Elizabeth A. Winzeler
Lab Overview
My laboratory is currently using a systems biology approach to understand
the molecular basis of malaria. To this end we are using genetical genomics
to discover susceptibility loci in mice and we are using genome-wide scans
of parasite variation to identify genes involved in host-parasite interactions
and drug resistance. We are also using bioinformatics and gene expression profiling
to identify transcriptional regulatory networks with a longterm goal of determining
how development is regulated in the malaria parasite.
Highlight
Malaria susceptibility or resistance in inbred strains of mice
Ramachandran, Vandana *,1, Henson, Kerstin 1, Spooner, Muriel 2, Luzadar, Angelina
2, Wiltshire, Tim 2, Waters, Andrew P3, Winzeler, Elizabeth 1
1. Cell Biology, The Scripps Research Institute, San Diego, CA, USA
2. Genomics Institute of the Novartis Foundation, La Jolla, CA, USA
3. LUMC, Leiden, Netherlands
Genotypic variation contributes substantially to an organism’s susceptibility
to infectious disease. Thus identifying the genetic basis of heritable host
changes associated with susceptibility to malaria infection could reveal molecular
pathways that might be targeted by novel therapeutics. To this end we are examining
disease progression and survival in inbred strains of mice that have been infected
with transgenic, luciferase-expressing Plasmodium berghei parasites, which
cause rodent malaria. We are scoring phenotypes such as parasitemia, survival,
cerebral malaria, neurological symptoms, and amount of luciferase activity
in the whole bodies and dissected organs (liver, lungs, spleen, brain). Because
the 48 commonly-used inbred mouse lines that are used in this study are descended
from only a handful of founders and share many haplotypes the genetic loci
associated with the different phenotypes can be mapped in silico by examining
their known genotypes at 150,000 SNPs. We confirm in this study that those
mice that are susceptible (eg. CBA/J, C3H/HeJ, C57Bl6/J) to cerebral malaria
(CM) have a lower parasitemia and have earlier and higher mortality rates compared
to those which are resistant (eg. WSB/EiJ, A/J, DBA/2J) to CM. We have identified
several genetic loci that appear to be associated with survival and are beginning
to test our predictions.
2006 Publications
Kidgell, C. and Winzeler, E.A. (2006) Using the genome to dissect the molecular
basis of drug resistance. Future Microbiol., 1(2):185-199.
Kidgell, C., Volkman, S.K., Daily, J., Borevitz, J.O., Plouffe, D., Zhou,
Y., Johnson, J.R., Le Roch, K.G., Sarr, O., Ndir, O., Mboup, S., Batalov,
S., Wirth,
D.F. and Winzeler, E.A. (2006) A systematic map of genetic variation in Plasmodium
falciparum. PLoS Pathog., 2(6):e57.
Winzeler, E. (2006) Applied systems biology and malaria. Nat Rev Microbiol.,
4(2):145-51.
Kumar, K.A., Garcia, C.R.S., Chandran, V.R., Van Rooijen, N., Zhou, Y.,
Winzeler, E. and Nussenzweig, V. (2006) Exposure of Plasmodium sporozoites
to the intracellular
concentration of potassium enhances infectivity and suppresses cell passage
activity. PloS Pathog., Submitted
Kidgell, C. and Winzeler, E. A. (2006) Using the Genome to Dissect the
Molecular Basis of Drug Resistance. Future Microbiology. Submitted
