Mass Spectrometry ◽  
In Vivo Model ◽  
Spectrometry Analysis

Abstract Background.  Accuracy in malaria diagnosis and staging is vital to reduce mortality and post infectious sequelae. In this study, we present a metabolomics approach to diagnostic staging of malaria infection, specifically Plasmodium falciparum infection in children. Methods.  A group of 421 patients between 6 months and 6 years of age with mild and severe states of malaria with age-matched controls were included in the study, 107, 192, and 122, individuals, respectively. A multivariate design was used as basis for representative selection of 20 patients in each category. Patient plasma was subjected to gas chromatography-mass spectrometry analysis, and a full metabolite profile was produced from each patient. In addition, a proof-of-concept model was tested in a Plasmodium berghei in vivo model where metabolic profiles were discernible over time of infection. Results.  A 2-component principal component analysis revealed that the patients could be separated into disease categories according to metabolite profiles, independently of any clinical information. Furthermore, 2 subgroups could be ide.jpegied in the mild malaria cohort who we believe represent patients with divergent prognoses. Conclusions.  Metabolite signature profiling could be used both for decision support in disease staging and prognostication.

scholarly journals 4-aminoquinoline analogs of chloroquine with shortened side chains retain activity against chloroquine-resistant Plasmodium falciparum.

1996 ◽  
Vol 40 (8) ◽  
pp. 1846-1854 ◽  
Author(s):  
R G Ridley ◽  
W Hofheinz ◽  
H Matile ◽  
C Jaquet ◽  
A Dorn ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Plasmodium Falciparum Malaria ◽  
Cross Resistance ◽  
In Vivo Model ◽  
Pharmacokinetic Analysis ◽  
European Patent ◽  
Side Chains ◽  
Resistant Strains

We have synthesized several 4-aminoquinolines with shortened side chains that retain activity against chloroquine-resistant isolates of Plasmodium falciparum malaria (W. Hofheinz, C. Jaquet, and S. Jolidon, European patent 94116281.0, June 1995). We report here an assessment of the activities of four selected compounds containing ethyl, propyl, and isopropyl side chains. Reasonable in vitro activity (50% inhibitory concentration, < 100 nM) against chloroquine-resistant P. falciparum strains was consistently observed, and the compounds performed well in a variety of plasmodium berghei animal models. However, some potential drawbacks of these compounds became evident upon in-depth testing. In vitro analysis of more than 70 isolates of P. falciparum and studies with a mouse in vivo model suggested a degree of cross-resistance with chloroquine. In addition, pharmacokinetic analysis demonstrated the formation of N-dealkylated metabolites of these compounds. These metabolites are similarly active against chloroquine-susceptible strains but are much less active against chloroquine-resistant strains. Thus, the clinical dosing required for these compounds would probably be greater for chloroquine-resistant strains than for chloroquine-susceptible strains. The clinical potential of these compounds is discussed within the context of chloroquine's low therapeutic ratio and toxicity.

scholarly journals Collective Oscillations in Coupled-Cell Systems

2021 ◽  
Vol 83 (6) ◽  
Author(s):  
Kuan-Wei Chen ◽  
Chih-Wen Shih
Keyword(s):  
Hopf Bifurcation ◽  
Single Cell ◽  
Single Cells ◽  
System Modeling ◽  
Average Frequency ◽  
Cell System ◽  
Coupled Systems ◽  
Cell Systems ◽  
Coupled Cell Systems ◽  
The One

AbstractWe investigate oscillations in coupled systems. The methodology is based on the Hopf bifurcation theorem and a condition extended from the Routh–Hurwitz criterion. Such a condition leads to locating the bifurcation values of the parameters. With such an approach, we analyze a single-cell system modeling the minimal genetic negative feedback loop and the coupled-cell system composed by these single-cell systems. We study the oscillatory properties for these systems and compare these properties between the model with Hill-type repression and the one with protein-sequestration-based repression. As the parameters move from the Hopf bifurcation value for single cells to the one for coupled cells, we compute the eigenvalues of the linearized systems to obtain the magnitude of the collective frequency when the periodic solution of the coupled-cell system is generated. Extending from this information on the parameter values, we further compute and compare the collective frequency for the coupled-cell system and the average frequency of the decoupled individual cells. To compare these scenarios with other biological oscillators, we perform parallel analysis and computations on a segmentation clock model.

scholarly journals The antigenic switching network of Plasmodium falciparum and its implications for the immuno-epidemiology of malaria

