Naturally acquired immunity to falciparum malaria protects millions of people routinely exposed to Plasmodium falciparum infection from severe disease and death. There is no clear concept about how this protection works. There is no general agreement about the rate of onset of acquired immunity or what constitutes the key determinants of protection; much less is there a consensus regarding the mechanism(s) of protection. This review summarizes what is understood about naturally acquired and experimentally induced immunity against malaria with the help of evolving insights provided by biotechnology and places these insights in the context of historical, clinical, and epidemiological observations. We advocate that naturally acquired immunity should be appreciated as being virtually 100% effective against severe disease and death among heavily exposed adults. Even the immunity that occurs in exposed infants may exceed 90% effectiveness. The induction of an adult-like immune status among high-risk infants in sub-Saharan Africa would greatly diminish disease and death caused by P. falciparum. The mechanism of naturally acquired immunity that occurs among adults living in areas of hyper- to holoendemicity should be understood with a view toward duplicating such protection in infants and young children in areas of endemicity.

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Acquired immunity to malaria.

Malaria is possibly the most serious infectious disease of humans, infecting 5-10% of the world's population, with 300-600 million clinical cases and more than 2 million deaths annually. Adaptive immune responses in the host limit the clinical impact of infection and provide partial, but incomplete, protection against pathogen replication; however, these complex immunological reactions can contribute to disease and fatalities. So, appropriate regulation of immune responses to malaria lies at the heart of the host-parasite balance and has consequences for global public health. This Review article addresses the innate and adaptive immune mechanisms elicited during malaria that either cause or prevent disease and fatalities, and it considers the implications for vaccine design.

Immunological processes in malaria pathogenesis.

Oxidative stress in malaria parasite-infected erythrocytes: Host-parasite interactions

Understanding of the biological basis for susceptibility to malaria in pregnancy was recently advanced by the discovery that erythrocytes infected with Plasmodium falciparum accumulate in the placenta through adhesion to molecules such as chondroitin sulphate A. Antibody recognition of placental infected erythrocytes is dependent on sex and gravidity, and could protect from malaria complications. Moreover, a conserved parasite gene-var2csa-has been associated with placental malaria, suggesting that its product might be an appropriate vaccine candidate. By contrast, our understanding of placental immunopathology and how this contributes to anaemia and low birthweight remains restricted, although inflammatory cytokines produced by T cells, macrophages, and other cells are clearly important. Studies that unravel the role of host response to malaria in pathology and protection in the placenta, and that dissect the relation between timing of infection and outcome, could allow improved targeting of preventive treatments and development of a vaccine for use in pregnant women.

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Malaria in pregnancy: pathogenesis and immunity.

The sick placenta: The role of malaria

Maternal anemia and low birth weight (LBW) may complicate malaria in pregnancy, and placental monocyte infiltrates have been associated with LBW, and anecdotally with anemia We examined placental pathology from 357 Malawian women Intervillous monocyte infiltrates were frequent in placental malaria and were not seen in uninfected placentas Histology was grouped according to a 5-point scale Dense monocyte infiltrates and presence of intramonocytic malaria pigment were associated with anemia and LBW Of factors associated with LBW and/or anemia in univariate analysis, gravidity (P = 0002), number of antenatal clinic (ANC) visits (P < 0001), malaria pigment in fibrin (P = 003), and monocyte malaria pigment (P = 00001) remained associated with lower birth weight by multivariate analysis Associated with maternal anemia were HIV infection (P < 00001), intervillous monocyte numbers (P < 00001), number of ANC visits (P = 0002), and recent febrile symptoms (P = 00001) Pigment-containing placental monocytes are associated with anemia and LBW due to malaria, and may have a causative role in their development

Placental monocyte infiltrates in response to plasmodium falciparum malaria infection and their association with adverse pregnancy outcomes

Malaria in pregnancy predisposes to maternal anemia and low birth weight (LBW). We examined the possible roles of the cytokines tumor necrosis factor alpha (TNF-alpha) and gamma interferon (IFN-gamma) in these adverse outcomes. We measured cytokine concentrations in placental, peripheral, and cord blood plasma in relation to malaria parasitemia and placental monocyte accumulation in 276 Malawian women. Maternal hemoglobin concentration, human immunodeficiency virus status, and infant birth weight were determined. Concentrations of TNF-alpha in placental blood were correlated with densities of Plasmodium falciparum-infected erythrocytes (P < 0.0001) and of intervillous monocyte infiltrates (P < 0.0001) on placental histology. Peripheral blood TNF-alpha concentrations were relatively low and were weakly associated with malaria. TNF-alpha concentrations were higher in placental blood, where they were strongly associated with malaria. Placental plasma TNF-alpha levels were higher in women who had LBW babies (P = 0.0027), women with febrile symptoms (P < 0.0001), and teenage mothers (P = 0.04) than in other women. The presence of TNF-alpha in cord blood was not associated with malaria infection. IFN-gamma levels were infrequently elevated, and elevated IFN-gamma levels were not associated with poor pregnancy outcomes. Placental production of TNF-alpha, but not of IFN-gamma, may be implicated in impaired fetal growth in Malawian women.

Elena Pollina

Papers

Placental monocyte infiltrates in response to plasmodium falciparum malaria infection and their association with adverse pregnancy outcomes

Placental tumor necrosis factor alpha but not gamma interferon is associated with placental malaria and low birth weight in Malawian women