Dinglasan Malaria Laboratory
Glycoproteomic Analysis of Malaria Transmission Biology
Discovery of novel interventions in the fight against malaria requires a pioneering approach to examine cell-cell interactions among the transmission stages of the parasite (i.e., sporozoite and ookinete) and their respective mammalian or mosquito host cells. Glycobiology offers such a unique approach. In model systems, glycans and glycoconjugates have been shown to be important structural components of cell walls and the extracellular matrix, modifiers of protein solubility (secretion) and stability (protection from enzyme degradation), modulators of glycoprotein trafficking both intra- and extracellularly (e.g., by modifying porosity of the glycocalyx), mediators of cell-cell and cell-matrix adhesion and intra- and extracellular signaling. Yet, despite their clear importance in cell biology, an appreciation of glycan posttranslational modification of critical proteins involved in host-pathogen interactions, especially in the context of malaria parasite development, remains undervalued.
In addition to using transgenic technologies (parasite) and RNAi (mosquito), we are also applying mass spectrometry and lectin/glycan arrays to answer some of the fundamental questions concerning how protein-glycan interactions mediate cell invasion across different parasite developmental stages (but most especially in the mosquito). Recent and on-going work have examined the role of glycosyltransferases, glycoconjugates (glycoproteins and proteoglycans) on the mosquito midgut surface as well as identified novel ookinete (parasite) lectin-like molecules.
A prime example of the fruit of our strategy is the discovery of a mosquito midgut ligand for Plasmodium ookinetes, the Anopheles gambiae midgut surface glycosylphosphotidylinositrol linked alanyl aminopeptidase N (AgAPN1) as described below. For more information check out: http://dinglasanlab.org/publications/expression-immunogenicity-histopathology-and-potency-mosquito-based-malaria.
The Anopheles gambiae midgut surface glycosylphosphotidylinositrol linked alanyl aminopeptidase N (AgAPN1) is highly conserved across Old and New World anophelines. The AnAPN1 Transmission blocking vaccine target is the N-terminal 135 amino acid fragment and is referred to as AnAPN1.