Investigating the effects of Plasmodium chabaudi chabaudi as-infected erythrocytes on dendritic cell function in vitro

During malaria infection there is significant depression of the host's immune response to concurrent infections and heterologous vaccine antigens as well as the response to the parasite itself. Using the murine Plasmodium chabaudi chabaudi AS model, I examined whether the malaria parasite can suppress immune responses via effects on dendritic cells (DC), which are important for initiating primary immune responses. As the morbidity and mortality associated with malaria are derived exclusively from the asexual erythrocytic stages, I investigated the effects that this stage has on DC function. I found that malaria infected erythrocytes (pRBC) do not directly activate bone marrow- derived DCs in vitro; rather, they inhibit the LPS induced upregulation of Class II MHC and costimulatory molecules (CD40 and CD86) on DCs and significantly reduce the ability of these cells to induce proliferation and effector function of naive T cells. Nevertheless, pRBC-treated DCs induce equivalent levels of the very early activation marker CD69 on antigen-specific naive T cells compared with RBC-treated DCs, indicating that T cells in both conditions are antigen experienced. Furthermore, the proliferation of T cells cultured with pRBC-treated DCs could be recovered by the addition of exogenous IL-2, suggesting that they are functionally anergic. In search of a mechanistic explanation for this parasite-mediated inhibition of DC function, I investigated the possible role of selected parasite components. Haemozoin, the end-product of the haemoglobin catabolism by intraerythrocytic malaria parasite, was found to contribute significantly to the immunosuppressive effects induced in DCs. A soluble factor(s) secreted by pRBCs was also found to affect the ability of DCs to mature in response to LPS treatment in vitro. Furthermore, following gene array analysis, I have identified a number of candidate molecules in pRBC-treated DC that may be involved in the observed alterations in functional activity. The present study provides a better insight of how the malaria parasite affects DC function and identifies a number of parasite-induced changes in these cells related to their decreased ability to induce effective primary immune responses. These observations may therefore facilitate the development of more effective vaccines and immunisation protocols