Malaria parasites contain a plastid organelle called the apicoplast that is required for parasite survival in humans and for transmission to mosquitoes. The apicoplast has long been recognized as an important source of new drug targets to combat the inevitable problem of drug resistance, however, it has proven difficult to identify and validate apicoplast proteins that are essential for parasite survival. This goal is now achievable using new genetic tools in combination with metabolic bypass of the apicoplast. Blood stage parasites treated with the isoprene compound IPP (isopentenyl pyrophosphate) survive apicoplast inhibitors - even those which result in disruption of the organelle and loss of the organellar genome. Recently, we used the IPP metabolic bypass to demonstrate that iron-sulfur cluster biosynthesis is essential for maintenance of the organelle. We propose to use reverse and forward genetic approaches in conjunction with metabolic bypass to identify other nuclear-encoded proteins which are essential for apicoplast function and parasite survival. We will also use a new conditional localization tool to further characterize the roles of specific proteins and the phenotypes associated with their loss. Our experiments will help to build a more complete picture of the metabolic pathways and non-metabolic processes required for apicoplast function and parasite survival. Ultimately, we intend to identify novel targets and to validate known targets for future development of drugs to cure malaria and stop its transmission.

Public Health Relevance

The apicoplast organelle is required for the survival of malaria parasites in humans and for parasite transmission to mosquitoes. Our goal is to identify and characterize parasite genes responsible for maintaining the apicoplast using forward and reverse genetics approaches. These studies will identify novel proteins essential for the survival of malaria parasites and have significant implications for the development of therapeutics targeting blood stage malaria parasites and parasite transmission.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI125534-03
Application #
9467432
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Mcgugan, Glen C
Project Start
2016-05-20
Project End
2021-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Microbiology/Immun/Virology
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
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