Medicine (RMH) - Theses
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ItemPregnancy-malaria: immunity and a mechanism for low birth weight( 2010)Introduction: Pregnant women are more susceptible to Plasmodium falciparum malaria than their non-pregnant peers and the consequences for the mother and child can include maternal anaemia and low birth weight (LBW). The development of immunity to P. falciparum in pregnancy is of importance for vaccine development and identifying women at risk of disease. Knowledge of the mechanisms of pathogenesis, such as how malaria results in LBW, is needed to effectively identify therapeutic targets and prevent adverse outcomes. Methods: In this thesis, the immune response towards P. falciparum was assessed in a cohort of women receiving intermittent preventive treatment in pregnancy (IPTp) by measuring antibody towards the surface of placental-binding parasitised red blood cell using flow cytometry. The dynamics of these antibody levels, from 14-26gw until six months post partum, were described, and the protective relationships between antibody and clinical outcomes in the women were examined. A mechanism for LBW in pregnancy-malaria was also investigated. This involved looking at the relationship between placental levels of proinflammatory cytokine interleukin-11β (IL-1β) (as measured by ELISA) and birth weight. And, modelling nutrient transport across the placenta in pregnancy-malaria using radiolabelled amino acids, placental cell lines and various malaria-associated stimuli, such as pro-inflammatory cytokines and monocyte:parasite products. Results: Among women receiving IPTp who are at low to moderate risk of parasitemia, development of immunity to the placental-binding parasite was dynamic. Many women in their first pregnancy did not develop an immune response. However, there was no evidence that this leads to lower immunity in successive pregnancies. In addition, it was found that immunity measured mid pregnancy did not predict protection against clinical outcomes such as birth weight, maternal haemoglobin or gestation length later in pregnancy. Regarding a mechanism for LBW, the proinflammatory cytokine IL-1β was increased in placentas of women with placental malaria and inflammation. This cytokine was negatively associated with birth weight and was shown to be able to decrease amino acid transport in an in-vitro model. Monocyte:parasite products in the supernatant of an inflammatory cell and parasite co-culture were also able to decrease placental amino acid transport in an in-vitro model. Interestingly pro-inflammatory cytokines TNF-α, IL-18 and chemokine IL-8 did not alter amino acid transport in the in-vitro model. Conclusions: Antibody dynamics and the relationships between antibody and outcome were described. Lower than expected parasitemia prevalence and a lack of association between antibody early pregnancy and outcome suggests that evaluating the protective efficacy of pregnancy-malaria vaccines may be difficult in the contexts of routine IPTp administration and falling malaria prevalence’s. Results from the nutrient transport models support a possible pathogenic mechanism for foetal growth restriction in placental malaria where monocyte:parasite products, such as IL-1b, decrease the activity of placental amino-acid transporters. These products may be therapeutic targets for the prevention of LBW in placental malaria.
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ItemEpidemiological and immunological studies of treatment for pregnancy associated malaria( 2010)Pregnant women are highly susceptible to malaria, and malaria in pregnancy causes a number of adverse outcomes such as maternal anaemia and delivery of low birth weight babies. Thus pregnant women are specifically targeted in malaria prevention efforts with control measures including IPTp and bed nets. Pregnant women are uniquely susceptible to malaria because Plasmodium falciparum infected erythrocytes can adhere to the placenta. This is mediated by the variant surface antigen (VSA) family Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). Accumulation of infected erythrocytes in the placenta may subsequently result in acquisition of immunity targeting this protein especially among multigravid women. Longitudinal data collected over 9 years from Malawian pregnant women demonstrated decreased prevalence of peripheral and placental malaria, maternal anaemia and LBW. In the same time frame coverage with IPTp SP and bed nets increased. SP IPT doses were associated with protection against placental parasitaemia, maternal anaemia and LBW from 1997-2001, but not from 2002-2006. Bed net use was associated with protection from peripheral or placental parasitemia and LBW throughout the study, but not with anaemia. These results indicated decreased maternal malaria infection correlated with improved pregnancy outcomes. Increased bed net coverage explains more of this change than SP use. SP resistance may be compromising its effectiveness. In chapter 4 of this thesis, I explored the protective effect of immunity against pregnant associated malaria variant surface antigens (VSA-PAM) using sera from a group of Malawian pregnant women who undertook anti-malarial treatment. My results showed that the level of immunity against VSA-PAM was associated with improved anti-malarial treatment outcomes and decreased maternal anaemia at delivery. The finding presented in this thesis validated further studies investigating the role of antibodies against VSA-PAM in protecting against placental malaria infection. The decreased protective effect of SP-IPTp also urged the importance of replacing SP from the first line anti-malarial treatment drugs.