Murine malaria parasite sequestration: CD36 is the major receptor, but cerebral pathology is unlinked to sequestration

doi:10.1073/pnas.0503386102

Murine malaria parasite sequestration: CD36 is the major receptor, but cerebral pathology is unlinked to sequestration

Departments of ^*Parasitology, ^¶Endocrinology and Metabolic Diseases, and ^∥Pathology, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands; ^‡Instituto Gulbenkian de Ciência, P-2781-901 Oeiras, Portugal; ^§Department of Parasitology, Prince Leopold Institute of Tropical Medicine, B-2000 Antwerp, Belgium; and ^**Department of Cell Biology, Lerner Research Institute, Cleveland, OH 44195

Edited by Diane E. Griffin, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (received for review April 30, 2005)

Abstract

Sequestration of malaria-parasite-infected erythrocytes in the microvasculature of organs is thought to be a significant cause of pathology. Cerebral malaria (CM) is a major complication of Plasmodium falciparum infections, and PfEMP1-mediated sequestration of infected red blood cells has been considered to be the major feature leading to CM-related pathology. We report a system for the real-time in vivo imaging of sequestration using transgenic luciferase-expressing parasites of the rodent malaria parasite Plasmodium berghei. These studies revealed that: (i) as expected, lung tissue is a major site, but, unexpectedly, adipose tissue contributes significantly to sequestration, and (ii) the class II scavenger-receptor CD36 to which PfEMP1 can bind is also the major receptor for P. berghei sequestration, indicating a role for alternative parasite ligands, because orthologues of PfEMP1 are absent from rodent malaria parasites, and, importantly, (iii) cerebral complications still develop in the absence of CD36-mediated sequestration, dissociating parasite sequestration from CM-associated pathology. Real-time in vivo imaging of parasitic processes may be used to evaluate the molecular basis of pathology and develop strategies to prevent pathology.

Footnotes

↵ †† To whom correspondence should be addressed at: Department of Parasitology, University of Leiden Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands. E-mail: waters{at}lumc.nl.
↵ † B.F.-F. and C.J.J. contributed equally to this work.
Author contributions: B.F.F., C.J.J., M.C.-R., M.M., and A.P.W. designed research; B.F.F., C.J.J., M.C.-R., M.A.M.d.B., S.G.v.D., and J.R. performed research; B.F.F., C.J.J., P.B., I.Q., C.L., P.J.V., and M.F. contributed new reagents/analytical tools; B.F.F., C.J.J., M.C.-R., S.G.v.D., M.A.M.d.B., M.M., and A.P.W. analyzed data; and B.F.F., C.J.J., M.M., and A.P.W. wrote the paper.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: CM, cerebral malaria; irbc, infected red blood cell.