Human Immune Responses to Plasmodium falciparum infection: Molecular Evidence for a Suboptimal THαβ(TH9) and TH17 Bias over Ideal and Effective Traditional TH1 Immunity

Using microarray analysis, we showed up-regulation of Toll-like receptors 1,2,4,7,8, NF-[kappa][BETA], TNF-[alpha], p38-MAPK and MHC molecules in human peripheral blood mononuclear cells following infection with Plasmodium falciparum. We report herein further studies based on time-course microarray analysis with a focus on malaria-induced host immunity. Results show that in early malaria; selected immunity-related genes were up-regulated including alpha, beta, and gamma interferon related genes, as well as genes of IL-15, CD36, chemokines (CXCL10, CCL2, S100A8/9, CXCL9, and CXCL11), TRAIL and IgG Fc receptors. During acute febrile malaria, up-regulated genes included alpha, beta, and gamma interferon related genes, IL-8, IL-1[beta], IL-10 downstream genes, TGFB1, oncostatin-M, chemokines, IgG Fc receptors, ADCC signaling, complement-related genes, granzymes, NK cell killer/inhibitory receptors and Fas antigen. During remission, genes for NK receptors, immunoglobins, and granzymes/perforin were up-regulated. When viewed in terms of immunity type, malaria infection appeared to induce a mixed TH1 response, in which α and β interferon driven responses appear to predominate over the more classic IL-12 driven pathway. In addition, TH17 pathway also appears to be playing a significant role in the immunity to Plasmodium falciparum. Gene markers of TH17 (neutrophil-related genes, TGFB1 and IL-6 family (oncostatin-M)) and TH[alpha]/[beta] (IFN-[alpha]/[beta] and NK cytotoxicity and ADCC gene) immunity were up-regulated. Initiation of TH[alpha]/[beta] immune response was associated with an IFN-[alpha]/[beta] response which ultimately resulted in IL-10 and IFN-[gamma] achieved via a different pathway from the more classic IL-12 TH1 pattern. Based on these observations, we speculate that in Plasmodium falciparum infection, TH[alpha]/[beta] and TH17 immunity may predominate over the more traditional TH1 response.