Severe malarial anemia (SMA) is the primary clinical manifestation of Plasmodium falciparum malaria in African children in holoendemic areas of malaria transmission. Dysregulation in pro- and anti-inflammatory cytokine production is associated with enhanced pathogenesis of SMA in infants and young children. Interleukin (IL)-12 is a pro-inflammatory cytokine associated with protection against childhood SMA. IL-23 is a recently discovered pro-inflammatory cytokine that shares a common p40 subunit with IL-12. Although not investigated in the context of SMA, IL-23 is associated with the pathogenesis of anemia in chronic inflammatory diseases. Moreover, both IL-12 and IL-23 initiate innate immune responses that are down- regulated by IL-10. Both IL-12 and IL-23 have also been reported to be important in the induction of antibody production. Protective innate immune responses occur through IL-18 synergizing with IL-12 to induce interferon (IFN)-gamma production from naive CD4+ T cells, while IL-23 promotes IL-17 production from activated memory CD4+ T cells. The primary goal of this proposal is to investigate the role of the IL-12 and IL-23 cytokine pathways during childhood malarial anemia. This will be accomplished by;1) determining the association between IL-12 and IL-23 signaling pathways with malarial anemia disease severity;2) determining the association between IL-12 and IL-23-induced CD4+ T cell responses and malarial anemia disease outcomes;and 3) determining the effect of IL-12 and IL-23 on the in vitro induction of IFN-gamma and IL-17, respectively, and the generation of antibody responses to malaria antigen stimulation. Successful completion of these experimental objectives will provide novel and important information about the role of the IL-12 and IL-23 cytokine pathways in regulating protective clinical immunity in young children naturally exposed to holoendemic P. falciparum malaria transmission.
| Davenport, Gregory C; Hittner, James B; Were, Tom et al. (2012) Relationship between inflammatory mediator patterns and anemia in HIV-1 positive and exposed children with Plasmodium falciparum malaria. Am J Hematol 87:652-8 |
| Ong'echa, John M; Davenport, Gregory C; Vulule, John M et al. (2011) Identification of inflammatory biomarkers for pediatric malarial anemia severity using novel statistical methods. Infect Immun 79:4674-80 |
| Ong'echa, John M; Raballah, Evans O; Kempaiah, Prakasha M et al. (2011) Polymorphic variability in the 3' untranslated region (UTR) of IL12B is associated with susceptibility to severe anaemia in Kenyan children with acute Plasmodium falciparum malaria. BMC Genet 12:69 |
| Ong'echa, John M; Remo, Allison M; Kristoff, Jan et al. (2008) Increased circulating interleukin (IL)-23 in children with malarial anemia: in vivo and in vitro relationship with co-regulatory cytokines IL-12 and IL-10. Clin Immunol 126:211-21 |
