Probing Mechanisms of P. falciparum Artemisinin Resistance Using Single-Cell Transcriptomics
Abstract
Topic Areas: Malaria and Antimicrobial Resistance The proposed research specifically addresses the fiscal year 2017 topic area relating to development of new ways to combat the Plasmodium parasite that causes malaria. New treatments are urgently needed for malaria as these parasites have become increasingly resistant to current treatment options. The work proposed here aims to determine how specific mutations make parasites resistant to artemisinin, the most potent antimalarial drug currently in use. These findings can then be used to prevent resistance and block resistant parasites from spreading. Malaria is a disease that is present in most tropical and subtropical regions of the world. This disease is caused by infection with parasites in the genus Plasmodium and is transmitted by the bite of an infected mosquito. The parasites first infect the liver without causing disease, and symptoms begin when the parasites emerge from the liver cells and start growing inside the patient’s red blood cells. This is termed the erythrocytic cycle. Disease states range from uncomplicated malaria characterized by fevers, malaise, and nausea, to severe malaria where destruction of red blood cells causing severe anemia and multi-organ failure. According to the most recent World Health Organization (WHO) World Malaria Report, malaria deaths have declined. Encouragingly, a few African nations managed to reduce deaths due to malaria by half with interventions such as increased access to insecticide-impregnated bed nets and effective antimalarials. Still, there are approximately 200 million cases per year and close to 500,000 deaths; 91% of these deaths were in Africa and 85% of which occurred in children under age 5. Though progress has been made, these remain startling statistics. New drugs are needed to further reduce the immense burden of malaria and prevent a resurgence of disease in the face of increasingly drug-resistant parasites. Illness and death from malaria can be prevented with early diagnosis and effective treatment. However, the emergence of parasites resistant to artemisinin, the cornerstone of combination therapy, threatens continued efforts to decrease malaria morbidity and mortality. These resistant parasite strains carry mutations that enable them to survive higher doses of artemisinin for longer amounts of time. However, even though all resistant parasites carry the resistance mutations when they are exposed to artemisinin, some of them are killed while others are able to survive. Currently, it is not understood how “survivors” differ from their “killed” sibling parasites. By using a recently developed technique that can measure which genes are active in individual cells rather than a mixture of cells, the work proposed here will identify genes that are only active in “survivor” cells. Understanding how these genes allow parasites to survive drug treatment will allow is to design strategies for reversing resistance or preventing its spread. Both will be critical for the global efforts towards long-term malaria control and eradication.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810222
Entities
People
- Bjorn Kafsack
Organizations
- United States Army
- Weill Cornell Medicine