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Innate Immune Responses to Human Malaria: Heterogeneous Cytokine Responses to Blood-Stage Plasmodium falciparum Correlate with Parasitological and Clinical Outcomes¹

Michael Walther^2,*,,, John Woodruff, Fanny Edele, David Jeffries, Jon E. Tongren, Elizabeth King, Laura Andrews, Philip Bejon^*, Sarah C. Gilbert, Joseph B. De Souza^,¶, Robert Sinden^||, Adrian V. S. Hill^*, and Eleanor M. Riley

^* Center for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University, Churchill Hospital, Oxford, United Kingdom; Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom; Medical Research Council Laboratories, Fajara, Banjul, The Gambia; The Wellcome Trust Centre for Human Genetics, Nuffield Department of Clinical Medicine, Oxford University, Oxford, United Kingdom; ^¶ Department of Immunology and Molecular Pathology, Royal Free and University College London Medical School, London, United Kingdom; and ^|| Department of Biological Sciences, Sir Alexander Fleming Building, Imperial College London, London, United Kingdom

Taking advantage of a sporozoite challenge model established to evaluate the efficacy of new malaria vaccine candidates, we have explored the kinetics of systemic cytokine responses during the prepatent period of Plasmodium falciparum infection in 18 unvaccinated, previously malaria-naive subjects, using a highly sensitive, bead-based multiplex assay, and relate these data to peripheral parasite densities as measured by quantitative real-time PCR. These data are complemented with the analysis of cytokine production measured in vitro from whole blood or PBMC, stimulated with P. falciparum-infected RBC. We found considerable qualitative and quantitative interindividual variability in the innate responses, with subjects falling into three groups according to the strength of their inflammatory response. One group secreted moderate levels of IFN- and IL-10, but no detectable IL-12p70. A second group produced detectable levels of circulating IL-12p70 and developed very high levels of IFN- and IL-10. The third group failed to up-regulate any significant proinflammatory responses, but showed the highest levels of TGF-. Proinflammatory responses were associated with more rapid control of parasite growth but only at the cost of developing clinical symptoms, suggesting that the initial innate response may have far-reaching consequences on disease outcome. Furthermore, the in vitro observations on cytokine kinetics presented here, suggest that intact schizont-stage infected RBC can trigger innate responses before rupture of the infected RBC.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Wellcome Trust (to E.M.R. and A.V.S.H.), the United Kingdom Medical Research Council (to E.M.R.) and the Malaria Vaccine Initiative at the Program for Appropriate Technology in Health, Seattle, WA (to A.V.S.H.). J.W. was funded by a Marshall Scholarship from the British Government, J.E.T. was funded by a scholarship from the Gates Malaria Partnership, and A.V.S.H. is a Wellcome Trust Principal Research Fellow.

² Address correspondence and reprint requests to Dr. Michael Walther, Medical Research Council Laboratories, Fajara, P.O. Box 273, Banjul, The Gambia. E-mail address: mwalther{at}mrc.gm

³ Abbreviations used in this paper: iRBC, infected RBC; uRBC, uninfected RBC; RT, room temperature; CI, confidence interval; DC, dendritic cell.

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