Sandra Cheesman

University of Edinburgh

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Richard Carter

University of York

Richard Culleton

Ehime University

Sittiporn Pattaradilokrat

Chulalongkorn University

Paul Hunt

Centre for Immunity, Infection and Evolution

Ana Afonso

Instituto Português de Oncologia Francisco Gentil

Andrew F. Read

Pennsylvania State University

Jacobus C. de Roode

Emory University

Pedro Cravo

Universidade Nova de Lisboa

Wathsala Wijayalath

Naval Medical Research Command

Shiroma Handunnetti

University of Colombo

Cooperative Institutions

University of Edinburgh

University of Colombo

Universidade Nova de Lisboa

Centre for Immunity, Infection and Evolution

Pennsylvania State University

National Institutes of Health

Infraestruturas de Portugal (Portugal)

Center for Disease Dynamics, Economics & Policy

Osaka University

Institut Pasteur

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Mixed Strain Infections and Strain-Specific Protective Immunity in the Rodent Malaria Parasite Plasmodium chabaudi chabaudi in Mice

Infection and Immunity (2006)

Sandra Cheesman Ahmed Raza Richard Carter

ABSTRACT Important to malaria vaccine design is the phenomenon of “strain-specific” immunity. Using an accurate and sensitive assay of parasite genotype, real-time quantitative PCR, we have investigated protective immunity against mixed infections of genetically distinct cloned “strains” of the rodent malaria parasite Plasmodium chabaudi chabaudi in mice. Four strains of P. c. chabaudi , AS, AJ, AQ, and CB, were studied. One round of blood infection and drug cure with a single strain resulted in a partial reduction in parasitemia, compared with levels for naïve mice, in challenge infections with mixed inocula of the immunizing (homologous) strain and a heterologous strain. In all cases, the numbers of blood-stage parasites of each genotype were reduced to similar degrees. After a second, homologous round of infection and drug cure followed by challenge with homologous and heterologous strains, the parasitemias were reduced even further. In these circumstances, moreover, the homologous strain was reduced much faster than the heterologous strain in all of the combinations tested. That the immunity induced by a single infection did not show “strain specificity,” while the immunity following a second, homologous infection did, suggests that the “strain-specific” component of protective immunity in malaria may be dependent upon immune memory. The results show that strong, protective immunity induced by and effective against malaria parasites from a single parasite species has a significant “strain-specific” component and that this immunity operates differentially against genetically distinct parasites within the same infection.

Plasmodium chabaudi

Heterologous

Strain (injury)

10.1128/iai.74.5.2996-3001.2006

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Citations (41)

Validation of Pyrosequencing™ for accurate and high throughput estimation of allele frequencies in malaria parasites

Molecular and Biochemical Parasitology (2006)

Sandra Cheesman Alison M. Creasey Kathryn A. Degnan Taco W. A. Kooij Ana Afonso

Plasmodium chabaudi

Pyrosequencing

Artesunate

Parasitology

clone (Java method)

10.1016/j.molbiopara.2006.12.008

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Citations (23)

Strain-Specific Protective Effect of the Immunity Induced by Live Malarial Sporozoites under Chloroquine Cover

PLoS ONE (2012)

Wathsala Wijayalath Sandra Cheesman Kazuyuki Tanabe Shiroma Handunnetti Richard Carter

The efficacy of a whole-sporozoite malaria vaccine would partly be determined by the strain-specificity of the protective responses against malarial sporozoites and liver-stage parasites. Evidence from previous reports were inconsistent, where some studies have shown that the protective immunity induced by irradiated or live sporozoites in rodents or humans were cross-protective and in others strain-specific. In the present work, we have studied the strain-specificity of live sporozoite-induced immunity using two genetically and immunologically different strains of Plasmodium cynomolgi, Pc746 and PcCeylon, in toque monkeys. Two groups of monkeys were immunized against live sporozoites of either the Pc746 (n = 5), or the PcCeylon (n = 4) strain, by the bites of 2–4 sporozoite-infected Anopheles tessellates mosquitoes per monkey under concurrent treatments with chloroquine and primaquine to abrogate detectable blood infections. Subsequently, a group of non-immunized monkeys (n = 4), and the two groups of immunized monkeys were challenged with a mixture of sporozoites of the two strains by the bites of 2–5 infective mosquitoes from each strain per monkey. In order to determine the strain-specificity of the protective immunity, the proportions of parasites of the two strains in the challenge infections were quantified using an allele quantification assay, Pyrosequencing™, based on a single nucleotide polymorphism (SNP) in the parasites' circumsporozoite protein gene. The Pyrosequencing™ data showed that a significant reduction of parasites of the immunizing strain in each group of strain-specifically immunized monkeys had occurred, indicating a stronger killing effect on parasites of the immunizing strain. Thus, the protective immunity developed following a single, live sporozoite/chloroquine immunization, acted specifically against the immunizing strain and was, therefore, strain-specific. As our experiment does not allow us to determine the parasite stage at which the strain-specific protective immunity is directed, it is possible that the target of this immunity could be either the pre-erythrocytic stage, or the blood-stage, or both.

