Integrated Analysis of Cytokine Profiles in Malaria Patients Discloses Selective Upregulation of TGF-beta 1, beta 3, and IL-9 in Mild Clinical Presentation

The proper control of Plasmodium infection requires a finely balanced immune response. Here, we evaluated the implication of TGF-beta 1 and TGF-beta 3 in this process using novel monoclonal antibodies to measure their plasma concentrations in comparison with other cytokines and the expression of FOXP3 mRNA. Plasma cytokine levels were measured in 80 patients with severe anaemic malaria and 186 with a mild presentation using ELISA, and rtPCR was used to measure FOXP3 mRNA expression. While no mature TGF-beta isoforms were detected in the plasma, the latent TGF-beta 1 and TGF-beta 3 were strongly upregulated in patients with mild malaria and nearly undetected in patients with severe disease. Similar selective upregulation in mild patients was observed for IL-9 and FOXP3 mRNA, while IL-7, IL-10, IL-17, and IL-27, although higher in mild cases, were also detected in severe disease. In contrast, a clearly skewed trend of severe cases towards higher pro-inflammatory (IL-6, IL-13, TNF-alpha) and Th1 (IFN-gamma) responses was observed, which was associated with a higher level of parasitaemia as well as lower IgG and higher IgM responses. Together, these results suggest that the stimulation of regulatory T cells through TGF-beta 1/TGF-beta 3 and IL-9 is paramount to an effective and balanced protective immunity in natural human malaria infection.