|Head of malaria gene expression laboratory|
1999-2003 Ph. D. in Parasitology at
the Faculty of Agriculture, Food and Environmental Quality Sciences, the Hebrew
University of Jerusalem.
1996-99 M. Sc. MAGNA CUM LAUDE in Animal Science at the Faculty of
Agriculture, Food and Environmental Quality Sciences, the Hebrew University of
1993-96 B. Sc. in Animal Science at the Faculty of
Agriculture, Food and Environmental Quality Sciences the Hebrew University of
2008 Senior lecturer, Department of Microbiology & Molecular Genetics, The Kuvin Center for Study of
Infectious and Tropical Diseases, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical
School, Jerusalem, Israel.
2007 Lecturer, Department of Parasitology, The Kuvin Center for Study of
Infectious and Tropical Diseases, The Hebrew University-Hadassah Medical
School, Jerusalem, Israel.
2003-2007 NIH postdoctoral fellow, Department of
Microbiology and Immunology, Weill Medical College of Cornell University. New
2001 International scholar, Department
of Microbiology, Pathology & Parasitology, College of Veterinary Medicine,
North Carolina State University, Raleigh, NC USA.
deadliest form of human malaria is caused by the protozoan parasite Plasmodium
falciparum that annually affects millions worldwide. The virulence of P.
falciparum is attributed to its ability to evade the human immune system,
by modifying the host red blood cell surface to adhere to the vascular
endothelium and to undergo antigenic variation. The main antigenic ligands
responsible for both cytoadherence and antigenic variation are members of
the P. falciparum Erythrocyte Membrane Protein-1 (PfEMP1) family.
These polymorphic proteins are encoded by a multi-copy gene family called
var. Each individual parasite expresses a single var gene at a time,
whereas the remaining ~60 var genes found in its genome are maintained
in a transcriptionally silent state. As the antibody response against the
single PfEMP1 expressed develops, small sub-populations
of parasites, which have switched expression to alternative forms of PfEMP1,
avoid the antibody response and re-establish infection. The regulation of var
gene expression is therefore responsible for both immune evasion and the
pathogenicity of the disease.
Immune evasion through antigenic variation in
malaria depends on the ability of the parasite to exclusively express only a
single var gene at a time, and then to switch expression to another gene
that will also be expressed in mutually exclusive manner. Recently, my research focused on the elucidation
of the molecular mechanisms that control antigenic switching and mutually
exclusive expression. Using genetic manipulation of cultured parasites, we have succeeded in interfering with this genetic pathway, creating parasites
in which we can control expression of the virulence genes, effectively knocking
out the entire gene family in a reversible way. Thus, for the first time
creating transgenic parasite lines that do not express the main virulence
factor of the disease. These experiments
demonstrated that the expression of the antigen is not required to keep the
rest of the var family in transcriptionally silent state, and that
mutually exclusive expression in malaria is not mediated through a negative
feedback as demonstrated in other eukaryotic systems.
transgenic parasites enabled us for the first time to control the switches that
turn the expression of individual var
genes on and off at their chromosome locations. This was used to study var gene switching in order to identify
if transcriptional switches favor the expression of particular subgroups of var genes and if var gene
activation within a clonal population of parasites follows a pre-determined
order. We showed that transcription of var
genes located in the central regions of chromosomes is remarkably stable and
without selection these genes rarely undergo transcriptional switches. In
contrast subtelomericaly located var
genes exhibit a more dynamic switching pattern with clonal parasite populations
readily switching to alternative var
loci. We also demonstarted that after selection for activation of either
subtelomeric or central var loci,
populations of parasites with completely different var gene expression
profiles develop over time, thus providing an explanation for how a parasite
population can exhibit heterogenous patterns of var gene activation despite the uniform bias towards expression of var genes with low off rates.
In addition, we showed that cooperative
interactions between two promoters found in each gene are required for both
silencing and mutually exclusive expression, and disruption of these
interactions results in simultaneous expression of multiple var genes
within the same parasite, thus definitively demonstrating the necessity for
cooperative regulatory elements for var gene regulation. Further,
heterologous promoters can serve in place of var intron promoter
elements for cooperative regulation, shedding light on the silencing mechanism
through promoter-promoter interaction.
These findings led us to explore the
hypothesis that a nuclear expression site is involved in var genes
regulation and mutually exclusive expression. we used transgenic parasite lines
in which var gene expression can be manipulated using drug selection,
and in which specific var loci have been tagged for visualization by
fluorescent in situ hybridization (FISH). Simultaneously active var
genes co-localize within the nucleus, providing the first strong evidence for a
postulated subnuclear var-specific expression site, but also suggesting
that it can accommodate multiple transcriptionally active var promoters.
Recently we provided evidence for a
tritratable, var-specific factor that is necessary for var gene
activation. By manipulating the copy number of var
promoter-containing episomes, it was possible to compete for this limiting
factor and repress transcription of all chromosomal var genes. When the
competing episomes were removed, the parasites did not return to their previous
var gene expression pattern, but rather displayed random var gene
activation, demonstrating that the epigenetic marks that control var
gene expression had been completely erased and thus linking active transcription
to the maintenance of cellular memory. We
also reported that the cellular memory that is involved in the control of var gene expression is associated with
methylation of histone H3 at lysine K9 as an epigenetic chromatin mark.
