Faculty & Research
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David A. Fidock, Ph.D. Antimalarial chemotherapy, resistance, pathogenesis, immunomodulation, Plasmodium falciparum parasite biology Lab Website: http://microbiology.columbia.edu/fidock/ |
Research
Biological investigations into Plasmodium falciparum, the etiologic agent of severe malaria, reveal an organism that is tremendously adept at overcoming therapeutic attack and evading host immunity. This haploid apicomplexan parasite causes disease in over half a billion individuals and kills over a million African children yearly, and prevents sterilizing immunity from being acquired even by individuals who have been infected thousands of times. Disease can result from severe anemia, hyperparasitemia, or other complications resulting from sequestration of parasitized red blood cells (RBC) in the microvasculature, a process that depends on the presentation of antigenically distinct parasite proteins on the infected RBC surface. Chemotherapeutic clearance of asexual blood stage parasites is the linchpin of malaria treatment and control, however it is systematically thwarted by the acquisition of resistance. The most dramatic consequence has been with chloroquine (CQ), for decades the gold standard until resistance appeared and pre-empted a dramatic increase in malaria mortality and morbidity rates, particularly in Africa. During my past 18 years of malaria research, I have investigated how P. falciparum invades and develops within hepatocytes and RBC, what immune effector mechanisms operate on these stages, how antimalarials act and how parasites counter their action, and how parasites are successfully transmitted to Anopheles mosquitoes, their definitive host. My laboratory’s ongoing and planned research channels these interests into several themes:
1) What are the parasite factors that mediate resistance to antimalarial drugs;
2) What biological processes are targeted by antimalarial drugs and what accounts for parasite death;
3) What biochemical and physiological functions are intrinsic to the digestive vacuole (DV) and the apicoplast, the site of action of CQ and of antibiotics respectively; and
4) How does P. falciparum regulate its virulence and prevent the establishment of protective immunity. These studies benefit from our extensive experience in P. falciparum transfection and we constantly strive for new innovations in genetics to enhance the power of these investigations.
Please see our lab website for more information about our research and publications.
Recent and Notable Articles
- Yu M., Kumar T.R.S., Nkrumah L.J., Coppi A., Retzlaff S., Li C.D., Kelly B.J., Moura P.A., Lakshmanan V., Freundlich J.S., Valderramos J.C., Vilcheze C., Siedner M., Tsai J.H.C., Falkard B., Sidhu A.B.S., Purcell L.A., Gratraud P., Kremer L., Waters A.P., Schiehser G., Jacobus D.P., Janse C.J., Ager A., Jacobs Jr. W.R., Sacchettini J.C., Heussler V., Sinnis P., Fidock D.A. (2008). The Fatty Acid Biosynthesis Enzyme FabI Plays a Key Role in the Development of Liver-Stage Malarial Parasites. Cell Host & Microbe.11: 567-78.
- Fidock D.A., Eastman R.E., Ward S.A. & Meshnick S.R. (2008). Recent highlights in antimalarial drug resistance and chemotherapy research. Trends in Parasitol. 24: 537-44.
- Lee M.C.S., Moura P.A., Miller E.A. & Fidock D.A. (2008). Plasmodium falciparum Sec24 marks transitional ER that exports a model cargo via a diacidic motif. Mol. Microbiol. 68: 1535-1546.
- Ekland E.H. & Fidock D.A. (2008). In vitro evaluations of antimalarial drugs and their relevance to clinical outcomes. Int. J. Parasitol. 38: 743-747.
- Greenwood B.M., Fidock D.A., Kyle D.E., Kappe S.H., Collins F.H. & Duffy P.E. (2008). Malaria: progress, perils, and prospects for eradication. J. Clin. Invest. 118: 1266-1276.
- Lee M.C.S. & Fidock D.A. (2008). Arresting malaria parasite egress from infected red blood cells. Nature Chem. Biol. 4: 161-162.
- Ekland E.H. & Fidock D.A. (2007). Advances in understanding the genetic basis of antimalarial drug resistance. Curr. Opinion Microbiol. 10: 363-70.
- Hunt P., Afonso A., Creasey A., Culleton R., Sidhu A.B.S., Logan J., Valderramos S., McNae I., Cheesman S., do Rosario V., Carter R., Fidock D.A. & Cravo P. (2007). Gene encoding a de-ubiquitinating enzyme is mutated in artemisinin- and chloroquine-resistant rodent malaria parasites. Mol. Microbiol. 65: 27-40.
- Sidhu A.B., Sun Q., Nkrumah L.J., Dunne M.W., Sacchettini J.C. and Fidock D.A. (2007). In vitro efficacy, resistance selection, and structural modeling studies implicate the malarial parasite apicoplast as the target of azithromycin. J. Biol. Chem. 282: 2494-504.
- Nkrumah L.N., Muhle R.A., Moura P.A., Ghosh P., Hatfull G., Jacobs Jr. W.R. and Fidock D.A. (2006). Efficient site-specific integration in Plasmodium falciparum chromosomes mediated by mycobacteriophage Bxb1 integrase. Nature Methods 3: 615-21.
- Lakshmanan V., Bray P.G., Verdier-Pinard D., Johnson D.J., Horrocks P., Muhle R.A., Alakpa G.E., Hughes R.H., Ward S.A., Krogstad D.J., Sidhu A.B.S. and Fidock D.A. (2005). A critical role for PfCRT K76T in Plasmodium falciparum verapamil-reversible chloroquine resistance. EMBO J. 24: 2294-305.
- Johnson D.J., Fidock D.A.*, Mungthin M., Lakshmanan V., Sidhu A.B.S., Bray P.G., and Ward S.A.* (2004) Evidence for a central role for PfCRT in conferring Plasmodium falciparum resistance to diverse antimalarial agents. Mol. Cell 15: 867-77. (*Co-corresponding authors)
- Fidock D.A., Rosenthal P.J., Croft S.L., Brun R. and Nwaka S. (2004). Antimalarial drug discovery: efficacy models for compound screening. Nature Rev. Drug Disc. 3: 509-20.
- Sidhu A.B.S., Verdier-Pinard D. and Fidock D.A. (2002). pfcrt mutations confer chloroquine resistance to Plasmodium falciparum malaria parasites. Science 298: 210-3
- Djimde A., Doumbo O.K., Cortese J.F., Kayentao K., Doumbo S., Diourte Y., Coulibaly D., Dicko A., Su X-z, Nomura T., Fidock D.A., Wellems T.E., and Plowe C.V. (2001). A molecular marker for chloroquine resistant falciparum malaria. New Engl. J. Med. 344: 257-63.
- Fidock D.A., Nomura T., Talley A.K., Cooper R.A., Dzekunov S.M., Ferdig M.T., Ursos L.M., Sidhu A.B.S., Deitsch K., Su X-z, Wootton J.C., Roepe P.D. and Wellems T.E. (2000). Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Mol. Cell 6: 681-71.