Chemical Attenuation of Plasmodium berghei Sporozoites Induces Sterile Immunity in Mice

Institute of Parasitology and Centre for Host-Parasite Interactions, McGill University, 21111 Lakeshore Road, Sainte-Anne-de-Bellevue, Quebec H9X3V9, Canada.
Infection and immunity (Impact Factor: 3.73). 04/2008; 76(3):1193-9. DOI: 10.1128/IAI.01399-07
Source: PubMed

ABSTRACT Radiation and genetic attenuation of Plasmodium sporozoites are two approaches for whole-organism vaccines that protect against malaria. We evaluated chemical attenuation of sporozoites as an alternative vaccine strategy. Sporozoites were treated with the DNA sequence-specific alkylating agent centanamycin, a compound that significantly affects blood stage parasitemia and transmission of murine malaria and also inhibits Plasmodium falciparum growth in vitro. Here we show that treatment of Plasmodium berghei sporozoites with centanamycin impaired parasite function both in vitro and in vivo. The infection of hepatocytes by sporozoites in vitro was significantly reduced, and treated parasites showed arrested liver stage development. Inoculation of mice with sporozoites that were treated in vitro with centanamycin failed to produce blood stage infections. Furthermore, BALB/c and C57BL/6 mice vaccinated with treated sporozoites were protected against subsequent challenge with wild-type sporozoites. Our findings demonstrate that chemically attenuated sporozoites could be a viable alternative for the production of an effective liver stage vaccine for malaria.

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Available from: Terry W Spithill, Sep 28, 2015
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    • "The lack of significant progress with subunit vaccines that contain only (parts of) single proteins, together with an enhanced understanding of the protective immunity to malaria has generated new interest in vaccines based on whole blood stage parasite49. Sporozoites that have been attenuated either by radiation or by genetic modification have shown promise as a whole parasite approach to pre-erythrocytic vaccination505152535455. Recent studies have demonstrated that the disruption of individual genes was not sufficient to completely attenuate parasite virulence. "
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    ABSTRACT: Blood stage malaria parasites causing a mild and self limited infection in mice have been obtained with either radiation or chemical mutagenesis showing the possibility of developing an attenuated malaria vaccine. Targeted disruption of plasmepsin-4 (pm4) or the merozoite surface protein-7 (msp7) genes also induces a virulence-attenuated phenotype in terms of absence of experimental cerebral malaria (ECM), delayed increase of parasitemia and reduced mortality rate. The decrease in virulence in parasites lacking either pm4 or msp7 is however incomplete and dependent on the parasite and mouse strain combination. The sequential disruption of both genes induced remarkable virulence-attenuated blood-stage parasites characterized by a self-resolving infection with low levels of parasitemia and no ECM. Furthermore, convalescent mice were protected against the challenge with P. berghei or P. yoelii parasites for several months. These observations provide a proof-of-concept step for the development of human malaria vaccines based on genetically attenuated blood-stage parasites.
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    • "Infected midguts and/or salivary glands were dissected on ice (Purcell et al., 2008). Hemocoel was dissected using volume displacement (perfusion) essentially as previously described (Hillyer et al., 2007). "
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    ABSTRACT: The completion of the Plasmodium (malaria) life cycle in the mosquito requires the parasite to traverse first the midgut and later the salivary gland epithelium. We have identified a putative kinase-related protein (PKRP) that is predicted to be an atypical protein kinase, which is conserved across many species of Plasmodium. The pkrp gene encodes a RNA of about 5300 nucleotides that is expressed as a 90kDa protein in sporozoites. Targeted disruption of the pkrp gene in Plasmodium berghei, a rodent model of malaria, compromises the ability of parasites to infect different tissues within the mosquito host. Early infection of mosquito midgut is reduced by 58-71%, midgut oocyst production is reduced by 50-90% and those sporozoites that are produced are defective in their ability to invade mosquito salivary glands. Midgut sporozoites are not morphologically different from wild-type parasites by electron microscopy. Some sporozoites that emerged from oocysts were attached to the salivary glands but most were found circulating in the mosquito hemocoel. Our findings indicate that a signalling pathway involving PbPKRP regulates the level of Plasmodium infection in the mosquito midgut and salivary glands.
    International journal for parasitology 03/2010; 40(8):979-88. DOI:10.1016/j.ijpara.2010.02.010 · 3.87 Impact Factor
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