<i>PLASMODIUM</i>SPOROZOITE MOLECULAR CELL BIOLOGY

Kappe, Stefan H. I.; Buscaglia, Carlos A.; Nussenzweig, Victor

doi:10.1146/annurev.cellbio.20.011603.150935

Cited by 140 publications

(140 citation statements)

References 164 publications

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“…1 A brief description of the Plasmodium falciparum (the most lethal malarial parasite) life cycle is required to better understand its molecular interactions in invasion. Following the bite of a malarial parasite-infected mosquito, the inoculated sporozoites (larva-like parasites present in the mosquito's salivary glands) migrate to the liver and invade hepatocytes through the interaction of a yet unknown large number of proteins [2][3][4] [step a in Figure 1A]. …”

Section: Rationale For Multiantigenic Multistage Vaccine Developmentmentioning

confidence: 99%

Emerging Rules for Subunit-Based, Multiantigenic, Multistage Chemically Synthesized Vaccines

2008

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S eventeen million people die of transmittable diseases and 2/3 of the world's population suffer them annually. Malaria, tuberculosis, AIDS, hepatitis, and reemerging and new diseases are a great threat to humankind. A logical and rational approach for vaccine development is thus desperately needed.Protein chemistry provides the best tools for tackling these problems. The tremendous complexity of microbes, the different pathways they use for invading host cells, and the immune responses they induce can only be resolved by using the minimum subunit-based (chemically produced ∼20-mer peptides), multiantigenic (most proteins involved in invasion), multistage (different invasion mechanisms) vaccine development approach.The most lethal form of malaria caused by Plasmodium falciparum (killing 3 million and affecting 500 million people worldwide annually) was used as target disease since many of its proteins, its invasion pathways, and its genome have been described recently. A New World primate (the Aotus monkey) is highly susceptibly to human malaria; its immune system molecules are 80 -100% identical to those of its human counterpart, making it an excellent model for vaccine development.Chemically synthesized ∼20-mer peptides, covering all the P. falciparum malaria proteins involved in red blood cell (RBC) invasion were synthesized by the classical t-Boc technology (based on synthetic SPf66 antimalarial vaccine information for identifying targets) and assayed in a highly sensitive, specific, and robust test for detecting receptor-ligand interactions between high-activity binding peptides (HABPs) and RBCs. HABPs were identified, some in which the molecule displays genetic variability (to be discarded due to their tremendous complexity) and elicits a strain-specific immune response and others that are conserved (no amino acid sequence variation).Conserved HABPs were synthesized in a polymeric form by adding cysteines at their N-and C-terminal ends to be used for monkey immunization. They became nonimmunogenic (no antibodies were induced) nonprotection inducers (monkeys were not protected against P. falciparum malaria challenge with a highly infective strain) suggesting a code of immunological silence or nonresponsiveness for these conserved HABPs.A large number of monkey trials involving a considerable number of Aotus monkeys were performed to break this code of immunological silence by replacing critical residues (determined by glycine peptide analogue scanning) to find that the following amino acid changes had to be made to render them antibody and protection inducing: FTR; WTY; LTH; ITN; MTK; PTD; QTE; CTT.The three-dimensional (3D) structure of >100 of these native modified HABPs (determined by 1 H NMR) revealed that the following structural changes had all to be achieved to allow a better fit into the major histocompatibility complex class II (MHC II)-peptide-TCR complex to properly activate the immune system: R-helix shortening, modifying their -turn, adopting segmental R-helix configuration, changing residue or...

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Section: Rationale For Multiantigenic Multistage Vaccine Developmentmentioning

confidence: 99%

Emerging Rules for Subunit-Based, Multiantigenic, Multistage Chemically Synthesized Vaccines

2008

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“…Sporozoites are uniformly covered with circumsporozoite protein (CS), a highly expressed and immunodominant surface protein antigen necessary for sporozoite development and host cell targeting (1,2). Gliding motility enables sporozoites to move directly through host cells to reach the vasculature and later to penetrate the liver.…”

mentioning

confidence: 99%

Unexpected fold in the circumsporozoite protein target of malaria vaccines

Doud

Koksal

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

101

157

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Circumsporozoite (CS) protein is the major surface component of Plasmodium falciparum sporozoites and is essential for host cell invasion. A vaccine containing tandem repeats, region III, and thrombospondin type-I repeat (TSR) of CS is efficacious in phase III trials but gives only a 35% reduction in severe malaria in the first year postimmunization. We solved crystal structures showing that region III and TSR fold into a single unit, an "αTSR" domain. The αTSR domain possesses a hydrophobic pocket and core, missing in TSR domains. CS binds heparin, but αTSR does not. Interestingly, polymorphic T-cell epitopes map to specialized αTSR regions. The N and C termini are unexpectedly close, providing clues for sporozoite sheath organization. Elucidation of a unique structure of a domain within CS enables rational design of next-generation subunit vaccines and functional and medicinal chemical investigation of the conserved hydrophobic pocket.

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“…Currently, only a few proteins of sporozoites have been described that play an essential role in establishing infection of the liver but are thought to be conserved in all species of Plasmodium. These include circumsporozoite protein (CS), thrombospondin-related anonymous protein (TRAP), microneme proteins essential for cell traversal (SPECT1, SPECT2 or PPLP1, and CelTOS) and PbIMC1a, which variously are involved in motility of sporozoites, recognition of surface receptors on host cells, and traversal and invasion of host cells (3)(4)(5)(6)(7)(8)(9)(10). Within the PV, the sporozoite transforms and grows (trophozoite stage) and multiplies (schizont stage) for a period of a few days, resulting in the generation and release of thousands of merozoites that invade red blood cells.…”

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confidence: 99%

Genetically attenuated, P36p-deficient malarial sporozoites induce protective immunity and apoptosis of infected liver cells

Dijk

Douradinha

Franke-Fayard

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

245

253

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Immunization with Plasmodium sporozoites that have been attenuated by ␥-irradiation or specific genetic modification can induce protective immunity against subsequent malaria infection. The mechanism of protection is only known for radiation-attenuated sporozoites, involving cell-mediated and humoral immune responses invoked by infected hepatocytes cells that contain longlived, partially developed parasites. Here we analyzed sporozoites of Plasmodium berghei that are deficient in P36p (p36p ؊ ), a member of the P48͞45 family of surface proteins. P36p plays no role in the ability of sporozoites to infect and traverse hepatocytes, but p36p ؊ sporozoites abort during development within the hepatocyte. Immunization with p36p ؊ sporozoites results in a protective immunity against subsequent challenge with infectious wild-type sporozoites, another example of a specifically genetically attenuated sporozoite (GAS) conferring protective immunity. Comparison of biological characteristics of p36p ؊ sporozoites with radiation-attenuated sporozoites demonstrates that liver cells infected with p36p ؊ sporozoites disappear rapidly as a result of apoptosis of host cells that may potentiate the immune response. Such knowledge of the biological characteristics of GAS and their evoked immune responses are essential for further investigation of the utility of an optimized GAS-based malaria vaccine.apoptosis ͉ attenuated vaccines ͉ host-pathogen interaction ͉ Plasmodium

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PLASMODIUMSPOROZOITE MOLECULAR CELL BIOLOGY

Cited by 140 publications

References 164 publications

Emerging Rules for Subunit-Based, Multiantigenic, Multistage Chemically Synthesized Vaccines

Emerging Rules for Subunit-Based, Multiantigenic, Multistage Chemically Synthesized Vaccines

Unexpected fold in the circumsporozoite protein target of malaria vaccines

Genetically attenuated, P36p-deficient malarial sporozoites induce protective immunity and apoptosis of infected liver cells

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