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      No Evidence that Knops Blood Group Polymorphisms Affect Complement Receptor 1 Clustering on Erythrocytes

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          Abstract

          Clustering of Complement Receptor 1 (CR1) in the erythrocyte membrane is important for immune-complex transfer and clearance. CR1 contains the Knops blood group antigens, including the antithetical pairs Swain-Langley 1 and 2 (Sl1 and Sl2) and McCoy a and b (McC a and McC b), whose functional effects are unknown. We tested the hypothesis that the Sl and McC polymorphisms might influence CR1 clustering on erythrocyte membranes. Blood samples from 125 healthy Kenyan children were analysed by immunofluorescence and confocal microscopy to determine CR1 cluster number and volume. In agreement with previous reports, CR1 cluster number and volume were positively associated with CR1 copy number (mean number of CR1 molecules per erythrocyte). Individuals with the McC b /McC b genotype had more clusters per cell than McC a / McC a individuals. However, this association was lost when the strong effect of CR1 copy number was included in the model. No association was observed between Sl genotype, sickle cell genotype, α+thalassaemia genotype, gender or age and CR1 cluster number or volume. Therefore, after correction for CR1 copy number, the Sl and McCoy polymorphisms did not influence erythrocyte CR1 clustering, and the effects of the Knops polymorphisms on CR1 function remains unknown.

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          Effect of a fall in malaria transmission on morbidity and mortality in Kilifi, Kenya

          Summary Background As efforts to control malaria are expanded across the world, understanding the role of transmission intensity in determining the burden of clinical malaria is crucial to the prediction and measurement of the effectiveness of interventions to reduce transmission. Furthermore, studies comparing several endemic sites led to speculation that as transmission decreases morbidity and mortality caused by severe malaria might increase. We aimed to assess the epidemiological characteristics of malaria in Kilifi, Kenya, during a period of decreasing transmission intensity. Methods We analyse 18 years (1990–2007) of surveillance data from a paediatric ward in a malaria-endemic region of Kenya. The hospital has a catchment area of 250 000 people. Clinical data and blood-film results for more than 61 000 admissions are reported. Findings Hospital admissions for malaria decreased from 18·43 per 1000 children in 2003 to 3·42 in 2007. Over 18 years of surveillance, the incidence of cerebral malaria initially increased; however, malaria mortality decreased overall because of a decrease in incidence of severe malarial anaemia since 1997 (4·75 to 0·37 per 1000 children) and improved survival among children admitted with non-severe malaria. Parasite prevalence, the mean age of children admitted with malaria, and the proportion of children with cerebral malaria began to change 10 years before hospitalisation for malaria started to fall. Interpretation Sustained reduction in exposure to infection leads to changes in mean age and presentation of disease similar to those described in multisite studies. Changes in transmission might not lead to immediate reductions in incidence of clinical disease. However, longitudinal data do not indicate that reductions in transmission intensity lead to transient increases in morbidity and mortality. Funding Wellcome Trust, Kenya Medical Research Institute.
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            P. falciparum rosetting mediated by a parasite-variant erythrocyte membrane protein and complement-receptor 1.

            The factors determining disease severity in malaria are complex and include host polymorphisms, acquired immunity and parasite virulence. Studies in Africa have shown that severe malaria is associated with the ability of erythrocytes infected with the parasite Plasmodium falciparum to bind uninfected erythrocytes and form rosettes. The molecular basis of resetting is not well understood, although a group of low-molecular-mass proteins called rosettins have been described as potential parasite ligands. Infected erythrocytes also bind to endothelial cells, and this interaction is mediated by the parasite-derived variant erythrocyte membrane protein PfEMP1, which is encoded by the var gene family. Here we report that the parasite ligand for rosetting in a P. falciparum clone is PfEMP1, encoded by a specific var gene. We also report that complement-receptor 1 (CR1) on erythrocytes plays a role in the formation of rosettes and that erythrocytes with a common African CR1 polymorphism (S1(a-)) have reduced adhesion to the domain of PfEMP1 that binds normal erythrocytes. Thus we describe a new adhesive function for PfEMP1 and raise the possibility that CR1 polymorphisms in Africans that influence the interaction between erythrocytes and PfEMP1 may protect against severe malaria.
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              Sickle cell trait and the risk of Plasmodium falciparum malaria and other childhood diseases.

              The gene for sickle hemoglobin (HbS) is a prime example of natural selection. It is generally believed that its current prevalence in many tropical populations reflects selection for the carrier form (sickle cell trait [HbAS]) through a survival advantage against death from malaria. Nevertheless, >50 years after this hypothesis was first proposed, the epidemiological description of the relationships between HbAS, malaria, and other common causes of child mortality remains incomplete. We studied the incidence of falciparum malaria and other childhood diseases in 2 cohorts of children living on the coast of Kenya. The protective effect of HbAS was remarkably specific for falciparum malaria, having no significant impact on any other disease. HbAS had no effect on the prevalence of symptomless parasitemia but was 50% protective against mild clinical malaria, 75% protective against admission to the hospital for malaria, and almost 90% protective against severe or complicated malaria. The effect of HbAS on episodes of clinical malaria was mirrored in its effect on parasite densities during such episodes. The present data are useful in that they confirm the mechanisms by which HbAS confers protection against malaria and shed light on the relationships between HbAS, malaria, and other childhood diseases.
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                Author and article information

                Contributors
                alex.rowe@ed.ac.uk
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                19 December 2017
                19 December 2017
                2017
                : 7
                : 17825
                Affiliations
                [1 ]ISNI 0000 0004 1936 7988, GRID grid.4305.2, Centre for Immunity, Infection and Evolution, Institute of Immunology and Infection Research, School of Biological Sciences, , University of Edinburgh, ; Edinburgh, UK
                [2 ]ISNI 0000 0004 1936 7988, GRID grid.4305.2, Clinical Surgery, , University of Edinburgh, ; Edinburgh, UK
                [3 ]Wellcome Trust Research Laboratories/Kenya Medical Research Institute, Centre for Geographic Medicine Research, Kilifi, Kenya
                [4 ]ISNI 0000 0001 2113 8111, GRID grid.7445.2, Department of Medicine, , Imperial College, ; London, UK
                [5 ]ISNI 0000 0001 2224 8486, GRID grid.1056.2, Present Address: Burnet Institute for Medical Research and Public Health, Melbourne, ; Victoria, 3004 Australia
                Author information
                http://orcid.org/0000-0002-7702-1892
                Article
                17664
                10.1038/s41598-017-17664-9
                5736761
                70a899e4-6452-4a57-a39c-a50430d3b3dc
                © The Author(s) 2017

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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                : 14 March 2017
                : 29 November 2017
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