Alice Butterworth

QIMR Berghofer Medical Research Institute

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James McCarthy

Peter Doherty Institute

Tina S. Skinner‐Adams

Griffith University

Katharine R. Trenholme

QIMR Berghofer Medical Research Institute

Michelle L. Gatton

Queensland University of Technology

Donald L. Gardiner

University of Queensland

Mei‐Fong Ho

Griffith University

Jenny Eng

McGill University

Tsungai Chipato

University of Zimbabwe

Katherine T. Andrews

Griffith University

John H. Adams

Center for Global Health

Cooperative Institutions

QIMR Berghofer Medical Research Institute

University of Queensland

Griffith University

University of Melbourne

Heinrich Heine University Düsseldorf

University of North Carolina at Chapel Hill

Harvard University

University of Edinburgh

Moredun Research Institute

Walter and Eliza Hall Institute of Medical Research

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Modelling the dynamics of Plasmodium falciparum histidine-rich protein 2 in human malaria to better understand malaria rapid diagnostic test performance

Malaria Journal (2012)

Louise Marquart Alice Butterworth James McCarthy Michelle L. Gatton

Abstract Background Effective diagnosis of malaria is a major component of case management. Rapid diagnostic tests (RDTs) based on Plasmodium falciparum histidine-rich protein 2 ( Pf HRP2) are popular for diagnosis of this most virulent malaria infection. However, concerns have been raised about the longevity of the Pf HRP2 antigenaemia following curative treatment in endemic regions. Methods A model of Pf HRP2 production and decay was developed to mimic the kinetics of Pf HRP2 antigenaemia during infections. Data from two human infection studies was used to fit the model, and to investigate Pf HRP2 kinetics. Four malaria RDTs were assessed in the laboratory to determine the minimum detectable concentration of Pf HRP2. Results Fitting of the Pf HRP2 dynamics model indicated that in malaria naïve hosts, P. falciparum parasites of the 3D7 strain produce 1.4 × 10 -13 g of Pf HRP2 per parasite per replication cycle. The four RDTs had minimum detection thresholds between 6.9 and 27.8 ng/mL. Combining these detection thresholds with the kinetics of Pf HRP2, it is predicted that as few as 8 parasites/μL may be required to maintain a positive RDT in a chronic infection. Conclusions The results of the model indicate that good quality Pf HRP2-based RDTs should be able to detect parasites on the first day of symptoms, and that the persistence of the antigen will cause the tests to remain positive for at least seven days after treatment. The duration of a positive test result following curative treatment is dependent on the duration and density of parasitaemia prior to treatment and the presence and affinity of anti- Pf HRP2 antibodies.

Rapid diagnostic test

Parasitology

10.1186/1475-2875-11-74

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Citations (40)

Plasmodium falciparumgametocytes: with a view to a kill

Parasitology (2013)

Alice Butterworth Tina S. Skinner‐Adams Don L. Gardiner Katharine R. Trenholme

SUMMARY Drugs that kill or inhibit the sexual stages of Plasmodium in order to prevent transmission are important components of malaria control programmes. Reducing gametocyte carriage is central to the control of Plasmodium falciparum transmission as infection can result in extended periods of gametocytaemia. Unfortunately the number of drugs with activity against gametocytes is limited. Primaquine is currently the only licensed drug with activity against the sexual stages of malaria parasites and its use is hampered by safety concerns. This shortcoming is likely the result of the technical challenges associated with gametocyte studies together with the focus of previous drug discovery campaigns on asexual parasite stages. However recent emphasis on malaria eradication has resulted in an upsurge of interest in identifying compounds with activity against gametocytes. This review examines the gametocytocidal properties of currently available drugs as well as those in the development pipeline and examines the prospects for discovery of new anti-gametocyte compounds.

Plasmodium (life cycle)

10.1017/s0031182013001236

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Citations (28)

Modelling the dynamics of Plasmodium falciparum histidine-rich protein 2 in human malaria to better understand malaria rapid diagnostic test performance

Faculty of Health (2012)

Louise Marquart Alice Butterworth James McCarthy Michelle L. Gatton

BACKGROUND: Effective diagnosis of malaria is a major component of case management. Rapid diagnostic tests (RDTs) based on Plasmodium falciparumhistidine-rich protein 2 (PfHRP2) are popular for diagnosis of this most virulent malaria infection. However, concerns have been raised about the longevity of the PfHRP2 antigenaemia following curative treatment in endemic regions. METHODS: A model of PfHRP2 production and decay was developed to mimic the kinetics of PfHRP2 antigenaemia during infections. Data from two human infection studies was used to fit the model, and to investigate PfHRP2 kinetics. Four malaria RDTs were assessed in the laboratory to determine the minimum detectable concentration of PfHRP2. RESULTS: Fitting of the PfHRP2 dynamics model indicated that in malaria naive hosts, P. falciparum parasites of the 3D7 strain produce 1.4 x 10(-)(1)(3) g of PfHRP2 per parasite per replication cycle. The four RDTs had minimum detection thresholds between 6.9 and 27.8 ng/mL. Combining these detection thresholds with the kinetics of PfHRP2, it is predicted that as few as 8 parasites/muL may be required to maintain a positive RDT in a chronic infection. CONCLUSIONS: The results of the model indicate that good quality PfHRP2-based RDTs should be able to detect parasites on the first day of symptoms, and that the persistence of the antigen will cause the tests to remain positive for at least seven days after treatment. The duration of a positive test result following curative treatment is dependent on the duration and density of parasitaemia prior to treatment and the presence and affinity of anti-PfHRP2 antibodies.

