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Multiple injections of γ-radiation-attenuated Plasmodium sporozoites (γ-spz) can induce long-lived, sterile immunity against pre-erythrocytic stages of malaria. Malaria antigen (Ag)-specific CD8 T cells that produce IFN-γ are key effector cells in this model of protection. Although there have been numerous reports dealing with γ-spz-induced CD8 T cells in the spleen, CD8 T cells most likely confer protection by targeting infected hepatocytes. Consequently, in this chapter we discuss observations and hypotheses concerning CD8 T cell responses that occur in the liver after an encounter with the Plasmodium parasite. Protracted protection against pre-erythrocytic stages requires memory CD8 T cells and we discuss evidence that γ-spz-induced immunity is indeed accompanied by the presence of intrahepatic CD44^hi CD45RB^lo CD62l^lo CD122^lo effector memory (EM) CD8 T cells and CD44^hi CD45RB^hi CD62l^hi CD122^hi central memory (CM) CD8 T cells. In addition, the EM CD8 T cells rapidly release IFN-γ in response to spz challenge. The possible role of Kupffer cells in the processing of spz Ags and the production of cytokines is also considered. Finally, we discuss evidence that is consistent with a model whereby intrahepatic CM CD8 T cells are maintained by IL-15 mediated-homeostatic proliferation while the EM CD8 T cells are conscripted from the CM pool in response to a persisting depot of liver-stage Ag.

Accumulating evidence provides strong support for the importance of innate immunity in shaping the subsequent adaptive immune response to blood-stage Plasmodium parasites, the causative agents of malaria. Early interactions between blood-stage parasites and cells of the innate immune system, including dendritic cells, monocytes/macrophages, natural killer (NK) cells, NKT cells, and γδ T cells, are important in the timely control of parasite replication and in the subsequent elimination and resolution of the infection. The major role of innate immunity appears to be the production of immunoregulatory cytokines, such as interleukin (IL)-12 and interferon (IFN)_-γ, which are critical for the development of type 1 immune responses involving CD4^+ Th1 cells, B cells, and effector cells which mediate cell-mediated and antibody-dependent adaptive immune responses. In addition, it is likely that cells of the innate immune system, especially dendritic cells, serve as antigen-presenting cells.Here, we reviewrecent data fromrodentmodels of blood-stagemalaria and from human studies, and outline the early interactions of infected red blood cells with the innate immune system. We compare and contrast the results derived from studies in infected laboratory mice and humans. These host species are sufficiently differentwith respect to the identity of the infecting Plasmodium species, the resulting pathologies, and immune responses, particularly where the innate immune response is concerned. The implications of these findings for the development of an effective and safemalaria vaccine are also discussed.

Immunity to malaria develops slowly with protection against the parasite lagging behind protection against disease symptoms. The data on the longevity of protective immune responses are sparse.However, studies of antibody responses associated with protection reveal that they consist of a short- and a long-lived component. Compared with the antibody levels observed in other infection and immunization systems, the levels of the short-lived antibody compartment drop below the detectable thresholdwithunusual rapidity. Theprevalenceof long-livedantibodies is comparable to that seen after bacterial and protozoan infections. There is even less available data concerning T cell longevity in malaria infection, but what there is seems to indicate that T cell memory is short in the absence of persistent antigen. In general, the degree and duration of parasite persistence represent a major factor determining how immune response longevity and protection correlate. The predilection for short-lived immune responses in malaria infection could be caused by a number of mechanisms resulting from the interplay of normal regulatory mechanisms of the immune system and immune evasion by the parasite. In conclusion, it appears that the parasite-host relationship has developed to favor some short-lived responses,which allowthe host to survivewhile allowing the parasite to persist.Anti-malarialimmune responses present a complexpicture, andmany aspects of regulationandlongevity of the response require further research.

Malaria remains a major global health problem and cerebral malaria is one of themost serious complications of this disease. Recent years have seen important advances in our understanding of the pathogenesis of cerebralmalaria. Extensive analysis of tissues and blood taken frompatients with cerebralmalaria has been complimented by the use of animal models to identify specific components of pathogenic pathways. In particular, an important role for CD8^+ T cells has been uncovered, as well divergent roles for members of the tumor necrosis factor (TNF) family of molecules, including TNF and lymphotoxin alpha. It has become apparent that theremay bemore than one pathogenic pathway leading to cerebral malaria. The last few years have also seen the testing of vaccines designed to target malaria molecules that stimulate inflammatory responses and thereby prevent the development of cerebral malaria. In this review, we will discuss the above advancements, as well as other important findings in research into the pathogenesis of cerebral malaria. As our understanding of pathogenic responses to Plasmodium parasites gathers momentum, the chance of a breakthrough in the development of treatments and vaccines to prevent death fromcerebralmalaria have become more realistic.

Glycosylphosphatidylinositols (GPIs) are found in the outer cell membranes of all eukaryotes. GPIs anchor a diverse range of proteins to the surface of Plasmodium falciparum , but may also exist free of protein attachment. In vitro and in vivo studies have established GPIs as likely candidate toxins in malaria, consistent with the prevailing paradigmthat attributes induction of inflammatory cytokines, fever and other pathology to parasite toxins released when schizonts rupture. Although evolutionarily conserved, sufficient structural differences appear to exist that impart upon plasmodial GPIs the ability to activate second messengers in mammalian cells and elicit immune responses. In populations exposed to P. falciparum , the antibody response to purified GPIs is characterised by a predominance of immunoglobulin (Ig)G over IgM and an increase in the prevalence, level and persistence of responses with increasing age. It remains unclear, however, if these antibodies or other cellular responses to GPIs mediate anti-toxic immunity in humans; anti-toxic immunity may comprise either reduction in the severity of disease or maintenance of the malaria-tolerant state (i.e. persistent asymptomatic parasitaemia). P. falciparum GPIs are potentially amenable to specific therapeutic inhibition and vaccination;more needs to be known about their dual roles in malaria pathogenesis and protection for these strategies to succeed.

Women in endemic areas become highly susceptible to malaria during first and second pregnancies, despite immunity acquired after years of exposure.Recent insights have advanced our understanding of pregnancymalaria caused by Plasmodium falciparum , which is responsible for the bulk of severe disease and death. Accumulation of parasitized erythrocytes in the blood spaces of the placenta is a key feature of maternal infection with P. falciparum . Placental parasites express surface ligands and antigens that differ from those of other P. falciparum variants, facilitating evasion of existing immunity, and mediate adhesion to specific molecules, such as chondroitin sulfate A, in the placenta. The polymorphic and clonally variant P. falciparum erythrocyte membrane protein 1, encoded by var genes, binds to placental receptors in vitro and may be the target of protective antibodies. An intense infiltration of immune cells, including macrophages, into the placental intervillous spaces, and the production of pro-inflammatory cytokines often occur in response to infection, and are associated with low birth weight and maternal anemia. Expression of α and β chemokines may initiate or facilitate this cellular infiltration during placental malaria. Specific immunity against placental-binding parasites may prevent infection or facilitate clearance of parasites prior to the influx of inflammatory cells, thereby avoiding a cascade of events leading to disease and death. Much less is known about pathogenic processes in P. vivax infections, and corresponding immune responses. Emerging knowledge of the pathogenesis and immunology of malaria in pregnancy will increasingly lead to new opportunities for the development of therapeutic and preventive interventions and new tools for diagnosis and monitoring.