Infection of humans with Plasmodia species results in prolonged, chronic disease, during which immunity is slow to develop. In rodents, malaria either follows a lethal course, or resolves within one to two months with subsequent resistance to re-infection. However one feature of malaria which is shared by naturally occurring and experimental disease is a decreased ability to generate immune responses to the parasite and other antigens during periods of active infection. Results from studies in both rodents and people spanning several decades have suggested that defective macrophage function is responsible for the observed immunosuppression, and that metabolites of the parasite such as hemozoin play a direct role in this phenomenon. Although macrophages from infected mice are known to inhibit antibody responses in vitro and in vivo, their role as antigen presenting cells for T cell responses has not been investigated. Furthermore, it is not clear what role other antigen presenting cells, specifically B cells and dendritic cells, play during infection.
The aim of the work proposed is to evaluate the ability of macrophages, B cells and dendritic cells to act as antigens presenting cells for malaria antigen using a murine model of P. yoelii, and to determine the fate of T cells which interact with each. Because of their differential abilities to take up antigen, it is likely that these subsets will not only present different arrays of malaria peptides for T cell recognition, but the function of phagocytic antigen presenting cells such as macrophages and immature dendritic cells may be dramatically altered by ingestion of parasite and its toxic products, whereas B cells would be spared this interaction because they are not phagocytic. A thorough understanding of what type of immune responses are provoked by APC subsets, and what kind of antigen they present, may aid in the design vaccines targeted to particular APC. This is particularly important when planning vaccine strategies for endemic areas, where vaccines are likely to already harbor a malaria infection which could alter the way their immune system handles antigen.
| Perry, James A; Olver, Christine S; Burnett, Robert C et al. (2005) Cutting edge: the acquisition of TLR tolerance during malaria infection impacts T cell activation. J Immunol 174:5921-5 |
| Perry, James A; Rush, Adam; Wilson, Randy J et al. (2004) Dendritic cells from malaria-infected mice are fully functional APC. J Immunol 172:475-82 |
