Proteases to Restrict Parasite Invasion
Dr. David O’Brochta, University of Maryland Center for Biosystems Research


Restriction proteases could be widely applicable in disease treatment but an animal system is needed to explore basic principles and determine long term potential.  The mosquito-parasite system is well-suited for this. Upon feeding on an infected host, mosquitoes acquire Plasmodium gametocytes that very quickly develop into gametes within the mosquito’s midgut.  Fusion of gametes results in the formation of diploid zygotes that rapidly mature into motile ookinetes that invade midgut cells and enter the haemolymph.  Parasite development at this stage results in the expression of a number of essential cell surface and secreted proteins that have been shown to be excellent targets for transmission-blocking vaccines.  Consequently, these same proteins are also excellent targets for restriction proteases and the mosquito/Plasmodium system is well-suited to demonstrating the applicability of restriction proteases to disease treatment.

The proposed restriction proteases are complex machines which require genetic encoding of the protease, targeting of the protease to the appropriated cells in the mosquito and regulated activity in response to the disease state.   Efforts to develop genetically altered mosquitoes that are resistant to Plasmodium infection are part of ambitious plans to control malaria transmission by manipulating vector insects and vector insect populations.   The protein engineering strategy being developed here will result in the creation of restriction proteases that will provide vector biologists with a powerful tool for developing parasite resistant mosquitoes.

The project is in collaboration with Dr. O’Brochta (University of Maryland Center for Bioscience and Biotechnology Research) who has pioneered the construction of transgenic mosquitoes with increased resistance to parasite infection as a way to break the transmission cycle.  Preliminary work has been funded by a Grant from the Bill and Melinda Gates Foundation to Dr. Bryan.