Identifaction of the genetic basis of primaquine resistance in malaria parasites

Summary

Principal Investigator: ERIKA LEA FLANNERY
Abstract: DESCRIPTION (provided by applicant): In 2009 approximately 225 million cases of malaria were reported resulting in 781,000 deaths, mostly in children under 5 years old. Of the 5 Plasmodium species that cause malaria, P. falciparum has the highest case fatality rate and is subsequently the most studied. This has resulted in a decrease in the prevalence of P. falciparum, yet in many of the countries where falciparum malaria has been eradicated, vivax malaria remains endemic. P. vivax is the most geographically widespread of the Plasmodium spp., and over one-third of the world's population is at risk of infection. P. vivax is uniquely different from P. falciparum in that P. vivax is able to persist in a dormant, asymptomatic stage in the liver that can reemerge months to years after initial infection to cause clinical disease. These relapse episodes help to sustain transmission in endemic regions. Primaquine is the only licensed drug that will eliminate dormant liver-stage P. vivax parasites and thus prevent relapse. The development of resistance is a consistent hurdle faced when trying to control malaria and primaquine resistance has been reported. Despite being in use for over 50 years, the mechanism of action of primaquine is unknown. The objective of this fellowship application is to identify the molecular determinants of primaquine resistance in Plasmodium spp. Identification of these determinants will inform the development of new antimalarials that target liver-stage P. vivax. To accomplish this objective, I will use an in vivo model to evolve primaquine resistance in Plasmodium parasites. P. vivax cannot be cultured in vitro, therefore I will use a rodent model of malaria, P. berghei. First I will develop a whole-genome sequencing approach to detect genetic polymorphisms in P. berghei. I will then evolve parasite resistance to primaquine by serial passage of blood stages of P. berghei in mice treated with increasing concentrations of primaquine. The whole-genome sequence of the starting evolution strain can then be compared with the resistance-evolved strain to determine genetic modifications that are associated with primaquine resistance. This resistant line can then be tested to see if it is also resistant in the liver stage by allowing mosquitoes infected with the resistant line to feed on mice treated with primaquine and subsequently see if a blood-stage infection develops. Identification of the molecular determinants of primaquine resistance can then be used to establish molecular markers that can detect resistance in field isolates. These molecular determinants will also inform drug discovery efforts to identify additional liver-stage acting antimalarials. Both applications of the proposed results will aide in the eradication of vivax malaria.
Funding Period: 2013-02-01 - 2016-01-31
more information: NIH RePORT

Top Publications

  1. pmc Using genetic methods to define the targets of compounds with antimalarial activity
    Erika L Flannery
    Department of Pediatrics, University of California, San Diego, School of Medicine, 9500 Gilman Drive 0741, La Jolla, California 92093, United States
    J Med Chem 56:7761-71. 2013
  2. pmc Antimalarial drug discovery - approaches and progress towards new medicines
    Erika L Flannery
    Department of Pediatrics, University of California San Diego School of Medicine, 9500 Gilman Drive 0741, La Jolla, California 92093, USA
    Nat Rev Microbiol 11:849-62. 2013

Detail Information

Publications2

  1. pmc Using genetic methods to define the targets of compounds with antimalarial activity
    Erika L Flannery
    Department of Pediatrics, University of California, San Diego, School of Medicine, 9500 Gilman Drive 0741, La Jolla, California 92093, United States
    J Med Chem 56:7761-71. 2013
    ..Here we discuss how in vitro evolution of drug-resistant strains of Plasmodium falciparum and subsequent whole-genome analysis can be used to find the targets of some of the many compounds discovered in whole-cell phenotypic screens...
  2. pmc Antimalarial drug discovery - approaches and progress towards new medicines
    Erika L Flannery
    Department of Pediatrics, University of California San Diego School of Medicine, 9500 Gilman Drive 0741, La Jolla, California 92093, USA
    Nat Rev Microbiol 11:849-62. 2013
    ..In this Review, we discuss the cell-, chemistry- and target-based approaches used to discover new drug candidates that are currently in clinical trials or undergoing preclinical testing. ..

