Infectious diseases such as HIV/AIDS, tuberculosis (TB), and malaria kill over 6 million people each year and these numbers are growing. Many of these pathogens have proven to be recalcitrant to drug and vaccine development in contrast to diseases such as smallpox and polio. A significant difference between these pathogens is that smallpox and polio demonstrate little immunogenic variation between strains and over time and space, such that lifetime protection can be acquired following exposure. Conversely, vaccine development for diseases such as HIV/AIDS, TB and malaria has proven more challenging in part due to the inability to identify appropriate antigens and epitopes. The difficulties inherent in vaccine development and acquired immunity can be demonstrated by the annual need for reformulated influenza vaccines, the emergence of new infectious diseases, the reemergence of previously controlled diseases, and the rapid appearance of resistant strains. All of this evidence points to a class of rapidly evolving pathogens that represent a moving target for the immune system and a threat to the public health system.

In collaboration with the Bioinformatics Center in the Institute of Chemical Research at Kyoto University we are developing a publicly accessible database termed varDB, which is designed to analyze for antigenic variation among a wide range of taxonomic groups. A number of different pathogens exhibit similar mechanisms to evade the host-immune systems including Plasmodium, HIV, Giardia, Borrelia and many Trypanosomes. The focus of varDB is to study common patterns among pathogens that share sophisticated immune system evasion mechanisms based on rapidly evolving protein families typically associated with host-parasite interactions. These organisms are highly adapted to the host environment and interact with the host through surface receptors while avoiding immune recognition. For example, surface antigen switching in malaria leads to surface receptors that avoid cross-reactive antibody development, whose expression correlates with disease severity.

All available gene, pseudogene, and protein sequences from known antigenic gene families are being compiled into a web database and facilities provided to allow users to upload sequence data for individual as well as comparative sequence analysis within and among species. Because gene families containing hypervariable regions pose unique alignment challenges, specialized alignment tools and expert alignments will be provided. Motif and subgroup identification tools are being included, and, where available, sequence data correlated with experimental phenotypic data, structural data, and functional annotations. A common interface allows data to be queried, selected, and filtered based on criteria such as phylogeny, disease symptoms, target proteins, and receptors as a tool to investigate common patterns of immune evasion conserved across evolution.

Many organisms belonging to a wide range of taxa, including viruses, bacteria, fungi, and protists employ some form of antigenic variation to avoid immune recognition by the host. Although the molecular and cellular mechanisms vary and are not evolutionary conserved among distantly related taxa, the shared environment of the host immune system may have resulted in convergent evolution of immune evasion strategies. The varDB database will provide a compilation of annotated sequence data on antigenic variation strategies across as many taxonomic groups as possible to facilitate comparative analysis within and among taxa. There are a number of databases devoted to immunology or sequence analysis of one or a limited group of pathogens, e.g. the Immune Epitope Database and Analysis Resource, PlasmoDB, and the Los Alamos HIV Database, but to our knowledge there is no centralized resource dedicated to compiling antigenic variation sequence data across such a wide range of taxa. varDB will serve as a clearinghouse for large variable antigenic protein groups involved in pathogenicity, assisting in the identification of conserved motifs responsible for pathogenicity. Accordingly, these results could be useful in 1) identifying new vaccine targets, 2) developing new therapeutics and 3) providing information on the fundamental biological processes involved in parasite virulence. Accordingly, the creation of varDB will fill an important niche and provide powerful tools to researchers around the world in their efforts to develop cures for these devastating diseases.

Another research focus involves targeting fatty acid synthesis for the development of new malaria chemoprophylaxis agents. A significant problem in coping with the malaria burden is parasite resistance to anti-malarials. Traditional treatments such as chloroquine are loosing their efficacy and parasites have already begun to evidence resistance to their replacements such as ACTs (artemisinin-based combination therapies). It is therefore vital to continue research into the anti-malarial development. Our efforts in lipidomics are well-suited to this task as the fatty acid synthesis pathway has been identified as a promising source of new drug targets. We are therefore employing lipidomics methods in the analysis of metabolic pathways to screen for new therapeutics for the treatment of malaria.

For information on the overall malaria research community in Sweden, please see the website for the Swedish Malaria Network.