A model of parity-dependent immunity to placental malaria.
Ontology highlight
ABSTRACT:
SUBMITTER: Walker PG
PROVIDER: S-EPMC3615483 | biostudies-other | 2013
REPOSITORIES: biostudies-other
Publications
A model of parity-dependent immunity to placental malaria.
Walker Patrick G T PG Griffin Jamie T JT Cairns Matt M Rogerson Stephen J SJ van Eijk Anna M AM ter Kuile Feiko F Ghani Azra C AC
Nature communications 20130101
Plasmodium falciparum placental infection during pregnancy is harmful for both mother and child. Protection from placental infection is parity-dependent, that is, acquired over consecutive pregnancies. However, the infection status of the placenta can only be assessed at delivery. Here, to better understand the mechanism underlying this parity-dependence, we fitted a model linking malaria dynamics within the general population to observed placental histology. Our results suggest that immunity re ...[more]
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Project description:Purpose of Review:Placental malaria is the primary mechanism through which malaria in pregnancy causes adverse perinatal outcomes. This review summarizes recent work on the significance, pathogenesis, diagnosis, and prevention of placental malaria. Recent Findings:Placental malaria, characterized by the accumulation of Plasmodium-infected red blood cells in the placental intervillous space, leads to adverse perinatal outcomes such as stillbirth, low birth weight, preterm birth, and small-for-gestational-age neonates. Placental inflammatory responses may be primary drivers of these complications. Associated factors contributing to adverse outcomes include maternal gravidity, timing of perinatal infection, and parasite burden. Summary:Placental malaria is an important cause of adverse birth outcomes in endemic regions. The main strategy to combat this is intermittent preventative treatment in pregnancy; however, increasing drug resistance threatens the efficacy of this approach. There are studies dissecting the inflammatory response to placental malaria, alternative preventative treatments, and in developing a vaccine for placental malaria.
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Project description:A large proportion of the death toll associated with malaria is a consequence of malaria infection during pregnancy, causing up to 200,000 infant deaths annually. We previously published the first extensive genetic association study of placental malaria infection, and here we extend this analysis considerably, investigating genetic variation in over 9,000 SNPs in more than 1,000 genes involved in immunity and inflammation for their involvement in susceptibility to placental malaria infection. We applied a new approach incorporating results from both single gene analysis as well as gene-gene interactions on a protein-protein interaction network. We found suggestive associations of variants in the gene KLRK1 in the single gene analysis, as well as evidence for associations of multiple members of the IL-7/IL-7R signalling cascade in the combined analysis. To our knowledge, this is the first large-scale genetic study on placental malaria infection to date, opening the door for follow-up studies trying to elucidate the genetic basis of this neglected form of malaria.
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| S-EPMC6589062 | biostudies-literature
Project description:BackgroundPlasmodium falciparum causes placental malaria, which results in adverse outcomes for mother and child. P. falciparum-infected erythrocytes that express the parasite protein VAR2CSA on their surface can bind to placental chondroitin sulfate A. It has been hypothesized that naturally acquired antibodies towards VAR2CSA protect against placental infection, but it has proven difficult to identify robust antibody correlates of protection from disease. The objective of this study was to develop a prediction model using antibody features that could identify women protected from placental malaria.MethodsWe used a systems serology approach with elastic net-regularized logistic regression, partial least squares discriminant analysis, and a case-control study design to identify naturally acquired antibody features mid-pregnancy that were associated with protection from placental malaria at delivery in a cohort of 77 pregnant women from Madang, Papua New Guinea.ResultsThe machine learning techniques selected 6 out of 169 measured antibody features towards VAR2CSA that could predict (with 86% accuracy) whether a woman would subsequently have active placental malaria infection at delivery. Selected features included previously described associations with inhibition of placental binding and/or opsonic phagocytosis of infected erythrocytes, and network analysis indicated that there are not one but multiple pathways to protection from placental malaria.ConclusionsWe have identified candidate antibody features that could accurately identify malaria-infected women as protected from placental infection. It is likely that there are multiple pathways to protection against placental malaria.FundingThis study was supported by the National Health and Medical Research Council (Nos. APP1143946, GNT1145303, APP1092789, APP1140509, and APP1104975).
