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Parasite genetic diversity does not influence TNF-mediated effects on the virulence of primary rodent malaria infections

Published online by Cambridge University Press:  18 September 2006

G. H. LONG ,
B. H. K. CHAN ,
J. E. ALLEN ,
A. F. READ  and
A. L. GRAHAM
G. H. LONG
Affiliation:
Institutes of Evolution, Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, King's Buildings, West Mains Road, Edinburgh EH9 3JT, Scotland
B. H. K. CHAN
Affiliation:
Institutes of Evolution, Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, King's Buildings, West Mains Road, Edinburgh EH9 3JT, Scotland
J. E. ALLEN
Affiliation:
Institutes of Evolution, Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, King's Buildings, West Mains Road, Edinburgh EH9 3JT, Scotland
A. F. READ
Affiliation:
Institutes of Evolution, Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, King's Buildings, West Mains Road, Edinburgh EH9 3JT, Scotland
A. L. GRAHAM
Affiliation:
Institutes of Evolution, Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, King's Buildings, West Mains Road, Edinburgh EH9 3JT, Scotland
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Abstract

The pro-inflammatory cytokine tumour necrosis factor alpha (TNF-α) is associated with malaria virulence (disease severity) in both rodents and humans. We are interested in whether parasite genetic diversity influences TNF-mediated effects on malaria virulence. Here, primary infections with genetically distinct Plasmodium chabaudi chabaudi (P.c.c.) clones varied in the virulence and cytokine responses induced in female C57BL/6 mice. Even when parasitaemia was controlled for, a greater day 7 TNF-α response was induced by infection with more virulent P.c.c. clones. Since many functions of TNF-α are exerted through TNF receptor 1 (TNFR1), a TNFR-1 fusion protein (TNFR-Ig) was used to investigate whether TNFR1 blockade eliminated clone virulence differences. We found that TNFR-1 blockade ameliorated the weight loss but not the anaemia induced by malaria infection, regardless of P.c.c. clone. We show that distinct P.c.c. infections induced significantly different plasma interferon gamma (IFN-γ), interleukin 6 (IL-6) and interleukin 10 (IL-10) levels. Our results demonstrate that regardless of P.c.c. genotype, blocking TNFR1 signalling protected against weight loss, but had negligible effects on both anaemia and asexual parasite kinetics. Thus, during P.c.c. infection, TNF-α is a key mediator of weight loss, independent of parasite load and across parasite genotypes.

Keywords

malariaPlasmodium chabauditumour necrosis factor-α (TNF-α)parasite genotypevirulenceimmunopathologydisease severitycachexia
Type
Research Article
Information
Parasitology , Volume 133 , Issue 6 , December 2006 , pp. 673 - 684
Copyright
2006 Cambridge University Press

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