Other Signaling Events Triggered by P falciparum

Other P. falciparum molecules have been reported to activate signaling in endothelial cells. The GPI anchor of two P. falciparum proteins MSP-1 (merozoite surface protein 1) and MSP-2 has been shown to stimulate nitric oxide production in human umbilical vein endothelial cells. The same glycolipid also upregulates the expression of ICAM-1, VCAM-1, and E-selectin on endothelial cells, leading to increased leukocyte and parasite adhesion. The latter effect of the GPI can be inhibited by the Src-family kinase antagonist herbimycin A, suggesting that the activation of non-receptor protein tyrosine kinases in endothelial cells may constitute a critical proximal event in integrating the regulation of IRBC adhesion by diverse signals. Further understanding of the cellular consequences cytoadherence is urgently required to provide the basis for novel modes of therapy against one of the most devastating infections of humankind.

Glossary

CD36: An 88-kDa transmembrane scavenger molecule found on microvascular endothelial cells, erythroblasts, monocytes, adipose tissue, platelets, dendritic cells, and microglial cells. CD36 serves many physiological roles such as the uptake of apoptotic bodies and lipids, fatty acid transport, and apoptosis of endothelial cells to prevent neovascularization and may have significant roles in the pathogenesis of atherosclerosis, diabetes, and Alzheimer's disease.

Cytoadherence: The process whereby erythrocytes infected with mature stages of Plasmodium falciparum adhere to vascular endothelium. Cytoadherence is mediated by the parasite protein Plasmodium falciparum erythrocyte membrane protein 1 expressed on the surface of the infected red cell and a number of endothelial adhesion molecules in a cascade of interactions resembling the adhesive events in leukocyte recruitment.

Intracellular signaling: A cascade of specific molecular interactions that facilitates information transduction from the inner cytoplasmic membrane leaflet throughout the interior of the cell into the nucleus and often results in changes in DNA regulation and expression.

Src family kinases: A family of nonreceptor protein tyrosine kinases that mediate intracellular signaling. These molecules include Src, Fyn, Yes, Fgr, Lyn, Hck, Lck, Blk, and Yrk and share characteristic src-homology domains (SH) that are regulated through tyrosine phosphorylation.

Bibliography

Asch, A. S., Liu, I., Briccetti, F. M., Barnwell, J. W., Kwakye-Berko, F., Dokun, A., Goldberger, J., and Pernambuco, M. (1993). Analysis of CD36 binding domains: Ligand specificity controlled by dephosphory-lation of an ectodomain. Science 263, 1436-1440. The first description of the importance of the phosphorylation state of the ectodomain of platelet CD36 as a determinant of its binding affinity for various ligands.

Febbraio, M., Hajjar, D. P., and Silverstein, R. L. (2001). CD36: A class B scavenger receptor involved in angiogenesis, atherosclerosis, inflammation, and lipid metabolism. J. Clin. Invest. 108, 785-791. Ho, M., and White, N. J. (1999). Molecular mechanisms of cytoadherence in malaria. Am. J. Physiol. 276 (Cell Physiol. 45), C1231-C1242. A comprehensive review of the roles of various adhesion molecules and parasite proteins involved in cytoadherence. Schofield, L., Novakovic, S., Gerold, P., Schwarz, R. T., McConville, M. J., and Tachado, S. D. (1996). Glycosylphosphatidylinositol toxin of Plasmodium upregulates intercellular adhesion molecules-1, vascular cell adhesion molecule-1, and E-selectin expression in vascular endothelial cells and increases leukocyte and parasite cytoadherence via tyrosine kinase-dependent signal transduction. J. Immunol. 156, 1886-1896. Shattil, S. J., and Brugge, J. S. (1991). Protein tyrosine phosphorylation and the adhesive functions of platelets. Curr. Opin. Cell Biol. 3, 869-879. Smith, J. D., Gamain, B., Baruch, D. I., and Kyes, S. (2001). Decoding the language of var genes and Plasmodium falciparum sequestration. Trends Parasitol. 17, 538-545. Yipp, B. G., Anand, S., Schollaardt, T., Patel, K. D., Looareesuwan, S., and Ho, M. (2000). Synergism of multiple adhesion molecules in mediating cytoadherence of Plasmodium falciparum-infected erythrocytes to microvascular endothelial cells under flow. Blood 96, 2292-2299. Yipp, B. G., Robbins, S. M., Resek, M. E., Baruch, D. I., Looareesuwan, S., and Ho, M. (2003). Src-family kinase signaling modulates the adhesion of Plasmodium falciparum on human microvascular endothelium under flow. Blood 101, 2850-2857. The first demonstration that IRBC adhesion to CD36 on microvascular endothelial cells leads to intracellular signaling in the host cell that could eventually result in a change in the phosphorylation state and hence binding affinity of CD36 for IRBCs. The findings also suggest the therapeutic potential of phos-phatase inhibitors such as levamisole in the treatment of severe falci-parum malaria.

Capsule Biography

Dr. Ho is a Professor in the Department of Microbiology and Infectious Diseases at the University of Calgary, Canada. She is a Senior Medical Scholar of the Alberta Heritage Foundation for Medical Research, and her laboratory primarily focuses on the molecular pathogenesis of severe P. falciparum malaria. Her work is supported by grants from the Canadian Institutes of Health Research and the Anemia Institute of Research and Education, Canada.

Bryan Yipp is an M.D./M.Sc. student at the University of Calgary who studies the molecular pathogenesis of Plasmodium falciparum in Dr. May Ho's laboratory.

Dr. Robbins is an Associate Professor in the Departments of Oncology and Biochemistry and Molecular Biology at the University of Calgary. He is a Senior Scholar of the Alberta Heritage Foundation for Medical Research and currently holds a Canada Research Chair in the area of Cancer Biology. His research, which has focused on defining signal transduc-tion pathways in various pathophysiological conditions, is supported by grants from the Canadian Institutes of Health Research, Cancer Research Society, Kids Cancer Care Foundation of Alberta, and the Alberta Cancer Board.

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