Chemogenomic Profiling of Plasmodium Falciparum Responses and Resistance

Project Summary/Abstract
Malaria is a leading cause of human death and illness, causing over 200 million cases of clinical
malaria and 400,000 deaths each year. Traditional measures to control and cure malaria are
threatened by emergence of artemisinin resistance (ART-R). Research into ART-R has focused
mostly on mechanisms allowing parasite to tolerate the oxidative stress and protein damage
resulting from ART’s mechanism of action. However, recent discoveries indicate that resistance-
associated mutations in the K13 slows cytostome function to diminish the available hemoglobin in
the food vacuole. Our preliminary results revealed that the parasite’s sensitivity and tolerance to
ART significantly overlaps with innate stress response pathways that enable P. falciparum survival
of malaria fever. Our experimental approach is to elucidate drug-gene associations and decipher
mechanisms of action and resistance to ART and other antimalarial drugs, using forward genetic
screens of P. falciparum mutants created by random piggyBac mutagenesis. This approach has
determined that genetic mutations in the major parasite processes critical for P. falciparum malarial
fever survival response significantly correlate with altered sensitivity to ART (DHA, AS), indicating
the parasite hijacked the heat-shock stress response pathways to cope with ART toxicity. We will
use small libraries of piggyBac clones and GO-focused libraries for iterative screens of different
phenotypes to functionally annotate interacting partners, pathways, and regulatory processes
linked to ART mechanism of action and resistance. We will use genome-level screens to identify
factors linked to ART mechanism of action. We will extend our analysis to P. knowlesi to
characterize the conserved high-value antimalarial drug targets by adapting and applying
chemogenomic profiling analysis to this vivax-like malaria parasite.

Grant Number: 5R01AI117017-10
NIH Institute/Center: NIH
Principal Investigator: John Adams