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Project description:Malaria in Pregnancy (MiP) is characterized by placental accumulation of Plasmodium-infected erythrocytes, intrauterine growth restriction (IUGR) and preterm delivery (PTD). Placental ATP-binding cassette (ABC) transporters mediate the efflux of nutrients, cytokines and xenobiotics. The expression and activity of these transporters are highly responsive to infection. We hypothesized that MiP would perturb the expression of placental ABC transporters, promoting PTD. Peripheral blood, spleens, livers and placentas of pregnant mice, infected with Plasmodium berghei ANKA on gestational day (GD) 13.5, were collected and analyzed on GD18.5. The primary consequences of human MiP, including IUGR, PTD (20%) and placental inflammation, were recapitulated in our mouse model. Electron microscopy revealed attenuated presence of labyrinthine microvilli and dilated spongiotrophoblasts -granular endoplasmic reticulum cisternae. Additionally, a decrease in placental Abca1 (ABCA1), Abcb1b (P-glycoprotein), Abcb9 and Abcg2 (BCRP) expression was observed in MiP mice. In conclusion, MiP associated with PTD impairs placental ABC transporters' expression, potentially modulating placental nutrient, environmental toxin and xenobiotic biodistribution within the fetal compartment, and may, at some degree, be involved with pregnancy outcome in MiP.
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Project description:Chronic inflammation during placental malaria (PM) caused by Plasmodium falciparum is most frequent in first-time mothers and is associated with poor maternal and fetal outcomes. In the first genome wide analysis of the local human response to sequestered malaria parasites, we identified genes associated with chronic PM, then localized the corresponding proteins and immune cell subsets in placental cryosections. Keywords: Disease state analysis
2007-07-01 | GSE7586 | GEO
Project description:BACKGROUND: Individuals continuously exposed to malaria gradually acquire immunity that protects from severe disease and high levels of parasitization. Acquired immunity has been incorporated into numerous models of malaria transmission of varying levels of complexity (e.g. Bull World Health Organ 50:347, 1974; Am J Trop Med Hyg 75:19, 2006; Math Biosci 90:385-396, 1988). Most such models require prescribing inputs of mosquito biting rates or other entomological or epidemiological information. Here, we present a model with a novel structure that uses environmental controls of mosquito population dynamics to simulate the mosquito biting rates, malaria prevalence as well as variability in protective immunity of the population. METHODS: A simple model of acquired immunity to malaria is presented and tested within the framework of the Hydrology, Entomology and Malaria Transmission Simulator (HYDREMATS), a coupled hydrology and agent-based entomology model. The combined model uses environmental data including rainfall, temperature, and topography to simulate malaria prevalence and level of acquired immunity in the human population. The model is used to demonstrate the effect of acquired immunity on malaria prevalence in two Niger villages that are hydrologically and entomologically very different. Simulations are conducted for the year 2006 and compared to malaria prevalence observations collected from the two villages. RESULTS: Blood smear samples from children show no clear difference in malaria prevalence between the two villages despite pronounced differences in observed mosquito abundance. The similarity in prevalence is attributed to the moderating effect of acquired immunity, which depends on prior exposure to the parasite through infectious bites - and thus the hydrologically determined mosquito abundance. Modelling the level of acquired immunity can affect village vulnerability to climatic anomalies. CONCLUSIONS: The model presented has a novel structure constituting a mechanistic link between spatial and temporal environmental variability and village-scale malaria transmission. Incorporating acquired immunity into the model has allowed simulation of prevalence in the two villages, and isolation of the effects of acquired immunity in dampening the difference in prevalence between the two villages. Without these effects, the difference in prevalence between the two villages would have been significantly larger in response to the large differences in mosquito populations and the associated biting rates.
| S-EPMC3750354 | biostudies-other
Project description:BackgroundPlacental Plasmodium falciparum malaria can trigger intervillositis, a local inflammatory response more strongly associated with low birthweight than placental malaria infection alone. Fetal growth (and therefore birthweight) is dependent on placental amino acid transport, which is impaired in placental malaria-associated intervillositis. Here, we tested the hypothesis that mechanistic target of rapamycin (mTOR) signaling, a pathway known to regulate amino acid transport, is inhibited in placental malaria-associated intervillositis, contributing to lower birthweight.MethodsWe determined the link between intervillositis, mTOR signaling activity, and amino acid uptake in tissue biopsies from both uninfected placentas and malaria-infected placentas with and without intervillositis, and in an in vitro model using primary human trophoblast (PHT) cells.ResultsWe demonstrated that (1) placental mTOR activity is lower in cases of placental malaria with intervillositis, (2) placental mTOR activity is negatively correlated with the degree of inflammation, and (3) inhibition of placental mTOR activity is associated with reduced placental amino acid uptake and lower birthweight. In PHT cells, we showed that (1) inhibition of mTOR signaling is a mechanistic link between placental malaria-associated intervillositis and decreased amino acid uptake and (2) constitutive mTOR activation partially restores amino acid uptake.ConclusionsOur data support the concept that inhibition of placental mTOR signaling constitutes a mechanistic link between placental malaria-associated intervillositis and decreased amino acid uptake, which may contribute to lower birthweight. Restoring placental mTOR signaling in placental malaria may increase birthweight and improve neonatal survival, representing a new potential therapeutic approach.
| S-EPMC5209943 | biostudies-literature