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Infection and Immunity, July 2009, p. 3033-3043, Vol. 77, No. 7
0019-9567/09/$08.00+0 doi:10.1128/IAI.00211-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Cellular Tumor Necrosis Factor, Gamma Interferon, and Interleukin-6 Responses as Correlates of Immunity and Risk of Clinical Plasmodium falciparum Malaria in Children from Papua New Guinea
Leanne J. Robinson,1,2
Marthe C. D'Ombrain,1,2
Danielle I. Stanisic,1,3
Jack Taraika,3
Nicholas Bernard,1
Jack S. Richards,1,2
James G. Beeson,1
Livingstone Tavul,3
Pascal Michon,3
Ivo Mueller,3,
and
Louis Schofield1,*
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria, Australia 3050,1 Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia 3010,2 Papua New Guinea Institute of Medical Research, P.O. Box 378, Madang MAD 511, Papua New Guinea3
Received 24 February 2009/ Returned for modification 25 March 2009/ Accepted 11 April 2009
The role of early to intermediate Plasmodium falciparum-induced cellular responses in the development of clinical immunity to malaria is not well understood, and such responses have been proposed to contribute to both immunity and risk of clinical malaria episodes. To investigate whether P. falciparum-induced cellular responses are able to function as predictive correlates of parasitological and clinical outcomes, we conducted a prospective cohort study of children (5 to 14 years of age) residing in a region of Papua New Guinea where malaria is endemic Live, intact P. falciparum-infected red blood cells were applied to isolated peripheral blood mononuclear cells obtained at baseline. Cellular cytokine production, including production of interleukin-2 (IL-2), IL-4, IL-6, IL-10, tumor necrosis factor (TNF) (formerly tumor necrosis factor alpha), and gamma interferon (IFN-
), was measured, and the cellular source of key cytokines was investigated. Multicytokine models revealed that increasing P. falciparum-induced IL-6 production was associated with an increased incidence of P. falciparum clinical episodes (incidence rate ratio [IRR], 1.75; 95% confidence interval [CI], 1.20 to 2.53), while increasing P. falciparum-induced TNF and IFN- production was associated with a reduced incidence of clinical episodes (IRR for TNF, 0.55 [95% CI, 0.38 to 0.80]; IRR for IFN-, 0.71 [95% CI, 0.55 to 0.90]). Furthermore, we found that monocytes/macrophages and 
-T cells are important for the P. falciparum-induced production of IL-6 and TNF. Early to intermediate cellular cytokine responses to P. falciparum may therefore be important correlates of immunity and risk of symptomatic malaria episodes and thus warrant detailed investigation in relation to the development and implementation of effective vaccines.
* Corresponding author. Mailing address: The Walter & Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria, Australia 3050. Phone: 61-3-93452474. Fax: 61-3-93470852. E-mail: schofield{at}wehi.edu.au
Published ahead of print on 20 April 2009.
I.M. and L.S. contributed equally to this study.
Infection and Immunity, July 2009, p. 3033-3043, Vol. 77, No. 7
0019-9567/09/$08.00+0 doi:10.1128/IAI.00211-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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