Biographical Sketch
A. B. in Chemistry, 1978, Bryn Mawr
College. Advisor: George C. Zimmerman
Ph. D. in Biochemistry, 1982, Massachusetts Institute of
Technology. Advisor: Christopher T. Walsh
Postdoctoral Fellow, 1983-1985, Research Associate,
1985-1987, Rockefeller University, Laboratory of Molecular Parasitology. Advisor: George
A. M. Cross.
Research Description
The secretory pathway is a major pathway
by which proteins and lipids are delivered to organelles to support the growth of their
membranes in a eukaryotic cell. Our laboratory studies how this pathway interacts with
vacuoles of intracellular pathogens. A major focus of our work has been the human malaria
parasite Plasmodium falciparum. This organism causes the most virulent of human
malarias and is the main reason for the spread of drug resistant parasites. Recently, we
have also begun studying how the secretory and endo-vacuolar pathways of epithelial cells
and macrophages move proteins and lipids to vacuoles of intracellular bacteria such as Salmonella
and Chlamydia. The long term objectives are to understand the common molecular
principles of vacuolar biogenesis of emerging and re-emerging infections.
Research Abstract
The central question for the malaria
research is how does a primitive, eukaryotic secretory pathway target proteins to vacuolar
and tubovesicular (TVM) membranes in the red cell? Emerging genetic techniques are being
developed and used to determine what signals on TVM proteins target these polypeptides to
the network and how gene knock outs influence assembly of the TVM and its functions in
nutrient and drug import, as well as antigen export to the red cell. Expression of
chimeras of green fluorescent protein (GFP) and plasmodial secretory markers are being
used to define stage-specific secretory membrane transport in live parasites. Additional
questions of interest also being addressed are: (i) how do plasmodial promoters regulate
stage specific gene expression in the secretory pathway? (ii) which malaria parasite
factors induce vacuole formation during invasion of red cells? (iii) which secretory
determinants provide molecular correlates of pathogenesis?
We also investigate whether an intersection of endo and
exocytic mechanisms is induced in vacuoles containing bacterial pathogens such as Salmonella
and Chlamydia, in mammalian epithelial cells and/or macrophages. The aim is the
identification bacterial genes that regulate trafficking/signaling processes as well as
host proteins recruited to the vacuoles by specific bacterial determinants. The work
should define unique and fundamental secretory mechanisms exploited by diverse
micro-organisms, that may provide new targets for immunological prophylaxis and/or
chemotherapy.
Publications
Lauer, S., Ghori, N. and Haldar, K. (1995)
Sphingolipid synthesis as a novel target for chemotherapy against malaria parasites. Proc.
Natl. Acad. Sci. USA 92:9181-9185.
VanWye, J. and Haldar, K. (1997) Expression of Green
Fluorescent Protein as a reporter for transformation in Plasmodium falciparum. Mol.
and Biochem. Parasitol. 87: 225-229.
Lauer, S., Rathod, P. K. Ghori, N. and Haldar, K.
(1997) A membrane network for nutrient import in red cells infected with the malaria
parasite.Science 276:1122-1125.
Haldar, K. (1998) Trafficking in malaria parasites. Curr
Opin. in Microbiology. 1: 466-471.
Akompong, T. VanWye, J., Ghori, N.
and Haldar, K (1999). Artemisinin and its derivatives are transported by a
vacuolar-network of P. falciparum. and their anti-malarial activities are additive
with toxic sphingolipid analogues that block the network. Mol. Biochem. Parasitol.
101: 71-79.
