Abstract
BackgroundSubtilisin-like protease 2 (SUB2) is a conserved serine protease utilized by Plasmodium parasites as a surface sheddase required for successful merozoite invasion of host red blood cells and has been implicated in ookinete invasion of the mosquito midgut. To determine if SUB2 is a suitable vaccine target to interfere with malaria parasite development, the effects of SUB2-immunization on the Plasmodium life cycle were examined in its vertebrate and invertebrate hosts.MethodsSwiss Webster mice were immunized with SUB2 peptides conjugated to Keyhole limpet hemocyanin (KLH) or KLH alone, and then challenged with Plasmodium berghei. To determine the effects of immunization on parasite development, infected mice were evaluated by blood film and Giemsa staining. In addition, collected immune sera were used to perform passive immunization experiments in non-immunized, P. berghei-infected mice to determine the potential role of SUB2 in parasite development in the mosquito.ResultsFollowing P. berghei challenge, SUB2-immunized mice develop a lower parasitaemia and show improved survival when compared to control immunized mice. Moreover, SUB2 immunization results in an increase in the number of multiply invaded red blood cells, suggesting that SUB2 antibodies interfere with merozoite invasion. Passive immunization experiments imply that SUB2 may not have a major role in ookinete invasion, but this requires further investigation.ConclusionBy interfering with red blood cell invasion, immunization against SUB2 limits malaria parasite development and confers protection from severe malaria. Together, these results provide proof-of-principle evidence for future investigation into the use of SUB2 as a vaccine or drug target to interrupt parasite development in more relevant human malaria models.Electronic supplementary materialThe online version of this article (doi:10.1186/1475-2875-13-313) contains supplementary material, which is available to authorized users.
Highlights
Subtilisin-like protease 2 (SUB2) is a conserved serine protease utilized by Plasmodium parasites as a surface sheddase required for successful merozoite invasion of host red blood cells and has been implicated in ookinete invasion of the mosquito midgut
Five species of Plasmodium parasites cause human malaria, yet the largest impacts to public health are primarily caused by Plasmodium falciparum in sub-Saharan Africa [2]
SUB2 immunization Synthetic SUB2 peptides conjugated to keyhole limpet haemocyanin (KLH) through the cysteine at the N(Sub2 Peptide #2- CRTSIKIVSKDKKTI) or C-terminus (Sub2 Peptide #1- KYSDRYEMTDELFDC) via a –SH bond were produced by GenScript Corporation (Piscataway, NJ, USA)
Summary
Subtilisin-like protease 2 (SUB2) is a conserved serine protease utilized by Plasmodium parasites as a surface sheddase required for successful merozoite invasion of host red blood cells and has been implicated in ookinete invasion of the mosquito midgut. Malaria parasites undergo a complex life cycle in their mosquito and human hosts, which require Plasmodium parasites to invade and replicate in multiple cell types and host environments. To accomplish these developmental progressions, Plasmodium parasites utilize specific invasion ligands and proteases to facilitate host cell invasion [3,4]. Recent evidence suggests that ookinete invasion of the mosquito midgut may involve multiple surface proteins and invasion pathways [5] While both merozoite invasion of the RBC and ookinete invasion of the midgut are rapid, these stages have attracted recent attention as targets for a blood stage [6,7,8] or transmission-blocking vaccines [9,10,11]
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