Brain gene expression, metabolism, and bioenergetics: interrelationships in murine models of cerebral and noncerebral malaria.
Malaria infection can cause cerebral symptoms without parasite invasion of brain tissue. We examined the relationships between brain biochemistry, bioenergetics, and gene expression in murine models of cerebral (Plasmodium berghei ANKA) and noncerebral (P. berghei K173) malaria using multinuclear NMR spectroscopy, neuropharmacological approaches, and real-time RT-PCR. In cerebral malaria caused by P. berghei ANKA infection, we found biochemical changes consistent with increased glutamatergic activity and decreased flux through the Krebs cycle, followed by increased production of the hypoxia markers lactate and alanine. This was accompanied by compromised brain bioenergetics. There were few significant changes in expression of mRNA for metabolic enzymes or transporters or in the rate of transport of glutamate or glucose. However, in keeping with a role for endogenous cytokines in malaria cerebral pathology, there was significant up-regulation of mRNAs for TNF-alpha, interferon-gamma, and lymphotoxin. These changes are consistent with a state of cytopathic hypoxia. By contrast, in P. berghei K173 infection the brain showed increased metabolic rate, with no deleterious effect on bioenergetics. This was accompanied by mild up-regulation of expression of metabolic enzymes. These changes are consistent with benign hypermetabolism whose cause remains a subject of speculation.
Rae
Caroline
C
Discipline of Biochemistry, School of Molecular and Microbial Biosciences, The University of Sydney, Sydney NSW 2006, Australia. c.rae@mmb.usyd.edu.au
McQuillan
James A
JA
Parekh
Sapan B
SB
Bubb
William A
WA
Weiser
Silvia
S
Balcar
Vladimir J
VJ
Hansen
Anna M
AM
Ball
Helen J
HJ
Hunt
Nicholas H
NH
D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D001692:Biological Transport; D001921:Brain / Q000378:metabolism*; D018076:DNA, Complementary / Q000235:genetics; D003847:Deoxyglucose / Q000378:metabolism; D004734:Energy Metabolism; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008288:Malaria / Q000235:genetics / Q000378:metabolism*; D016779:Malaria, Cerebral / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008808:Mice, Inbred CBA; D023421:Models, Animal; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D019906:Nuclear Magnetic Resonance, Biomolecular; D018512:Parasitemia / Q000235:genetics / Q000378:metabolism; D010962:Plasmodium berghei
D018076:DNA, Complementary; D009419:Nerve Tissue Proteins; D001224:Aspartic Acid; D003847:Deoxyglucose