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Robert Noble ◽  
Zóe Christodoulou ◽  
Sue Kyes ◽  
Robert Pinches ◽  
Chris I Newbold ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antigenic Variation ◽  
Survival Rates ◽  
Severe Infection ◽  
Switching Network ◽  
Random Pattern ◽  
Transcription Analysis ◽  
Fitness Advantage

Antigenic variation in the human malaria parasite Plasmodium falciparum involves sequential and mutually exclusive expression of members of the var multi-gene family and appears to follow a non-random pattern. In this study, using a detailed in vitro gene transcription analysis of the culture-adapted HB3 strain of P. falciparum, we show that antigenic switching is governed by a global activation hierarchy favouring short and highly diverse genes in central chromosomal location. Longer and more conserved genes, which have previously been associated with severe infection in immunologically naive hosts, are rarely activated, however, implying an in vivo fitness advantage possibly through adhesion-dependent survival rates. We further show that a gene’s activation rate is positively associated sequence diversity, which could offer important new insights into the evolution and maintenance of antigenic diversity in P. falciparum malaria.

scholarly journals Limited Cross-Reactivity among Domains of the Plasmodium falciparum Clone 3D7 Erythrocyte Membrane Protein 1 Family

2006 ◽  
Vol 74 (12) ◽  
pp. 6778-6784 ◽  
Author(s):  
Louise Joergensen ◽  
Louise Turner ◽  
Pamela Magistrado ◽  
Madeleine A. Dahlbäck ◽  
Lasse S. Vestergaard ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Membrane Protein ◽  
Erythrocyte Membrane ◽  
Antigenic Variation ◽  
Asymptomatic Infection ◽  
Cross Reactivity ◽  
Enzyme Linked Immunosorbent Assay ◽  
Erythrocyte Membrane Protein ◽  
A Domains ◽  
Antibody Epitopes

ABSTRACT The var gene-encoded Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family is responsible for antigenic variation and sequestration of infected erythrocytes during malaria. We have previously grouped the 60 PfEMP1 variants of P. falciparum clone 3D7 into groups A and B/A (category A) and groups B, B/C, and C (category non-A). Expression of category A molecules is associated with severe malaria, and that of category non-A molecules is associated with uncomplicated malaria and asymptomatic infection. Here we assessed cross-reactivity among 60 different recombinant PfEMP1 domains derived from clone 3D7 by using a competition enzyme-linked immunosorbent assay and a pool of plasma from 63 malaria-exposed Tanzanian individuals. We conclude that naturally acquired antibodies are largely directed toward epitopes varying between different domains with a few, mainly category A, domains sharing cross-reactive antibody epitopes. Identification of groups of serological cross-reacting molecules is pivotal for the development of vaccines based on PfEMP1.

Ultrastructural observations on the in vitro cytoadherence of Plasmodium falciparum infected red blood cells

1990 ◽  
Vol 48 (3) ◽  
pp. 914-915
Author(s):  
D.J.P. Ferguson ◽  
A.R. Berendt ◽  
J. Tansey ◽  
K. Marsh ◽  
C.I. Newbold
Keyword(s):  
Plasmodium Falciparum ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Umbilical Vein ◽  
Cell Types ◽  
Amelanotic Melanoma ◽  
Cytoplasmic Process ◽  
Umbilical Vein Endothelial Cells

In human malaria, the most serious clinical manifestation is cerebral malaria (CM) due to infection with Plasmodium falciparum. The pathology of CM is thought to relate to the fact that red blood cells containing mature forms of the parasite (PRBC) cytoadhere or sequester to post capillary venules of various tissues including the brain. This in vivo phenomenon has been studied in vitro by examining the cytoadherence of PRBCs to various cell types and purified proteins. To date, three Ijiost receptor molecules have been identified; CD36, ICAM-1 and thrombospondin. The specific changes in the PRBC membrane which mediate cytoadherence are less well understood, but they include the sub-membranous deposition of electron-dense material resulting in surface deformations called knobs. Knobs were thought to be essential for cytoadherence, lput recent work has shown that certain knob-negative (K-) lines can cytoadhere. In the present study, we have used electron microscopy to re-examine the interactions between K+ PRBCs and both C32 amelanotic melanoma cells and human umbilical vein endothelial cells (HUVEC).We confirm previous data demonstrating that C32 cells possess numerous microvilli which adhere to the PRBC, mainly via the knobs (Fig. 1). In contrast, the HUVEC were relatively smooth and the PRBCs appeared partially flattened onto the cell surface (Fig. 2). Furthermore, many of the PRBCs exhibited an invagination of the limiting membrane in the attachment zone, often containing a cytoplasmic process from the endothelial cell (Fig. 2).

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