Our laboratory?s overarching goals support NIAID?s mission to better understand, treat, and prevent infectious diseases by focusing on pre-erythrocytic malaria vaccine development through identification of protective cytotoxic T cell (CTL) antigens using novel biological and immunological methods. Subunit vaccines that efficiently stop the Plasmodium sporozoite (spz) or liver stage (LS) completely protect against malarial disease and will enable eradication efforts. There are currently no FDA-approved malaria subunit vaccines for use in humans although attenuated spz show sterile protection against challenge in multiple Phase 1/2 clinical trials. This project aims to identify parasite proteins exported from the parasite to the host for testing as novel vaccine subunits. Two proximity labeling methods will be used to identify parasite proteins exported to the parasitophorous vacuolar membrane and/or host cell cytoplasm during LS infection. Such exported proteins are more likely to be sampled by host antigen processing pathways for display on Class I MHC as CTL antigens. Since little is known about LS protein trafficking, this work may identify export motifs that would expand our basic knowledge of LS parasite biology. Selected proteins will be tested to validate their export in vitro and those that demonstrate true export will be tested in preliminary immunization/challenge studies. Exported proteins may be ideal CTL target antigens and could be incorporated into our ongoing efforts to develop effective multi-subunit CTL DNA vaccines.
Malaria vaccines that block parasite development in the liver depend on cytotoxic T cells that kill infected hepatocytes displaying epitopes derived from exported liver-stage proteins. This project aims to identify liver stage proteins exported from the parasite to the host cell using proximity labeling strategies, to validate export of some of these proteins, and to undertake preliminary testing of novel exported proteins as T cell vaccine antigens.