Research Grants30

  1. Lead optimization of DHODH inhibitors for malaria
    Margaret A Phillips; Fiscal Year: 2013
    ..Successful completion of these aims will identify additional DHODH inhibitors with the potential to be advanced for the treatment of malaria. ..
  2. Resistance of Malaria Parasites to Artemisinin-Based Combination Therapies
    Philip Jon Rosenthal; Fiscal Year: 2013
    ..abstract_text> ..
  3. Research to control and eliminate malaria in SE Asia and SW Pacific
    JAMES WALTER KAZURA; Fiscal Year: 2013
    ..Synergy among the ICEMR projects and cores and incorporation ICEMR findings into national programs will help answer unresolved key issues related to malaria control and elimination locally and in the SE Asia region. ..
  4. Program for Resistance, Immunology, Surveillance &Modeling of Malaria in Uganda
    MATTHEW G DORSEY; Fiscal Year: 2013
    ..In addition to the research activities described, this program will place a strong emphasis on local training and capacity building, the transfer of technology, and building strong relationships between researchers and policy makers. ..
  5. Systems Analysis Vaccine Responses in Healthy and Hyporesponsive Humans
    Anna Karolina Palucka; Fiscal Year: 2013
    ..abstract_text> ..
  6. Malaria Transmission and the Impact of Control Efforts in Southern Africa
    Peter C Agre; Fiscal Year: 2013
    ....
  7. Population-based Approach to Malaria Research and Control
    Donald J Krogstad; Fiscal Year: 2013
    ..Understanding these relationships is critical to both the evaluation of current intervention effectiveness and in the translation of new tools for prevention and treatment of the disease and its transmission. ..
  8. Center for the Study of Complex Malaria in India
    Jane M Carlton; Fiscal Year: 2013
    ..CSCMi projects will be supported by Administrative, Data Management, and Genomics Cores to be located at the NIMR's new facility in Dwarka, New Delhi. ..
  9. Role of pfcrt in chloroquine resistance in P. falciparum
    DAVID ARMAND FIDOCK; Fiscal Year: 2013
    ....
  10. Discovery of chemically validated malaria liver stage targets
    Elizabeth A Winzeler; Fiscal Year: 2013
    ..The inability to eliminate cryptic liver forms creates a barrier to malaria eradication. We propose to find new targets that are critical to the liver stages as well as the blood stages with the long term aim of designing better drugs. ..
  11. Genetic screen for P. vivax CQR
    Qin Cheng; Fiscal Year: 2013
    ..vivax CQR. The outcome will enable large-scale monitor and surveillance of the spread of CQR P. vivax, provide predictive value for treatment outcome and provide information for policy changes. ..
  12. Vaccination with purified, cryopreserved, infectious Plasmodium vivax sporozoites
    STEPHEN LEV HOFFMAN; Fiscal Year: 2013
    ..They will potentially provide an immune correlate of protection that can be used in humans, and inform better design of an immunization regimen for a PvSPZ vaccine for humans. ..
  13. Novel Broad-spectrum Antimalarials
    Victor Melendez; Fiscal Year: 2013
    ....
  14. The effect of peptide therapy and allergen provocation on Fel d1-specific T Cells
    Mark Larché; Fiscal Year: 2013
    ..Additionally this Aim will assess the effects of peptide immunotherapy in the murine allergen challenge model ..
  15. Development of Small Molecules as Antiprotozoal Agents
    Shuren Zhu; Fiscal Year: 2013
    ..The project involves standard approaches to drug development, but the multidisciplinary team and multi- institution collaboration that has been assembled will accelerate the generation of clinical candidates. ..
  16. T cell Inhibitory receptor blockade in chronic blood-stage malaria
    John T Harty; Fiscal Year: 2013
    ..chabaudi chabaudi blood-stage infection. Aim 4. Determine if and how inhibitory receptor blockade during chronic blood-stage infection impacts cross- species and cross-stage-specific protective immunity to reinfection. ..
  17. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  18. Within Host Selection of P. falciparum Variants by Artemisinin Combination Therap
    JONATHAN JAMES JULIANO; Fiscal Year: 2013
    ....
  19. Mitochondrial Functions in Malaria Parasites
    Akhil B Vaidya; Fiscal Year: 2013
    ..These studies have the potential to be highly valuable in developing strategies for chemotherapeutic intervention affecting validated targets of malaria parasites. ..
  20. Drugs targeting erythrocytic and exoerythrocytic stages of malaria
    Roman Manetsch; Fiscal Year: 2013
    ..The three chemotypes possess in vivo liver stage activity, in vivo blood stage activity, gametocytocidal activity, and/or activity in the mosquitoes. ..
  21. Impact of Distinct Eco-epidemiology on Malaria Drug Resistance in Ghana
    Anita Ghansah; Fiscal Year: 2013
    ....