title: Innate immune responses to human malaria: heterogeneous cytokine responses to blood-stage Plasmodium falciparum correlate with parasitological and clinical outcomes.
abstract: 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-gamma 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-gamma and IL-10. The third group failed to up-regulate any significant proinflammatory responses, but showed the highest levels of TGF-beta. 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.
authors.affiliation: Center for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University, Churchill Hospital, Oxford, United Kingdom. mwalther@mrc.gm
authors.forename: Michael
authors.initials: M
authors.lastname: Walther
authors.forename: John
authors.initials: J
authors.lastname: Woodruff
authors.forename: Fanny
authors.initials: F
authors.lastname: Edele
authors.forename: David
authors.initials: D
authors.lastname: Jeffries
authors.forename: Jon E
authors.initials: JE
authors.lastname: Tongren
authors.forename: Elizabeth
authors.initials: E
authors.lastname: King
authors.forename: Laura
authors.initials: L
authors.lastname: Andrews
authors.forename: Philip
authors.initials: P
authors.lastname: Bejon
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Gilbert
authors.forename: Joseph B
authors.initials: JB
authors.lastname: De Souza
authors.forename: Robert
authors.initials: R
authors.lastname: Sinden
authors.forename: Adrian V S
authors.initials: AV
authors.lastname: Hill
authors.forename: Eleanor M
authors.initials: EM
authors.lastname: Riley
mesh_terms: D000328:Adult; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis*; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D007700:Kinetics; D008288:Malaria / Q000276:immunology*; D010963:Plasmodium falciparum / Q000276:immunology*; D052939:Schizonts / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D016207:Cytokines; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma