Developmental Biology of Sporozoite-Host Interactions in<i>Plasmodium falciparum</i>Malaria: Implications for Vaccine Design

Garcı́a, Javier; Puentes, Álvaro; Patarroyo, Manuel E.

doi:10.1128/cmr.00063-05

Cited by 56 publications

(70 citation statements)

References 139 publications

(279 reference statements)

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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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“…It means that the parasite must be able to attack different target cells and for this purpose more specialized proteins may be required. (Garcia et al, 2006).…”

Section: Proteome Analysismentioning

confidence: 99%

Analysis of immunogenicity of different protein groups from malaria parasite Plasmodium falciparum

Krzyczmonik

Świtnicki

Kaczanowski

2012

Infection, Genetics and Evolution

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It was observed that pressure of host immune system leads to diversifying selection (which can be measured in terms of pN/pS ratio). In this research we checked whether Plasmodium falciparum proteins containing experimentally evident epitopes from the IEDB database are subject to diversifying selection. We also investigated which life stage of this parasite and which proteins are subject to the strongest immune pressure. To answer these questions we used information about experimentally evident epitopes from Plasmodium, that interact with human immune system and sequences of different isolates of P. falciparum.We confirmed the expectations that proteins containing IEDB epitopes are subject to stronger diversifying selection which is evidenced by higher pN/pS ratio. A stage characterized by the highest average pN/pS ratio is that of the sporozoite. The greatest fraction of putative antigens is also present at this stage. We also found that the sporozoite stage is particularly interesting for further analysis as it potentially contains the highest number of unidentified epitopes.

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“…CS, a Plasmodial multifunctional protein responsible for the invasion of Mosquito's salivary gland, binding of the sporozites to the host liver and inactivating their cell creation mechanism Plasmodial [29]. Because of these properties, CS is considered a good component for vaccine design.…”

Section: Malaria Vaccine Candidate Peptides P18 and P32mentioning

confidence: 99%

“…Two peptides derived from CS, P18 and P32 are being studied for possible engagement in the design. Their residues were retrieved from literature [29] and UNIPROT database [30] and examined.…”

Section: Malaria Vaccine Candidate Peptides P18 and P32mentioning

confidence: 99%

Novel Computerized Approaches to Investigating Pharmacological Activities

Nwankwo¹

2015

CBB

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Abstract:Complementing clinical assessments using computerized procedures with the view of completely disengaging from clinical procedures may become inevitable in future. Huge biological and pharmacological data (such as sequences) are churned out daily such that it is becoming difficult to process them without the aid of computers. Computerized approaches including Digital Signal Processing (DSP)-based Bioinformatics procedures like Informational Spectrum Method (ISM) are rational techniques that need be incorporated into pharmacological studies. By means of ISM and one biological parameter or Amino Acid Scale (AAS), we have preliminarily shown how pharmacological activities can be decoded using computerized techniques. However, for effective engagement of ISM, some basic information must be made available and engaged. Firstly, the sequence information comprising of the consensus sequences and all the mutations involved must be assembled and engaged. Pharmacological activities (e.g. drug resistance) are known to be expressed in the genes/proteins (e.g. MDR1 and MDR2, pfdr1, etc). Secondly, biological parameters must be identified and engaged. This calls for good knowledge of the drugs' mechanisms of action at the atomic level. This is because it has been identified that, at one point mutation; more than one biological parameter may be involved. To obtain the entirety of pharmacological activities exhibited therefore, aggregation of the contributions from each mutation and parameter is needed.We have then unveiled and compared the pharmacological activities of anti-retroviral agents (Enfuvirtide and Sifuvirtide), and potencies of Malaria vaccine candidates, peptides P18 and P32 (Innocentive Challenge Winning Solver Award, ID: 9933477), etc. A biomedical device called Computer-Aided Drug Resistance Calculator (Patent Application filed in 2014) is developed using this novel computerized approach. The device will rationally help assess a pharmacological property (drug resistance). Other researchers have recorded in-silico pharmacological assessments. Clinically and computationally derived outcomes are found to correlate. We therefore propose that these computerized approaches be engaged in deciphering pharmacological activities where sequence information and biological parameters are available. These approaches are rational. They also present pharmacological findings in numerical terms. In this era of rational, computerized, informatics-and robotics-based procedures, these approaches are envisaged to transform pharmacological investigation procedures especially now that pharmacological activities could be deciphered from their protein sequences or those of their protein targets and the genes/proteins expressing them. The procedures engaged in this study are expected to be embodied into Pharmaco-informatics program.

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Developmental Biology of Sporozoite-Host Interactions inPlasmodium falciparumMalaria: Implications for Vaccine Design

Cited by 56 publications

References 139 publications

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

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

Analysis of immunogenicity of different protein groups from malaria parasite Plasmodium falciparum

Novel Computerized Approaches to Investigating Pharmacological Activities

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