Malaria is one of the most prevalent and devastating human diseases, with approximately half a billion clinical cases, including 2 million deaths, occurring each year. Although there has been significant recent progress toward developing a viable vaccine, many key aspects of pathogenesis and host response to infection remain unclear. Greater insight into this complex interplay of host and parasite is likely to lead to improved vaccine design.
To dissect the cellular and molecular interactions between malaria parasites and the immune system at different stages of the parasite's life cycle in a mammal, experimental rodent malaria models have been widely used. A number of Plasmodium species can infect mice and cause malaria, and, depending on the parasite species and the mouse strain, disease can range from mild to severe and even to lethal. For example, in the mouse model of Plasmodium berghei ANKA infection, BALB/c mice are resistant to murine cerebral malaria, whereas C57Bl/6 and CBA/J mice are susceptible and develop a lethal syndrome that reproduces many of the neurological and behavioral features of human cerebral malaria.
In terms of immunity to Plasmodium infections, parasite-specific CD8+ T cells have been shown to control liver-stage infection, whereas protective immunity to the blood stages is largely humoral—although CD4+ T cells alone can affect infection. Interestingly, severe disease such as cerebral malaria appears to be mediated by immune pathology, involving a number of components of both innate and adaptive immunity. Thus, while mice deficient in CD4+ T cells or B cells are more susceptible to infection, it has been reported that mice unable to make TNF-α or IFN-γ or depleted of CD8+ T cells are protected from cerebral malaria. Although CD8+ T cells are implicated in severe disease, it is not known whether they are parasite specific or even whether blood-stage infection can induce a specific CD8+ T cell response.
Despite extensive evidence that Plasmodium species are capable of stimulating the immune system, numerous studies have described immune suppression associated with infection, suggesting that Plasmodium parasites subvert immunity to promote persistence. Immune suppression has been reported for Plasmodium infection of both mice and humans, and the reports include evidence of suppressed reactivity to parasite antigens as well as reduced capacity to generate immunity to secondary viral infections or to model antigens. Various mechanisms have been suggested as underlying such suppression, including induction of CD4+ T cell apoptosis, suppression of dendritic cell function, and the generation of suppressive cytokines.
The observed humoral and cell-mediated immunity to malaria is, however, hard to reconcile with evidence of immune suppression, but it might be explained by the ability of suppressive mechanisms to reduce but not prevent induction of immunity. Recently, we provided evidence that overt infection of the blood by P. berghei leads to suppression of immunity as a consequence of apparently normal dendritic cell activation. We showed that, whereas dendritic cells in infected mice are fully competent in their ability to activate T cells provided they express antigen–major histocompatibility complexes on the surface, their activated phenotype leads to a failure to capture newly encountered antigenic material and thus failure to present such antigens. In this case, dendritic cells are not directly suppressed but merely follow their normal maturation pathway after they encounter activating stimuli. The net effect, however, is one of rapid generalized immunosuppression because, as systemic infection progresses, all dendritic cells are activated, leaving no immature dendritic cells to capture subsequently encountered antigens.
Although systemic dendritic cell activation by P. berghei infection explained the reduced reactivity to subsequently encountered antigens—for example, those associated with viral infection—this earlier study did not determine whether reactivity to the Plasmodium antigens themselves could also be reduced. If dendritic cells were activated by direct encounter with parasites, then presumably they would capture parasite antigens at the time of activation and effectively present them. On the other hand, if parasitemia led to release of soluble innate signals such as TNF-α, then perhaps dendritic cells would be activated before capturing parasites and therefore fail to present their antigens.
Dendritic cells are not a single cell type; in the mouse, perhaps six or more subsets can be distinguished. They can be separated into five subsets of conventional dendritic cells and a sixth subset of plasmacytoid dendritic cells. Of these, only four subsets are found in the spleen— namely, the plasmacytoid dendritic cells (pDCs) and three conventional subsets, distinguished by expression of CD4 and CD8α into CD4+CD8–(CD4), CD4–CD8+(CD8α), and CD4–CD8– dendritic cell subpopulations. The conventional dendritic cells are thought to enter the spleen most likely as precursors, residing normally in an immature state in this organ. As immature dendritic cells, they are able to capture antigens and, upon encountering activating stimuli such as toll-like receptor ligands, mature into fully immunogenic antigen-presenting cells. At present, there is limited knowledge about the individual function of each subset, except perhaps about CD8α dendritic cells and pDCs, to which a number of functions have been attributed.
To address issues such as the subtype of dendritic cells presenting parasite antigens and the role of CD8+ killer T cells in severe disease, our studies involve the generation of transgenic P. berghei parasites expressing model T cell epitopes. We are using these transfectants to answer the important question of whether blood-stage infection can lead to the induction of specific CD8+ killer T cell responses. Our initial studies show that infection leads to the effective dendritic cell–dependent induction of both CD4+ helper T cell and CD8+ killer T cell responses. Furthermore, although the priming phase is shortlived, it is able to generate killer T cell effectors that can mediate severe, lethal disease. We are investigating whether, to cause cerebral malaria, CD8+ killer T cells need to recognize parasite antigens within the brain; we are also addressing the nature of cells recognized by these killer T cells. By carefully dissecting the types of dendritic cells involved in initiating CD4+ helper and CD8+ killer T cell responses, we hope to distinguish the requirements for inducing protective antibody responses from those involved in generation of immunopathology. Greater understanding of how malaria mediates immunosuppression may also be useful in the design of malarial vaccines.
Last updated August 2009