21. Dzikowski, R. &
Deitsch, K. 2009. Genetics of antigenic variation in Plasmodium
falciparum. Curr Genet (in press).
D. N. & Dzikowski, R. 2009.
PfEMP1: An antigen that plays a key role in the pathogenicity and immune
evasion of the malaria parasite Plasmodium falciparum. Int J Biochem
Cell B (in press).
19. Dzikowski, R.
& Deitsch, K.
2008. Active transcription is required for maintenance of epigenetic memory in
the malaria parasite Plasmodium falciparum.
J Mol Biol 382: 288-297.
18. Dzikowski, R.,
Li, F., Amulic, B.,
Eisberg, A., Frank, M., Patel, S., Wellems, T. E. & Deitsch, K. 2007.
Mechanisms underlying mutually exclusive expression of virulence genes in
malaria parasites. EMBO Rep 8(10): 959-965.
17. Functional Genomics Workshop Group, The Broad Institute of Harvard and
MIT. 2007. Mechanism of gene regulation in Plasmodium. Am J Trop Med Hyg
16. Frank, M.*, Dzikowski, R.*
& Deitsch, K. 2007. Variable switching rates of malaria virulence genes are associated with chromosomal position.
Equal authorship contribution
T., Dzikowski, R.
Frank, M., Li, F., Jiwani, A. Z., Hartl, D. L. & Deitsch,
K. 2007. Epigenetic memory
at malaria virulence genes. Proc Natl Acad Sci USA104(3): 899-902.
Templeton, T. J. & Deitsch K. W. 2006. Variant antigen
gene expression in malaria. Cell Microbiol 8(9): 1371-1381
12. Frank, M., Dzikowski, R., Costantini, D.,
Amulic, B., Berdougo, E. & Deitsch, K. W. 2006. Strict pairing of var promoters
and introns is required for var gene silencing in the malaria parasite Plasmodium
falciparum. J Biol Chem 281(15): 9942-995.
11. Dzikowski, R., Frank,
M. & Deitsch, K. W. 2006. Mutually exclusive expression of virulence genes
by malaria parasites is regulated independently of antigen production. PLoS
Pathog 2(3): e22.
10. Dzikowski, R. &
Deitsch, K. W. 2006. Antigenic variation by protozoan parasites: insights from Babesia
bovis. Mol Microbiol 59(2): 364-366.
9. Dzikowski, R
., Hulata, G., Harpaz,
S. & Karplus, I. 2004. Inducible
reproductive plasticity of the guppy Poecilia reticulata in response to
predation cues. J Exp Zool
8. Dzikowski R.,
Levy M.G., Poore M.F., Flowers J.R. & Paperna I. 2004. Clinostomum complanatum and Clinostomum marginatum (Rudolphi,
1819) (Digenea: Clinostomatidae) are separate species based on
differences in rDNA. J Parasitol 90: 413-414.
7. Dzikowski R
., Levy M.G., Poore
M.F., Flowers J.R. & Paperna I. 2004. Use of rDNA polymorphism for identification of Heterophyidae infecting freshwater fishes. Dis Aquat Organ 59: 35-41.
6. Dzikowski R
., Levy M.G., Poore
M.F., Flowers J.R. & Paperna I. 2003. Genetic and morphologic differentiation of Bolbophorus
and B. levantinus
(Digenea: Diplostomatidae), based on rDNA
SSU polymorphism and SEM. Dis Aquat Organ 57: 231-235.
Dzikowski, R., Diamant, A. & Paperna, I. 2003.
metacercariae of fish as sentinels for a changing limnological environment. Dis
Aquat Organ 55:
4. Dzikowski, R., Diamant, A. & Paperna, I. 2003. Multi-annual changes in parasite
communities of the rabbitfish Siganus rivulatus (Siganidae) in the Gulf
of Aqaba, Red Sea. Helgol Mar Res 57: 228-225.
Dzikowski, R., Diamant, A. & Paperna, I. 2003. Use of fish
parasitological species richness indices in analyzing anthropogenically –
impacted coastal marine ecosystems. Helgol Mar Res
2. Levy, M.G., Flowers, J.R.,
Poore, M.F., Khoo, L., Pote, L.M., Mullen, J.E., Paperna, I., Dzikowski, R.
& Litaker, R.W. 2002. Morphologic, pathologic, and genetic investigations
Trematoda) affecting cultured Ictalurus
in the Mississippi delta. J Aquat Anim Health 14: 235-246.
Hulata, G., Karplus, I. & Harpaz, S. 2001. Effect of temperature and
dietary L-carnitine supplementation on reproductive performance of female guppy
Aquaculture 199: 323-332.
United States – Israel Binational Science Foundation grant no. 2007350 “The
nuclear envelope of the malaria parasite Plasmodium
falciparum”. In collaboration with Dr. Kirk Deitsch, Cornell University.
2008-2011 The Marie
Curie International Reintegration Grant (IRG) grant no. 203675 “The role of a nuclear expression site in the
regulation of virulence genes in malaria parasites”
2008 The German Israeli
Foundation (GIF) young scientist grant no. 2163-1725.11/2006 “Interaction between malaria parasite surface antigens
and host immune system”
2008 The Lejwa Fund For Biochemistry. "Gene activation in malaria parasites"