Exploration of the control of Plasmodium falciparum intraerythrocytic growth and development is in its infancy. Understanding the signals and effectors of parasite progression will enhance our knowledge of how this parasite survives in its host cell and will uncover new targets for chemotherapy. PfHO-1 is a heme oxygenase-like protein of unknown function expressed in intraerythrocytic malaria parasites. We have found that PfHO-1 has a porphyrin-responsive DNA- binding activity and associates preferentially with genes that are involved in protein synthesis. Our hypothesis is that PfHO-1 responds to heme accumulation from hemoglobin degradation and is crucial for intra-erythrocytic P. falciparum development. The goal of the study proposed here is to test this hypothesis. We will assess the response of PfHO-1 to perturbation of intracellular porphyrin levels in intraerythrocytic P. falciparum and in an E. coli reporter system. We will impair PfHO-1 action by a new double-positive selection gene knockout approach and by conditional expression of a porphyrin-unresponsive version of the protein. These studies will allow us to establish whether PfHO-1 plays an important role in sensing cellular porphyrin levels and participating in critical aspects of cellular homeostasis. The proposed experiments will also develop new technologies for porphyrin manipulation and for selection of deleterious phenotypes in reverse genetically engineered parasites.

Public Health Relevance

Malaria is one of the world's devastating diseases: there are several hundred million cases worldwide and more than one thousand in this country, mostly imported from other countries. We have discovered a malaria parasite protein that responds to heme, a key metabolite for the organism when it is inside human red blood cells. Characterizing the function of this important protein has the potential to spur development of new antimalarial chemotherapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI110712-01
Application #
8662416
Study Section
Special Emphasis Panel (ZRG1-IDM-M (02))
Program Officer
Mcgugan, Glen C
Project Start
2014-02-06
Project End
2016-01-31
Budget Start
2014-02-06
Budget End
2015-01-31
Support Year
1
Fiscal Year
2014
Total Cost
$179,409
Indirect Cost
$54,409
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130