Strain (injury)

Anti malarial

Malarial parasites

10.1371/journal.pone.0045861

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Citations (8)

Topoisomerase II of the Malarial parasite

Sandra Cheesman

Malarial parasites

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Gene encoding a deubiquitinating enzyme is mutated in artesunate‐ and chloroquine‐resistant rodent malaria parasites^§

Molecular Microbiology (2007)

Paul Hunt Ana Afonso Alison M. Creasey Richard Culleton Amar Bir Singh Sidhu

Summary Artemisinin‐ and artesunate‐resistant Plasmodium chabaudi mutants, AS‐ART and AS‐ATN, were previously selected from chloroquine‐resistant clones AS‐30CQ and AS‐15CQ respectively. Now, a genetic cross between AS‐ART and the artemisinin‐sensitive clone AJ has been analysed by Linkage Group Selection. A genetic linkage group on chromosome 2 was selected under artemisinin treatment. Within this locus, we identified two different mutations in a gene encoding a deubiquitinating enzyme. A distinct mutation occurred in each of the clones AS‐30CQ and AS‐ATN, relative to their respective progenitors in the AS lineage. The mutations occurred independently in different clones under drug selection with chloroquine (high concentration) or artesunate. Each mutation maps to a critical residue in a homologous human deubiquitinating protein structure. Although one mutation could theoretically account for the resistance of AS‐ATN to artemisinin derivates, the other cannot account solely for the resistance of AS‐ART, relative to the responses of its sensitive progenitor AS‐30CQ. Two lines of Plasmodium falciparum with decreased susceptibility to artemisinin were also selected. Their drug‐response phenotype was not genetically stable. No mutations in the UBP‐1 gene encoding the P. falciparum orthologue of the deubiquitinating enzyme were observed. The possible significance of these mutations in parasite responses to chloroquine or artemisinin is discussed.

Plasmodium chabaudi

Artesunate

Deubiquitinating enzyme

10.1111/j.1365-2958.2007.05753.x

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Citations (170)

PP3 STRAIN-SPECIFIC PROTECTIVE IMMUNITY INDUCED BY INFECTION WITH PRE-ERYTHROCYTIC STAGES OF PLASMODIUM CYNOMOLGI IN TOQUE MONKEY

Sisira Pathirana Wathsala Wijayalath Sandra Cheesman Thushali Ranasinghe Jagath Rajakaruna

Strain specific protective immunity to malaria infection (SSPI) was investigated using two strains of Plasmodium cynomolgi, Pc746 and PcCeylon, in toque monkey. Two groups of monkeys were immunized against either Pc746 (n=5) or PcCeylon (n=4), by giving bites with 2-4 sporozoite-infected Anopheles tessellates mosquitoes per monkey. Primary blood infection was prevented during immunization by treating the monkeys with chloroquine for 6 days starting from day 5 after infective mosquito bites and secondary, hypnozoite-induced, blood infection was prevented by treating the monkeys one month later with primaquine. The two immunized groups and a group of unimmunized monkeys (n=4) were given a mixed-strain sporozoite challenge infection, by feeding a similar number of infective mosquitoes, which were infected with each strain, 140 and 100 days respectively after immunizing infection. Parasite DNA was collected for 5-8 consecutive days after parasitaemia reached 0.05% or above. The proportions of the two parasite strains in these samples were quantified using a PyrosequencingTM assay based on SNPs in MSP1 and CSP genes. Results In the challenge infection in immunized monkeys the earliest recorded proportion of parasites of an immunizing strain was significantly lower than its proportion in monkeys immunized against a heterologous strain (P=0.014 and 0.027 for the two SNPs) and the proportions of immunizing strain tended to decline further during the period of sample collection. Conclusion

Heterologous

Strain (injury)

Primaquine

Plasmodium (life cycle)

