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Conference Agenda

Overview and details of the sessions of this conference. Please select a date or location to show only sessions at that day or location. Please select a single session for detailed view (with abstracts and downloads if available).

Daily Overview

Session

CP8: Drugs & Drug Resistance 1 - 10 min talks
Location: Lecture Theatre 1
Session Chair: Christopher Hart, Griffith University
Session Chair: Hannah Smith, Griffith University

Presentation 4

Plasmepsin IX and X dual inhibitor impairs sporozoite development in mosquitoes and their infectivity in human hepatocytes

Elena Lantero Escolar^1,2, John A. McCauley³, David B. Olsen³, Alan F. Cowman^1,2, Justin A. Boddey^1,2

1: Walter and Eliza Hall Institute of Medical Research, Australia; 2: University of Melbourne, Australia; 3: Merck & Co., Inc., USA

WM382 is an inhibitor for Plasmepsin IX and X in Plasmodium spp blood and liver stages. These proteases are essential and ubiquitous in Plasmodium spp., where they process diverse proteins involved in egress and invasion of host cells. This makes them ideal targets for drug intervention. Plasmepsin IX and X are also expressed in sporozoites. To decipher their role in this stage, WM382 was administered to mosquitoes after Plasmodium falciparum infection. The number of developing oocysts was the same irrespective of WM382 treatment, though a modest increase in size was detected following drug administration, suggesting differential parasite development. Furthermore, the number of salivary gland sporozoites was dramatically reduced when mosquitoes were treated with WM382. This phenotype points to a defect in egress of P. falciparum sporozoites from the oocyst. We identified accumulation of unprocessed precursors of the essential protein AMA1 in haemolymph and salivary gland sporozoites when treating with WM382, while processing of CSP remained unaffected. Some WM382-treated sporozoites could still invade salivary glands but they displayed significant loss-of-function phenotypes during cell traversal and infection of human HC04 hepatocytes. These results show a role of plasmepsin IX/X during the mosquito stages, raising the possibility of control interventions during transmission.