PubMed Health⌕ Search

Biomedical subjects

Michal Fried

Publications and source records attributed to Michal Fried.

11 recordsLinked to original sources
PubMed2006

Red blood cells that do and red blood cells that don't: how to resist a persistent parasite.

Sixty years ago, Haldane proposed that certain abnormalities in red blood cells could be selected as malaria-resistance genes. Population studies have confirmed that many human polymorphisms confer resistance to severe malaria, although the mechanisms of protection remain unknown. A recent article proposes a new mechanism for explaining the protective effects of hemoglobin C (HbC). HbC-containing red blood cells have modified displays of malaria surface proteins that reduce parasite adhesiveness and could reduce the risk of severe disease.

Animals↗
PubMed2006

Plasmodium falciparum: chondroitin sulfate A is the major receptor for adhesion of parasitized erythrocytes in the placenta.

Plasmodium falciparum parasites that sequester in the placenta bind to the molecule chondroitin sulfate A (CSA). Women become resistant to malaria during pregnancy as they acquire antibodies that inhibit parasite adhesion to CSA, suggesting that a vaccine against placental malaria is feasible. Hyaluronic acid (HA) and non-immune IgG have also been proposed as receptors for P. falciparum adhesion in the placenta, but evidence for their roles is inconclusive. In this study, CSA, HA, and IgG were simultaneously assessed for their relative contributions to placental adhesion. Placental parasites collected in Tanzania uniformly adhered to the molecule CSA, and soluble CSA completely inhibited adhesion of most samples to placental cryosections. Three of 46 placental parasite samples also adhered to immobilized HA, but HA failed to inhibit adhesion of any placental parasites to placental cryosections. Similarly, non-immune IgG and protein A failed to inhibit adhesion of parasite samples to placental cryosection. P. falciparum adhesion in the placenta appears to be a non-redundant process that requires CSA as a receptor. Vaccines that elicit functional antibodies against CSA-binding parasites may confer resistance to pregnancy malaria.

Adolescent↗
PubMed2006

Hypertension and maternal-fetal conflict during placental malaria.

BACKGROUND: Malaria and hypertension are major causes of maternal mortality in tropical countries, especially during first pregnancies, but evidence for a relationship between these syndromes is contradictory. METHODS AND FINDINGS: In a cross-sectional survey of Tanzanian parturients, the rate of hypertension was similar in placental malaria (PM)-positive (11/85 = 13%) and PM-negative (73/602 = 12%) individuals. However, we found that PM was associated with hypertension in first-time mothers aged 18-20 y but not other mothers. Hypertension was also associated with histologic features of chronic malaria, which is common in first-time mothers. Levels of soluble vascular endothelial growth factor receptor 1 (sVEGFR1), a preeclampsia biomarker, were elevated in first-time mothers with either PM, hypertension, or both, but levels were not elevated in other mothers with these conditions. In first-time mothers with PM, the inflammatory mediator vascular endothelial growth factor (VEGF) was localized to maternal macrophages in the placenta, while sVEGFR1, its soluble inhibitor, was localized to the fetal trophoblast. CONCLUSIONS: The data suggest that maternal-fetal conflict involving the VEGF pathway occurs during PM, and that sVEGFR1 may be involved in the relationship between chronic PM and hypertension in first-time mothers. Because placental inflammation causes poor fetal outcomes, we hypothesize that fetal mechanisms that promote sVEGFR1 expression may be under selective pressure during first pregnancies in malaria-endemic areas.

Adult↗
PubMed2005

Maternal malaria and gravidity interact to modify infant susceptibility to malaria.

BACKGROUND: In endemic areas, placental malaria due to Plasmodium falciparum is most frequent and severe in first-time mothers, and increases the risk of infant mortality in their offspring. Placental malaria may increase the susceptibility of infants to malaria parasitemia, but evidence for this effect is inconclusive. METHODS AND FINDINGS: During 2002-2004, we monitored parasitemia in 453 infants, including 69 who were born to mothers with placental malaria, in a region of northeastern Tanzania where malaria transmission is intense. We used a Cox proportional hazards model to evaluate the time from birth to first parasitemia, and a generalized estimating equations logistic regression model to evaluate risk of any parasitemia throughout the first year of life. Compared with infants whose mothers did not have placental malaria at delivery ("PM-negative"), offspring of mothers with placental malaria at delivery ("PM-positive") were 41% more likely to experience their first parasitemia at a younger age (adjusted hazard ratio [AHR] = 1.41, 95% confidence interval [CI] 1.01-1.99). The odds of parasitemia throughout infancy were strongly modified by the interaction between placental malaria and gravidity (p for interaction = 0.008, Type 3 likelihood ratio test). Offspring of PM-negative primigravidae had lower odds of parasitemia during infancy (adjusted odds ratio [AOR] = 0.67, 95% CI 0.50-0.91) than offspring of PM-negative multigravidae, and offspring of PM-positive primigravidae had the lowest odds (AOR = 0.21, 95% CI 0.09-0.47). In contrast, offspring of PM-positive multigravidae had significantly higher odds of parasitemia (AOR = 1.59, 95% CI 1.16-2.17). CONCLUSION: Although parasitemia is more frequent in primigravid than multigravid women, the converse is true in their offspring, especially in offspring of PM-positive women. While placental malaria is known to increase mortality risk for first-born infants, it surprisingly reduced their risk of parasitemia in this study. Placental malaria of multigravidae, on the other hand, is a strong risk factor for parasitemia during infancy, and therefore preventive antimalarial chemotherapy administered to multigravid women close to term may reduce the frequency of parasitemia in their offspring.

