Pathogenic roles of CD14, galectin-3, and OX40 during experimental cerebral malaria in mice.
An in-depth knowledge of the host molecules and biological pathways that contribute towards the pathogenesis of cerebral malaria would help guide the development of novel prognostics and therapeutics. Genome-wide transcriptional profiling of the brain tissue during experimental cerebral malaria (ECM ) caused by Plasmodium berghei ANKA parasites in mice, a well established surrogate of human cerebral malaria, has been useful in predicting the functional classes of genes involved and pathways altered during the course of disease. To further understand the contribution of individual genes to the pathogenesis of ECM, we examined the biological relevance of three molecules -- CD14, galectin-3, and OX40 that were previously shown to be overexpressed during ECM. We find that CD14 plays a predominant role in the induction of ECM and regulation of parasite density; deletion of the CD14 gene not only prevented the onset of disease in a majority of susceptible mice (only 21% of CD14-deficient compared to 80% of wildtype mice developed ECM, p<0.0004) but also had an ameliorating effect on parasitemia (a 2 fold reduction during the cerebral phase). Furthermore, deletion of the galectin-3 gene in susceptible C57BL/6 mice resulted in partial protection from ECM (47% of galectin-3-deficient versus 93% of wildtype mice developed ECM, p<0.0073). Subsequent adherence assays suggest that galectin-3 induced pathogenesis of ECM is not mediated by the recognition and binding of galectin-3 to P. berghei ANKA parasites. A previous study of ECM has demonstrated that brain infiltrating T cells are strongly activated and are CD44(+)CD62L(-) differentiated memory T cells [1]. We find that OX40, a marker of both T cell activation and memory, is selectively upregulated in the brain during ECM and its distribution among CD4(+) and CD8(+) T cells accumulated in the brain vasculature is approximately equal.
Oakley
Miranda S
MS
Division of Bacterial, Parasitic and Allergenic Products, Center for Biologics and Evaluation Research, Food and Drug Administration, Bethesda, MD, USA.
Majam
Victoria
V
Mahajan
Babita
B
Gerald
Noel
N
Anantharaman
Vivek
V
Ward
Jerrold M
JM
Faucette
Lawrence J
LJ
McCutchan
Thomas F
TF
Zheng
Hong
H
Terabe
Masaki
M
Berzofsky
Jay A
JA
Aravind
L
L
Kumar
Sanjai
S
D000818:Animals; D015153:Blotting, Western; D005260:Female; D005434:Flow Cytometry; D037502:Galectin 3 / Q000235:genetics / Q000502:physiology*; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000502:physiology*; D016779:Malaria, Cerebral / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020641:Polymorphism, Single Nucleotide; D053262:Receptors, OX40 / Q000235:genetics / Q000502:physiology*
D037502:Galectin 3; C485095:Lgals3 protein, mouse; D018950:Lipopolysaccharide Receptors; D053262:Receptors, OX40; C505717:Tnfrsf4 protein, mouse