Cross-species malaria immunity induced by chemically attenuated parasites
Michael F. Good, Jennifer M. Reiman, I. Bibiana Rodriguez, Koichi Ito, Stephanie K. Yanow, Ibrahim M. El-Deeb, Michael R. Batzloff, Danielle I. Stanisic, Christian Engwerda, Terry Spithill, Stephen L. Hoffman, Moses Lee, Virginia McPhun
Michael F. Good, Jennifer M. Reiman, I. Bibiana Rodriguez, Koichi Ito, Stephanie K. Yanow, Ibrahim M. El-Deeb, Michael R. Batzloff, Danielle I. Stanisic, Christian Engwerda, Terry Spithill, Stephen L. Hoffman, Moses Lee, Virginia McPhun
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Research Article Infectious disease

Cross-species malaria immunity induced by chemically attenuated parasites

Abstract

Vaccine development for the blood stages of malaria has focused on the induction of antibodies to parasite surface antigens, most of which are highly polymorphic. An alternate strategy has evolved from observations that low-density infections can induce antibody-independent immunity to different strains. To test this strategy, we treated parasitized red blood cells from the rodent parasite Plasmodium chabaudi with seco-cyclopropyl pyrrolo indole analogs. These drugs irreversibly alkylate parasite DNA, blocking their ability to replicate. After administration in mice, DNA from the vaccine could be detected in the blood for over 110 days and a single vaccination induced profound immunity to different malaria parasite species. Immunity was mediated by CD4+ T cells and was dependent on the red blood cell membrane remaining intact. The human parasite, Plasmodium falciparum, could also be attenuated by treatment with seco-cyclopropyl pyrrolo indole analogs. These data demonstrate that vaccination with chemically attenuated parasites induces protective immunity and provide a compelling rationale for testing a blood-stage parasite-based vaccine targeting human Plasmodium species.

Authors

Michael F. Good, Jennifer M. Reiman, I. Bibiana Rodriguez, Koichi Ito, Stephanie K. Yanow, Ibrahim M. El-Deeb, Michael R. Batzloff, Danielle I. Stanisic, Christian Engwerda, Terry Spithill, Stephen L. Hoffman, Moses Lee, Virginia McPhun

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Figure 2

Tracking of attenuated parasites stained with DiI and HO. rbcs from a P. chabaudi–infected mouse (parasitemia, 39.8%; Supplemental Figure 5A) were treated with centanamycin, stained with DiI and HO, and then injected i.v. into naive AJ mice (3 mice, 5 × 107 cells per mouse). rbcs from an uninfected mouse were stained with DiI alone and injected into other mice (3 mice, 5 × 107 cells per mouse).

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Tracking of attenuated parasites stained with DiI and HO. rbcs from a P....
DiI+HO– cells (nrbcs) or DiI+HO+ cells (prbcs) in the peripheral blood of recipient mice were analyzed over time by flow cytometry and the percentage of these cells of the total injected nrbcs or prbcs calculated based on an assumption of the recipient mice each containing a total of 5 × 109 rbcs (A). Spleen and liver cells of recipient mice were prepared by mechanical disruption. rbcs were gated and DiI+HO+ cells identified. The percentages of DiI+HO+ cells of the total rbcs in the spleen and liver were then calculated (B). Free rbcs were then lysed using NH4Cl-Tris buffer to allow estimation of rbc uptake by white cells. Percentages of DiI+HO+F4/80+ or DiI+HO+CD11c+ cells in total F4/80+ (C) or CD11c+ cells (D) in the spleen and liver were then calculated. Two independent experiments were performed (total n = 4–6 mice per time point), and representative graphs are shown. Means ± SEM are shown.