Farrell Research Project Summary

Infectious diseases have a detrimental effect on human health and are one of the leading causes of human deaths. While vaccines are the gold standard for the prevention of infectious disease, vaccines are not currently available for some of the most deadly disease causing pathogens (e.g., HIV and Malaria). As such, therapeutics are required for the treatment of such diseases, and in cases where vaccines prove ineffective. To date, these therapeutics have been extremely effective at quelling the effects of many infectious diseases, however, given the continued rise in the number of drug resistant pathogens, new therapies and therapeutic strategies are required to target these resistant pathogens in order to prevent catastrophic outbreaks. It is widely accepted that the selective pressures imposed by traditional therapeutics gives rise to these drug resistant pathogens, as such, pathogen virulence factors are now being targeted in order to prevent infectious diseases, as it is believed that this approach will limit the selective pressures that lead to the rise of drug resistant pathogens. While a number of these molecules have been shown to be efficacious for the treatment of infectious diseases, small molecules that target virulence factors are often applied prophylactically or in combination with traditional therapeutics. While antibody therapeutics that target virulence factors have been demonstrated to effectively act alone in the prevention and clearance of numerous infectious disease causing pathogens. Although these therapeutics hold great promise, the administration of antibodies in the regions that are predominantly affected by infectious diseases remains a cause of concern. As such, this project aims to develop virulence factor neutralizing small molecules and peptides that are also capable of eliciting an immune response against the pathogen. We aim to achieve this by preparing antivirulence molecules that can interact with the innate immune system, specifically with mannose recognizing C-type lectins, such as the mannose binding lectin, the mannose receptor and DC-Sign, in order to effect pathogen clearance. To test our hypothesis we aim
to prepare molecules that target a virulence factor, namely the apical membrane antigen 1 (AMA1) protein, of the malaria causing parasite Plasmodium falciparum. We envision that the newly designed constructs will be capable of neutralizing the function of AMA1 while concomitantly eliciting an immune response toward the malaria causing pathogen that will facilitate immune induced clearance.