Abstract
During the clinically silent liver stage of a Plasmodium infection the parasite replicates from a single sporozoite into thousands of merozoites. Infection of humans and rodents with large numbers of sporozoites that arrest their development within the liver can cause sterile protection from subsequent infections. Disruption of genes essential for liver stage development of rodent malaria parasites has yielded a number of attenuated parasite strains. A key question to this end is how increased attenuation relates to vaccine efficacy. Here, we generated rodent malaria parasite lines that arrest during liver stage development and probed the impact of multiple gene deletions on attenuation and protective efficacy. In contrast to P. berghei strain ANKA LISP2(–) or uis3(–) single knockout parasites, which occasionally caused breakthrough infections, the double mutant lacking both genes was completely attenuated even when high numbers of sporozoites were administered. However, different vaccination protocols showed that LISP2(–) parasites protected better than uis3(–) and double mutants. Hence, deletion of several genes can yield increased safety but might come at the cost of protective efficacy.
Highlights
Malaria is transmitted through the bite of a mosquito, which injects Plasmodium sporozoites into the host
Like in the NK65 strain we could not detect any differences in blood stage or early mosquito stage development and sporozoites accumulated in similar numbers in mosquitoes as they did for the wild type
Their development was attenuated compared to wild type controls as the parasites did not form mature merozoites within 65 h as shown by altered merozoite surface protein 1 (MSP1) staining restricted to the surrounding parasite plasma membrane (Fig. 1C)
Summary
Malaria is transmitted through the bite of a mosquito, which injects Plasmodium sporozoites into the host. Successful experimental vaccines that protect from natural infection have first been generated by radiation treatment of Plasmodium sporozoites[1] These damaged parasites could still enter hepatocytes but, at the right doses of radiation, did not replicate and failed to develop into merozoites[2]. We show that complete disruption of LISP2 caused a growth arrest during liver stage development and yielded a genetically attenuated rodent malaria parasite line. Uis3(–) ANKA parasites showed a different phenotype as they were not completely attenuated and arrested later in development than uis3(–) NK65 and P. yoelii parasites, respectively[28] This allowed us to test two attenuated parasites and a parasite lacking both genes for attenuation and vaccination efficacy
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