Parasitology

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A single parasite gene determines strain-specific protective immunity against malaria: The role of the merozoite surface protein I

International Journal for Parasitology (2010)

Sandra Cheesman ELAINE M. O'MAHONY Sittiporn Pattaradilokrat Kathryn A. Degnan Sara Knott

Plasmodium chabaudi

10.1016/j.ijpara.2010.02.003

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Citations (22)

Linkage Group Selection: Towards Identifying Genes Controlling Strain Specific Protective Immunity in Malaria

PLoS ONE (2007)

Sittiporn Pattaradilokrat Sandra Cheesman Richard Carter

Protective immunity against blood infections of malaria is partly specific to the genotype, or strain, of the parasites. The target antigens of Strain Specific Protective Immunity are expected, therefore, to be antigenically and genetically distinct in different lines of parasite. Here we describe the use of a genetic approach, Linkage Group Selection, to locate the target(s) of Strain Specific Protective Immunity in the rodent malaria parasite Plasmodium chabaudi chabaudi. In a previous such analysis using the progeny of a genetic cross between P. c. chabaudi lines AS-pyr1 and CB, a location on P. c. chabaudi chromosome 8 containing the gene for merozoite surface protein-1, a known candidate antigen for Strain Specific Protective Immunity, was strongly selected. P. c. chabaudi apical membrane antigen-1, another candidate for Strain Specific Protective Immunity, could not have been evaluated in this cross as AS-pyr1 and CB are identical within the cell surface domain of this protein. Here we use Linkage Group Selection analysis of Strain Specific Protective Immunity in a cross between P. c. chabaudi lines CB-pyr10 and AJ, in which merozoite surface protein-1 and apical membrane antigen-1 are both genetically distinct. In this analysis strain specific immune selection acted strongly on the region of P. c. chabaudi chromosome 8 encoding merozoite surface protein-1 and, less strongly, on the P. c. chabaudi chromosome 9 region encoding apical membrane antigen-1. The evidence from these two independent studies indicates that Strain Specific Protective Immunity in P. c. chabaudi in mice is mainly determined by a narrow region of the P. c. chabaudi genome containing the gene for the P. c. chabaudi merozoite surface protein-1 protein. Other regions, including that containing the gene for P. c. chabaudi apical membrane antigen-1, may be more weakly associated with Strain Specific Protective Immunity in these parasites.

Plasmodium chabaudi

Genetic linkage

Negative selection

10.1371/journal.pone.0000857

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Citations (30)

Real-time quantitative PCR for analysis of genetically mixed infections of malaria parasites: technique validation and applications

Molecular and Biochemical Parasitology (2003)

Sandra Cheesman Jacobus C. de Roode Andrew F. Read Richard Carter

Plasmodium chabaudi

clone (Java method)

Repeatability

10.1016/s0166-6851(03)00195-6

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Citations (72)

Evidence for strain‐specific protective immunity against blood‐stage parasites of Plasmodium cynomolgi in toque monkey

Parasite Immunology (2008)

Wathsala Wijayalath Sandra Cheesman Jagath Rajakaruna Shiroma Handunnetti R Carter

SUMMARY We have conducted experiments to test the induction of strain‐specific protective immunity against Plasmodium cynomolgi infections in toque monkeys. Plasmodium cynomolgi is closely related biologically and genetically to the human malaria parasite, P. vivax . Two groups of monkeys were immunized against either of two strains of P. cynomolgi , namely PcCeylon and Pc746, by giving two successive drug‐cured infections with asexual blood‐stage parasites of one or the other strain, 12‐weeks apart. To test for strain‐specific protective immunity these infection‐immunized monkeys were challenged 8 weeks later with a mixture of asexual blood‐stage parasites of both strains. A pyrosequencing‐based assay was used to quantify the proportion of parasites that survived in the challenge infections. The assay was based on a SNP within the P. cynomolgi Merozoite Surface Protein‐1 gene. Compared to their behaviour in nonimmunized monkeys, the growth of parasites of the homologous (immunizing) strain in mixed‐strain challenge infections in the immunized monkeys were reduced relative to that of the nonimmunizing strain. These results indicate the development of blood infection‐induced strain‐specific protective immunity against P. cynomolgi in toque monkeys. The work prepares for using genetic analysis to identify target antigens of strain‐specific protective immunity in this host and malaria parasite combination.

Plasmodium (life cycle)

Strain (injury)

Parasitology

10.1111/j.1365-3024.2008.01065.x

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Citations (9)