By: Ioana Bujila

Title: Response of dendritic cells exposed to Plasmodium falciparum derived stimuli; from mRNA to protein.

Even today, malaria is one of the most common and devastating infectious diseases
worldwide. Infection with Plasmodium parasites, the causative agent of malaria, alters the immune response of the human host. One example is the modulatory effects observed on the functionality and phenotypes of dendritic cells (DCs). DCs play a vital role in the induction of the adaptive immune system by presenting antigens to naïve T cells. Important events in the ability of DCs to prime naïve T cells include migration to the site of infection and secondary lymphoid tissues and up-regulation of co-stimulatory molecules and maturation markers.

In manuscript I, we aimed to investigate the early effects of parasite-derived metabolite nHz on DC functionality and phenotypes. We also wanted to compare the nHz-initiated responses to those of the synthetic analog, β-hematin. We could show that human monocyte-derived DCs (moDC) exposed to nHz were partially activated as indicated by the induction of the proinflammatory chemokine monocyte chemoattractant protein-1 (MCP-1) at both mRNA and protein levels. moDCs responded to nHz by up-regulating cell surface expression of MHC class II and in some cases CD86. However, after nHz exposure, CD83 cell surface expression was completely absent. Exposure to β-hematin showed similar results as nHz. Taken together, our data suggest that following nHz and β-hematin exposure, moDCs are partially activated as shown by MCP-1 secretion and up-regulation of MHC class II and CD86 expression, but the lack of CD83 expression renders them immature and potentially poor inducers of adaptive immune responses.

In the preliminary results, we investigated the potential involvement of post-translational modifications in the effects induced by nHz observed in manuscript I. nHz-exposure seemingly resulted in higher levels of H3K9ac, a mark associated with actively transcribed genes, in the promoter region of MCP-1 and to a lesser extent in the promoter region of HLADRb compared to unstimulated control. In addition, nHz-exposure also led to higher levels of the transcription factors NF-κB and IRF3 in the promoter region of MCP-1. It is tempting to speculate that NF-κB and IRF3 might play a role in moDCs ability to produce MCP-1 in response to nHz. Overall, our preliminary results suggest a role for post-translational modifications in the nHz-induced response of moDCs.

In conclusion, we show an effect of nHz and β-hematin on chemokine and maturation profiles in human moDCs.

Host: Prof. Ann-Kristin Östlund Farrants