In malaria endemic settings, adults develop ABT-263 solubility dmso protective immunity after repeated exposures (2), but women are more

susceptible to malarial infection when they become pregnant (1). Severe clinical manifestations associated with this infection include premature delivery and intrauterine growth restriction, contributing to low birth weight (LBW), stillbirth, abortion and maternal mortality (3–5). Increased synthesis of inflammatory cytokines like tumour necrosis factor (TNF), interleukin (IL)-2 and interferon (IFN)-γ (6–8) has been shown in malaria during pregnancy, and levels of TNF in particular have been associated with maternal anaemia and LBW (6,9). Interestingly, such pathogenic immune responses to malaria appear to be influenced by host genetic factors. For example, infants homozygous for TNF2, a polymorphism in the TNF promoter region that is associated with increased TNF production (10), are at increased risk of preterm birth and mortality, suggesting that poor birth outcomes in malaria endemic areas are precipitated by a genetically determined maternal tendency to produce high levels of this inflammatory cytokine (11). In mice, the immune response to malaria is complex and varies as a function

of mouse genetic background (12) and anatomical sites analysed. Moreover, it is dependent on parasite species and strain as well as on route of infection. In B6 mice, early production of TNF, IFN-γ, IL-12 (13) and granulocyte–macrophage colony-stimulating factor (14) is required for resistance to Molecular motor blood-stage CDK inhibitor P. chabaudi AS infection. In contrast, susceptible A/J mice mount early, predominantly Th2-biased cytokine responses (15) and succumb to infection (16). Treatment of these mice with recombinant IL-12 early in infection results in increased production of IFN-γ and TNF and facilitates elimination of parasites and survival (17). Interestingly, A/J mice overcome their Th2-cytokine bias later in infection, exhibiting increased TNF expression in the liver and high serum TNF levels coincident with the time that they begin to succumb to infection (18). Recently, we initiated studies of malaria

during pregnancy using P. chabaudi AS infection in B6 mice as a model platform (19–21). This model recapitulates the severe pregnancy outcomes, namely foetal loss, seen in low endemic areas and in some heavily exposed primigravidae (1). Importantly, similar to human malaria during pregnancy (6,9), TNF plays a critical role in embryo loss in this model; antibody-mediated neutralization of this cytokine rescues mid-gestational pregnancy (21). Because TNF is well known to have a negative impact on pregnancy outcomes even in the absence of infection (22,23), the tendency to produce this factor in response to malarial infection may represent a common pathogenic factor that relative to other host elements is central to disease pathogenesis.