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Plasmepsin 4-deficient Plasmodium berghei are virulence attenuated and induce protective immunity against experimental malaria.

ABSTRACT: Plasmodium parasites lacking plasmepsin 4 (PM4), an aspartic protease that functions in the lysosomal compartment and contributes to hemoglobin digestion, have only a modest decrease in the asexual blood-stage growth rate; however, PM4 deficiency in the rodent malaria parasite Plasmodium berghei results in significantly less virulence than that for the parental parasite. P. berghei Deltapm4 parasites failed to induce experimental cerebral malaria (ECM) in ECM-susceptible mice, and ECM-resistant mice were able to clear infections. Furthermore, after a single infection, all convalescent mice were protected against subsequent parasite challenge for at least 1 year. Real-time in vivo parasite imaging and splenectomy experiments demonstrated that protective immunity acted through antibody-mediated parasite clearance in the spleen. This work demonstrates, for the first time, that a single Plasmodium gene disruption can generate virulence-attenuated parasites that do not induce cerebral complications and, moreover, are able to stimulate strong protective immunity against subsequent challenge with wild-type parasites. Parasite blood-stage attenuation should help identify protective immune responses against malaria, unravel parasite-derived factors involved in malarial pathologies, such as cerebral malaria, and potentially pave the way for blood-stage whole organism vaccines.

SUBMITTER: Spaccapelo R

PROVIDER: S-EPMC2797883 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Plasmepsin 4-deficient Plasmodium berghei are virulence attenuated and induce protective immunity against experimental malaria.

Spaccapelo Roberta R Janse Chris J CJ Caterbi Sara S Franke-Fayard Blandine B Bonilla J Alfredo JA Syphard Luke M LM Di Cristina Manlio M Dottorini Tania T Savarino Andrea A Cassone Antonio A Bistoni Francesco F Waters Andrew P AP Dame John B JB Crisanti Andrea A

The American journal of pathology 20091217 1

Plasmodium parasites lacking plasmepsin 4 (PM4), an aspartic protease that functions in the lysosomal compartment and contributes to hemoglobin digestion, have only a modest decrease in the asexual blood-stage growth rate; however, PM4 deficiency in the rodent malaria parasite Plasmodium berghei results in significantly less virulence than that for the parental parasite. P. berghei Deltapm4 parasites failed to induce experimental cerebral malaria (ECM) in ECM-susceptible mice, and ECM-resistant ...[more]

PMID: 20019192

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Project description:BackgroundDuring childhood, residents of areas with stable transmission of Plasmodium falciparum parasites acquire substantial protective immunity to malaria, and adults therefore rarely experience clinical disease episodes. However, susceptibility to infection reappears in pregnant women, particularly primigravidae. This is due to appearance of antigenic parasite variants that are restricted to pregnancy. Variant-specific immunity also governs pregnancy-associated recrudescence of Plasmodium berghei infection in pregnant mice. Pregnancy-related changes in the plasma cytokine levels of mice with immunity acquired prior to first pregnancy have not been studied in detail previously, and were the topic of the present study.MethodsA multiplexed bead assay was used to measure plasma levels of IL-5, IL-10, IL-12, IL-13, IFN-? and TNF in BALB/c mice immunized against P. berghei K173 by repeated infection and drug cure before the first pregnancy. The association between cytokine levels on the one hand and parasitaemia and haemoglobin levels on the other, in mice that had never been pregnant or were pregnant for the first, second or third time were evaluated by Mann-Whitney test and Spearman rank-order correlation analysis.ResultsPregnancy per se did not further increase the already high cytokine levels in mice previously immunized by repeated infection and drug cure. Levels of all the cytokines except IL-10 were correlated with each other, and with parasitaemia and haemoglobin levels. Furthermore, levels of all cytokines were positively correlated with parity, except IL-10, which was negatively correlated with parity. High levels of IL-10 and low levels of the other cytokines were associated with poor pregnancy outcome.ConclusionsHigh levels of IL-10 and low levels of the other cytokines were associated with poor pregnancy outcome in this mouse model of placental malaria. Since the model replicates key parasitological and immunological features of placental P. falciparum malaria, it underpins its usefulness in immunology and pathogenesis studies of this important cause of mother/child morbidity in endemic areas.

Dataset Information

Plasmepsin 4-deficient Plasmodium berghei are virulence attenuated and induce protective immunity against experimental malaria.

Publications

Plasmepsin 4-deficient Plasmodium berghei are virulence attenuated and induce protective immunity against experimental malaria.

Similar Datasets

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