Article

Structural characteristics of immunogenic liver-stage antigens derived from P. falciparum malarial proteins.

Fundación Instituto de Inmunología de Colombia (FIDIC), Cra. 50 No. 26-20 Bogotá, Colombia.
Biochemical and Biophysical Research Communications (impact factor: 2.48). 06/2009; 384(4):455-60. DOI:10.1016/j.bbrc.2009.04.138 pp.455-60
Source: PubMed

ABSTRACT A fully effective antimalarial vaccine must contain multiple proteins from the different development stages of Plasmodium falciparum parasites involved in host-cell invasion or their biologically active fragments. It must therefore include sporozoite molecules able to induce protective immunity by blocking the parasite's access to hepatic cells, and/or proteins involved in the development of this stage, amongst which are included the Liver Stage Antigen-1 (LSA-1) and the Sporozoite and Liver Stage Antigen (SALSA). Our studies have focused on the search for an association between the structure of high activity binding peptides (HABPs), including both conserved native and their modified analogues, and their ability to bind to the MHC Class II HLA-DR molecules during formation of the MHCII-peptide-TCR complex leading to inducing the appropriate immune response. These studies are part of a logical and rational strategy for developing multi-stage, multi-component, minimal subunit-based vaccines, mainly against the P. falciparum malaria.

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    Article: Plasmodium falciparum liver stage antigen-1 is cross-linked by tissue transglutaminase.
    William S Nicoll, John B Sacci, Carlo Rodolfo, Giuseppina Di Giacomo, Mauro Piacentini, Zoe Jm Holland, Christian Doerig, Michael R Hollingdale, David E Lanar
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    ABSTRACT: Plasmodium falciparum sporozoites injected by mosquitoes into the blood rapidly enter liver hepatocytes and undergo pre-erythrocytic developmental schizogony forming tens of thousands of merozoites per hepatocyte. Shortly after hepatocyte invasion, the parasite starts to produce Liver Stage Antigen-1 (LSA-1), which accumulates within the parasitophorous vacuole surrounding the mass of developing merozoites. The LSA-1 protein has been described as a flocculent mass, but its role in parasite development has not been determined. Recombinant N-terminal, C-terminal or a construct containing both the N- and C- terminal regions flanking two 17 amino acid residue central repeat sequences (LSA-NRC) were subjected to in vitro modification by tissue transglutaminase-2 (TG2) to determine if cross-linking occurred. In addition, tissue sections of P. falciparum-infected human hepatocytes were probed with monoclonal antibodies to the isopeptide ε-(γ-glutamyl)lysine cross-bridge formed by TG2 enzymatic activity to determine if these antibodies co-localized with antibodies to LSA-1 in the growing liver schizonts. This study identified a substrate motif for (TG2) and a putative casein kinase 2 phosphorylation site within the central repeat region of LSA-1. The function of TG2 is the post-translational modification of proteins by the formation of a unique isopeptide ε-(γ-glutamyl)lysine cross-bridge between glutamine and lysine residues. When recombinant LSA-1 protein was crosslinked in vitro by purified TG2 in a calcium dependent reaction, a flocculent mass of protein was formed that was highly resistant to degradation. The cross-linking was not detectably affected by phosphorylation with plasmodial CK2 in vitro. Monoclonal antibodies specific to the very unique TG2 catalyzed ε- lysine cross-bridge co-localized with antibodies to LSA-1 in infected human hepatocytes providing visual evidence that LSA-1 was cross-linked in vivo. While the role of LSA-1 is still unknown these results suggest that it becomes highly cross-linked which may aid in the protection of the parasite as it develops.
    Malaria Journal 01/2011; 10:14. · 3.19 Impact Factor
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Keywords

activity binding peptides
 
appropriate immune response
 
biologically active fragments
 
conserved native
 
different development stages
 
effective antimalarial vaccine
 
host-cell invasion
 
LSA-1
 
MHC Class II HLA-DR molecules
 
MHCII-peptide-TCR complex
 
minimal subunit-based vaccines
 
multi-stage
 
parasite's access
 
Plasmodium falciparum parasites
 
rational strategy
 
sporozoite molecules able