Rapid diagnostic test

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Targeting Plasmodium falciparum gametocytes

Alice Butterworth

Plasmodium (life cycle)

10.14264/uql.2015.496

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Additional file 2: Figure S2. of The development of sexual stage malaria gametocytes in a Wave Bioreactor

Corine G. Demanga Jenny Eng Donald L. Gardiner Alison Roth Alice Butterworth

The proliferation of asexual blood stage malaria parasite in the Wave Bioreactor. a Parasitemia curves of Plasmodium falciparum 3D7 and FCR3 strains cultured in 3â5 days; b Time course of glucose consumption and lactate production; c pH fluctuations over period of culture. (PPTX 23Â kb)

10.6084/m9.figshare.c.3769631_d2.v1

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Saquinavir Inhibits the Malaria Parasite's Chloroquine Resistance Transporter

Antimicrobial Agents and Chemotherapy (2012)

Rowena E. Martin Alice Butterworth Donald L. Gardiner Kiaran Kirk James McCarthy

The antiretroviral protease inhibitors (APIs) ritonavir, saquinavir, and lopinavir, used to treat HIV infection, inhibit the growth of Plasmodium falciparum at clinically relevant concentrations. Moreover, it has been reported that these APIs potentiate the activity of chloroquine (CQ) against this parasite in vitro. The mechanism underlying this effect is not understood, but the degree of chemosensitization varies between the different APIs and, with the exception of ritonavir, appears to be dependent on the parasite exhibiting a CQ-resistant phenotype. Here we report a study of the role of the P. falciparum chloroquine resistance transporter (PfCRT) in the interaction between CQ and APIs, using transgenic parasites expressing different PfCRT alleles and using the Xenopus laevis oocyte system for the heterologous expression of PfCRT. Our data demonstrate that saquinavir behaves as a CQ resistance reverser and that this explains, at least in part, its ability to enhance the effects of CQ in CQ-resistant P. falciparum parasites.

Saquinavir

Amodiaquine

Ritonavir

Protease inhibitor (pharmacology)

Indinavir

10.1128/aac.00166-12

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An improved method for undertaking limiting dilution assays for in vitro cloning of Plasmodium falciparum parasites

Malaria Journal (2011)

Alice Butterworth Alan J. Robertson Mei‐Fong Ho Michelle L. Gatton James McCarthy

Obtaining single parasite clones is required for many techniques in malaria research. Cloning by limiting dilution using microscopy-based assessment for parasite growth is an arduous and labor-intensive process. An alternative method for the detection of parasite growth in limiting dilution assays is using a commercial ELISA histidine-rich protein II (HRP2) detection kit. Detection of parasite growth was undertaken using HRP2 ELISA and compared to thick film microscopy. An HRP2 protein standard was used to determine the detection threshold of the HRP2 ELISA assay, and a HRP2 release model was used to extrapolate the amount of parasite growth required for a positive result. The HRP2 ELISA was more sensitive than microscopy for detecting parasite growth. The minimum level of HRP2 protein detection of the ELISA was 0.11ng/ml. Modeling of HRP2 release determined that 2,116 parasites are required to complete a full erythrocytic cycle to produce sufficient HRP2 to be detected by the ELISA. Under standard culture conditions this number of parasites is likely to be reached between 8 to 14 days of culture. This method provides an accurate and simple way for the detection of parasite growth in limiting dilution assays, reducing time and resources required in traditional methods. Furthermore the method uses spent culture media instead of the parasite-infected red blood cells, enabling culture to continue.

Cloning (programming)

Limiting

Parasitology

10.1186/1475-2875-10-95

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The Frequency of Malaria Is Similar among Women Receiving either Lopinavir/Ritonavir or Nevirapine-based Antiretroviral Treatment

PLoS ONE (2012)

Tina S. Skinner‐Adams Alice Butterworth Kimberly A. Porter Ronald D’Amico Fred Sawe

HIV protease inhibitors (PIs) show antimalarial activity in vitro and in animals. Whether this translates into a clinical benefit in HIV-infected patients residing in malaria-endemic regions is unknown. We studied the incidence of malaria, as defined by blood smear positivity or a positive Plasmodium falciparum histidine-rich protein 2 antigen test, among 444 HIV-infected women initiating antiretroviral treatment (ART) in the OCTANE trial (A5208; ClinicalTrials.gov: NCT00089505). Participants were randomized to treatment with PI-containing vs. PI-sparing ART, and were followed prospectively for ≥48 weeks; 73% also received cotrimoxazole prophylaxis. PI-containing treatment was not associated with protection against malaria in this study population.

Nevirapine

Lopinavir

Ritonavir

Antiretroviral treatment

Protease inhibitor (pharmacology)

10.1371/journal.pone.0034399

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Citations (13)

PAR volume 140 issue 14 Cover and Back matter

Parasitology (2013)

Robert Walker David Ferguson Catherine Chaussain Nicholas L. Smith Alice Butterworth

An abstract is not available for this content so a preview has been provided. As you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

Content (measure theory)

10.1017/s003118201300190x

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The Frequency of Malaria Is Similar among Women Receiving either Lopinavir/Ritonavir or Nevirapine-based Antiretroviral Treatment

Carolina Digital Repository (University of North Carolina at Chapel Hill) (2012)

Tina S. Skinner‐Adams Alice Butterworth Kimberly A. Porter Ronald D’Amico Fred Sawe

Nevirapine

Lopinavir

Ritonavir

Lopinavir/ritonavir

Antiretroviral treatment

10.17615/eaqg-7793

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