Vaccine Development Pathogenic agents often alter the proteins expressed on their cell surfaces to escape detection by the host immunosurveillance systems. By analyzing these changes with GeneChip arrays, scientists can visualize all of the genes expressed under in vivo conditions, allowing the identification of even rarely expressed, but potentially important, potential vaccine candidates.
Plasmodium falciparum, the parasite that causes Malaria, is responsible for millions of deaths every year. The increasing prevalence of drug-resistant strains means that there is an urgent need to better understand the function and biological role of P. falciparum genes to develop new anti-malarial interventions. Le Roch et al. used GeneChip CustomExpress Arrays to examine genome-wide expression in P. falciparum during nine stages of parasite development. Rather than examining only annotated genes, they employed a tiling strategy to space probes every 150 bases across the genome on the array. This unbiased ab initio strategy allows the researcher to detect all expressed transcripts, not just annotated ones. Using this approach, they were able to group the expressed genes into one of 15 clusters, and found that most genes used in current vaccine trials are expressed at the same time and map to the same clusters. By examining the
uncharacterized genes from that vaccine cluster, they anticipate identifying additional vaccine candidates.
This same group (Volkman et al.) has also used GeneChip Arrays to scan for SNPs on P. falciparum chromosome 2, and found that most were located in the subtelomeric 100 kb regions at each end of the chromosome or in known antigenic determinants and proteins associated with the cell membrane. A number of uncharacterized genes that were identified in these regions represent potential vaccine candidates. In the same manner that vaccine candidates cluster together in gene expression studies, variation in genomic composition also clusters, demonstrated in studies like this one. Understanding the genetic differences between different strains and isolates of a pathogen allows researchers to identify antigenic determinants that might otherwise have been missed.
Neisseria meningitidis is a leading cause of bacterial meningitis and septicemia globally and affects predominantly infants and teenagers. Meningococci are divided into 12 serogroups, with five of these accounting for virtually all cases of meningococcal disease. Kurz et al. analyzed genome-wide expression in N. meningitidis serogroup B in three key steps of meningococcal infection, and identified 279 differentially expressed genes when exposed to human sera. Of these, 23 were genes encoding membrane and cell surface proteins that may constitute attractive vaccine candidates. The expression of genes encoding general membrane proteins was repressed, suggesting a mechanism for evasion of immune surveillance, while the expression of the highly variable membrane protein PorA that does not induce cross-protective immunity, was induced.
References
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Le Roch, K.G., et al. Discovery of gene function by expression profiling of the malaria parasite life cycle. Science301: 1503-1508 (2003).
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Volkman, S. K., et al. Excess polymorphisms in genes for membrane proteins in Plasmodium falciparum. Science298: 216-218 (2002).
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Kurz, S. et al. Transcriptome-based antigen identification for Neisseria meningitidis. Vaccine21: 768-775 (2003).
Related Scientific Publications
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Le Roch, K. G. et al. Monitoring the chromosome 2 intraerythrocytic transcriptome of Plasmodium falciparum using oligonucleotide arrays. American Journal of Tropical Medicine and Hygiene67: 233-243 (2002).
Pathogenic agents often alter the proteins expressed on their cell surfaces to escape detection by the host immunosurveillance systems. By analyzing these changes with GeneChip arrays, scientists can visualize all of the genes expressed under in vivo conditions, allowing the identification of even rarely expressed, but potentially important, potential vaccine candidates.
Neisseria meningitidis is a leading cause of bacterial meningitis and septicemia globally and affects predominantly infants and teenagers. Meningococci are divided into 12 serogroups, with five of these accounting for virtually all cases of meningococcal disease. Kurz et al. analyzed genome-wide expression in N. meningitidis serogroup B in three key steps of meningococcal infection, and identified 279 differentially expressed genes when exposed to human sera. Of these, 23 were genes encoding membrane and cell surface proteins that may constitute attractive vaccine candidates. The expression of genes encoding general membrane proteins was repressed, suggesting a mechanism for evasion of immune surveillance, while the expression of the highly variable membrane protein PorA that does not induce cross-protective immunity, was induced.