Adult↗
PubMed2005

Malaria vaccines: using models of immunity and functional genomics tools to accelerate the development of vaccines against Plasmodium falciparum.

Naturally acquired immunity and immunity acquired after immunization with attenuated parasites indicate that a vaccine against malaria is feasible. Several obstacles have stymied malaria vaccine development, among them our poor understanding of protective immunity and technical difficulties for studying gene and protein expression in the Plasmodium falciparum parasite. Pregnancy malaria offers a model approach for vaccine development: recent findings have elucidated the basis for disease pathogenesis and protective immunity in this syndrome, and this understanding has focused the effort to identify the optimal antigens for a pregnancy malaria vaccine. In parallel, functional genomics tools are overcoming several of the obstacles for studying protein expression in the malaria parasite, vastly accelerating the pace for antigen discovery. Together, these conceptual and technological advances allow a rational approach to vaccine antigen selection, in which a finite number of antigens are selected from the entire genome by merit of the expression patterns and specific features. These candidate antigens are then subjected to detailed studies according to criteria established by the understanding of pathogenesis and protective immunity, to identify the optimal antigens for inclusion in subunit vaccines.

Animals↗
PubMed2004

Mass spectrometric analysis of Plasmodium falciparum erythrocyte membrane protein-1 variants expressed by placental malaria parasites.

Surface proteins from Plasmodium falciparum are important malaria vaccine targets. However, the surface proteins previously identified are highly variant and difficult to study. We used tandem mass spectrometry to characterize the variant antigens (Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1)) expressed on the surface of malaria-infected erythrocytes that bind to chondroitin sulfate A (CSA) in the placenta. Whereas PfEMP1 variants previously implicated as CSA ligands were detected, in unselected parasites four novel variants were detected in CSA-binding or placental parasites but not in unselected parasites. These novel PfEMP1 variants require further study to confirm whether they play a role in placental malaria.

Animals↗
PubMed2003

Plasmodium falciparum adhesion in the placenta.

Plasmodium falciparum parasites sequester in the human placenta, and placental malaria is associated with disease and death of both mother and child. Placental isolates of P. falciparum uniformly bind to chondroitin sulfate A on the syncytiotrophoblast. Forms of the variant surface antigen PfEMP1 that bind chondroitin sulfate A in vitro (PfEMP1(varCSA)) are highly conserved in many field isolates. Two related forms of PfEMP1(varCSA) are commonly expressed by placental isolates, but these are also transcribed by most non-placental isolates. PfEMP1(varCSA) gene transcription is not upregulated when parasites are selected to bind chondroitin sulfate A, but other PfEMP1 forms may be upregulated. Young ring-stage parasites derived from chondroitin sulfate A-binding isolates may also bind to the endothelium through a process that does not involve PfEMP1 or chondroitin sulfate A. Adhesins and other surface proteins of placental parasites are targets of naturally occurring antibodies associated with protection and therefore could be used to develop vaccines that prevent malaria in pregnancy.

Animals↗
PubMed2003

Antibodies that inhibit Plasmodium falciparum adhesion to chondroitin sulfate A are associated with increased birth weight and the gestational age of newborns.

Antibodies that inhibit Plasmodium falciparum adhesion to the placental receptor chondroitin sulfate A are associated with a reduced risk of placental malaria, but whether these antibodies lead to improved pregnancy outcomes is unknown. We measured antiadhesion antibody levels in parturient women in western Kenya, where malaria transmission is intense. Secundigravid women with antiadhesion activity in their plasma delivered babies that were on average 398 g heavier (P = 0.019) and 2 weeks more mature (P = 0.002) than babies delivered to secundigravidas without antiadhesion activity. Our findings support the development of antiadhesion vaccines to prevent poor fetal outcomes due to pregnancy malaria.

Animals↗
PubMed2002

Two DBLgamma subtypes are commonly expressed by placental isolates of Plasmodium falciparum.

Adhesion to chondroitin sulfate A (CSA), a distinguishing feature of malaria parasites obtained from the human placenta, might be mediated by the Duffy-binding-like (DBL) gamma domain of the variant surface antigen Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP1). We studied transcription of var genes (that encode PfEMP1) in placental parasites by amplifying and sequencing DBLgamma fragments from genomic DNA and cDNA of field isolates collected in western Kenya. We amplified DBLgamma fragments with divergent sequences from individual isolates by using various sequence-specific or degenerate primers. Transcripts detected with degenerate primers clustered phylogenetically within two DBLgamma subtypes with homology to chr5_1.gen_150 or FCR3.varCSA. Interestingly, the DBLalpha encoded by chr5_1.gen_150 was recently found to be commonly expressed by placental isolates from Malawi (Mol. Biochem. Parasitol. 185 (2002) 1207). The findings are consistent with earlier serologic evidence that surface antigens of placental parasites have conserved features, and suggest that vaccines based on DBLgamma may only need to target a limited number of variants.

Adolescent↗