Stress response and Artemisinin resistance in malaria parasite

One-third of the world population lives in zones at risk of contracting malaria, a treatable vector borne infectious disease. Due to its worldwide distribution, malaria possesses a major health risk for US military personnel deployed to endemic countries. The current recommended standard treatments are artemisinin combination therapies (ACTs). These therapies combine a fast-acting artemisinin (or a derivative) drug with a long-lived antimalarial drug, and they are very effective therapeutics against Plasmodium falciparum, the parasite responsible for over 90% of malaria-related deaths. Unfortunately, recent reports of artemisinin-resistant P. falciparum strains from Southeast Asia raise the spectrum of treatment failure and increase mortality. This situation creates an urgent need to find new artemisinin partner drugs to use in combination therapies in order to contain the spread of these resistant parasites and extend artemisinin effectiveness. The long-term goal is to identify and develop a new generation of antimalarial compounds to be used as single agents or in combination therapies with known antimalarial drugs.

Research on artemisinin-resistant P. falciparum has recently revealed that these parasites have a significant increase in the expression of genes associated with the UPR including GRP78. The UPR is a highly conserved cellular stress response pathway that provides an adaptive stress response to the P. falciparum parasite when exposed to environmental challenges like artemisinin exposure. The hypothesis is that in P. falciparum artemisinin-resistant parasites, the UPR pathway is elevated when compared with sensitive ones. Therefore, inhibition of GRP78 could restore parasite sensitivity to artemisinin. To test the hypothesis, following aims will be developed: (1) characterization of GRP78 expression in artemisinin-resistant P. falciparum parasites and (2) determine if inhibition of GRP78 in artemisinin-resistant P. falciparum parasites reverts resistance. The result from our proposal will be identification of GRP78’s role in artemisinin resistance. This project will also validate the GRP78 chaperone as a drug target against artemisinin-resistant malaria parasites. Finally, the results will validate the role of the UPR in artemisinin resistance, and this might open new therapeutic avenues to combat drug resistance in malaria.

Basic Science
Drug Resistance

Jun 2016 — Dec 2017

$273,842

United States