From inhibitors to enzymatic deficiencies: exploring alterations in erythrocyte glycolysis as an antimalarial strategy.

Project Summary/Abstract The malaria parasite Plasmodium falciparum is responsible for millions of cases of malaria and over 500,000 global deaths each year. Resistance to current first-line antimalarial regimens, artemisinin-based therapies, is spreading in Southeast Asia and Africa. This continued spread threatens current malaria control and eradication efforts, and new antimalarials with novel mechanisms of action are urgently needed. All currently approved antimalarials target parasite-specific enzymes and pathways. Host-directed therapies, which target host proteins or pathways that are essential to the parasite, could serve as a novel antimalarial strategy. Determining the role of host pathways in the parasite lifecycle will inform future host-targeting antimalarial drug development. This project aims to determine the role of erythrocyte glycolysis in the Plasmodium falciparum intraerythrocytic lifecycle. In Specific Aim 1, the candidate will inhibit glycolysis in terminal erythrocytes and determine how this disruption affects P. falciparum growth, progression through the lifecycle, and susceptibility to oxidative stress. In Specific Aim 2, the candidate will use gene editing to generate pyruvate kinase-deficient erythrocytes and examine how prolonged disruptions in glycolysis affect the parasite. The results of the proposed experiments will yield a comprehensive understanding of why erythrocyte glycolysis is essential to the P. falciparum intraerythrocytic lifecycle and establish its tractability as an antimalarial target. The candidate is a pediatric infectious diseases specialist committed to studying host-parasite interactions in malaria parasites. The proposed training and research project will be conducted at the Children’s Hospital of Philadelphia (CHOP) and the University of Pennsylvania (UPenn). These two institutions are leaders in the study of host-pathogen interactions and erythrocyte biology and development and provide an ideal environment for the proposed research and career development. The candidate will be mentored by Dr. Audrey John with the support of an experienced and diverse advisory committee, including Drs. Stella Chou, Stefano Rivella, Akhil Vaidya, and Sarah Tishkoff. The candidate’s long-term goal is to develop a research program that examines host-parasite interactions in malaria infection and leverages these interactions to identify potential antimalarial targets and develop therapies. Completion of the proposed research and career development will provide a strong foundation for the candidate’s future career.