Today at least 2.6 billion people live in areas of risk for Plasmodium vivax transmission;106 - 313 million cases of vivax malaria annually. While Duffy blood group negativity (Duffy (-)) has been considered to confer resistance to vivax malaria, our recent findings show that P. vivax has gained the capacity to infect erythrocytes and cause disease in Duffy (-) people in Madagascar. Our surveys of school-aged children revealed P. vivax PCR-positivity in 8.8% of asymptomatic Duffy (-) children. We also observed mono-infection P. vivax clinical disease in 4.9% of Duffy (-) people who reported for treatment during in vivo drug efficacy surveys;blood smear diagnosis confirmed P. vivax. Interestingly, preliminary population studies using 6 unlinked microsatellite markers suggested that Duffy (-) infections were caused by multiple P. vivax strains. While our results indicate that P. vivax invasion in Madagascar can occur independent of the erythrocyte's Duffy blood group antigen, we do not know if invasion is dependent or independent of the parasite's 'so-called'Duffy binding protein (PvDBP), the parasite ligand considered essential for invasion of human red blood cells. By DNA sequencing the PvDBP locus we have identified one allele to be over-represented in Duffy (-) infections. Additionally, recent whole genome sequencing has revealed that Malagasy P. vivax strains (and no P. vivax strains outside Madagascar) carry a PvDBP duplication. Overall, our findings suggest that P. vivax in Madagascar is evolving new erythrocyte infection mechanisms. To begin understanding how P. vivax has gained capacity to infect Duffy(-) erythrocytes we propose to study population genetic features of the parasite population while performing in-depth cell and molecular biological analysis of P. vivax strains of Madagascar. Resulting data from these studies will allow us to address the following Specific Aims.
Aim 1 - Determine associations between P. vivax strains and susceptibility of Duffy (-) people to P. vivax blood-stage infection and clinical malaria.
Aim 2 - Assess interactions between P. vivax erythrocyte binding ligands and human erythrocytes that influence merozoite attachment and human red cell invasion.
Aim 3 - Test alternative invasion pathways of Malagasy P. vivax strains in vitro for Duffy (-) and Duffy (+) erythrocytes. Our studies will determine differential susceptibility of Duffy (+) and Duffy (-) people to P. vivax disease. Planne in vitro studies will provide insight regarding new P. vivax erythrocyte invasion mechanisms, with special emphasis on Duffy-independent invasion. Finally, we will determine whether molecular variations involved in P. vivax binding to, and invasion of Duffy (+) and Duffy (-) erythrocytes indicates capacity of Madagascar P. vivax strains to spread into other populations.

Public Health Relevance

Today 2.6 billion people live in areas of risk for Plasmodium vivax (Pv) transmission;106 - 313 million cases of vivax malaria annually. Duffy blood group negativity has been considered to confer resistance to vivax malaria, however, our recent findings indicate that Pv has gained the capacity to infect erythrocytes and cause disease in Duffy-negative people in Madagascar. Epidemiology coupled with cell and molecular biology will investigate Pv strains infecting Duffy-negative vs. Duffy-positive people to identify parasite molecules involved in the Pv Duffy-independent invasion pathway.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AI097366-02
Application #
8731173
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Rao, Malla R
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Cleveland
State
OH
Country
United States
Zip Code
44106