Host erythrocyte polymorphisms and exposure to Plasmodium falciparum in Papua New Guinea

Malaria Journal Host erythrocyte polymorphisms and exposure to Plasmodium falciparum in Papua New Guinea Freya JI Fowkes 1 2 Pascal Michon 2 3 Lynn Pilling 2 Ruth M Ripley 6 Livingstone Tavul 0 Heather J Imrie 2 Caira M Woods 1 Charles S Mgone 5 7 Adrian JF Luty 4 8 Karen P Day 1 2 0 Papua New Guinea Institute of Medical Research , Madang , Papua New Guinea 1 Department of Medical Parasitology, New York University School of Medicine , New York , USA 2 The Peter Medawar Building for Pathogen Research, Department of Zoology, University of Oxford , UK 3 PNG Institute of Medical Research , Madang , Papua New Guinea 4 Department of Parasitology, Institute for Tropical Medicine, University of Tubingen , Tubingen , Germany 5 African Malaria Network Trust , Dar es Salaam , Tanzania 6 Department of Statistics, University of Oxford , UK 7 European Developing Countries Clinical Trials Partnership , Tygerberg, Cape Town , South Africa 8 Medical Parasitology, MMB-NCMLS, Radboud University Nijmegen Medical Centre , Nijmegen , The Netherlands host genotypes. Background: The protection afforded by human erythrocyte polymorphisms against the malaria parasite, Plasmodium falciparum, has been proposed to be due to reduced ability of the parasite to invade or develop in erythrocytes. If this were the case, variable levels of parasitaemia and rates of seroconversion to infected-erythrocyte variant surface antigens (VSA) should be seen in different Methods: To test this hypothesis, P. falciparum parasitaemia and anti-VSA antibody levels were measured in a cohort of 555 asymptomatic children from an area of intense malaria transmission in Papua New Guinea. Linear mixed models were used to investigate the effect of +-thalassaemia, complement receptor-1 and south-east Asian ovalocytosis, as well as glucose-6-phosphate dehydrogenase deficiency and ABO blood group on parasitaemia and age-specific seroconversion Results: No host polymorphism showed a significant association with both parasite prevalence/ density and age-specific seroconversion to VSA. Conclusion: Host erythrocyte polymorphisms commonly found in Papua New Guinea do not effect exposure to blood stage P. falciparum infection. This contrasts with data for sickle cell trait and highlights that the above-mentioned polymorphisms may confer protection against malaria via distinct mechanisms. - Background Human erythrocyte polymorphisms have long been thought to play a role in resistance to malaria. High frequencies of host erythrocyte polymorphisms such as +thalassaemia, haemoglobin (Hb) S, Hb C, Hb E, complement receptor-1 (CR1) deficiency, glucose-6-phosphate dehydrogenase (G6PD) deficiency and south-east Asian ovalocytosis (SAO) are found in malaria endemic areas. Case-control studies have demonstrated that these polymorphisms reduce the risk of severe falciparum malaria rather than mild malaria [1-22]. Experimentally, research has focused on examining the interactions between the parasite and the erythrocyte to try to understand possible mechanisms of protection of these polymorphisms. In vitro experiments have suggested reduced ability of Plasmodium falciparum to invade or sustain growth in abnormal erythrocytes [23]. Enhanced clearance of infected erythrocytes by phagocytosis, and increased enhanced susceptibility of P. falciparum-infected abnormal erythrocytes to oxidative stress, have also been proposed [24-28]. It has also been hypothesized that +-thalassaemia, CR1 deficiency and blood group O may protect via reduced rosetting [5,21,29-32], the phenomenon whereby nonparasitized erythrocytes bind to parasitized erythrocytes. It is well documented that individuals with sickle cell trait (HbAS) have lower parasite densities compared to HbAA individuals in asymptomatic, mild and severe malaria [18-20,33-44]. This, together with the observation that the time to reappearance of P. falciparum is lower in HbAS individuals after drug treatment [39], provides compelling evidence for a direct interaction of the parasite with the HbS containing erythrocytes or of improved immunity controlling the level of parasitaemia in those with sickle cell trait. However, data on other erythrocyte polymorphisms is less clear cut. Clinical studies have rarely demonstrated differences in parasite density among genotypes in symptomatic malaria. Epidemiological studies in asymptomatic individuals are inconsistent. Cross-sectional studies have shown that +-thalassaemia [45,46], SAO [47,48], G6PD [49-53] and ABO polymorphisms (no studies have examined CR1) have reduced parasite rates/densities while other studies provide no evidence of an effect of these polymorphisms on parasite densities [4,11,54-65]. Data from a single time point may not accurately represent exposure to infection and therefore results of these studies are hard to interpret. There are two possible ways to measure exposure to malaria blood stage infection: 1) by comparing parasite prevalence/density and, 2) by comparing age-specific antibody seroconversion to major blood stage antigens among host genotypes. Seroconversion to P. falciparuminfected erythrocyte variant surface antigens (VSA), which include P. falciparum erythrocyte membrane protein-1 (PfEMP-1) and rifins, has been shown to be dependent on the intensity of transmission [66]. Antibody levels in endemic areas reflect the level of IgG seroconversion to P. falciparum-infected erythrocyte VSA [67]. Furthermore, a study in Tanzania showed that insecticide-treated bednets limited the repertoire of recognized VSA and reduced antibody levels [68]. Seroconversion can also be considered as a marker for the level of cumulative exposure to the parasite as it increases with age [69]. The more exposure to P. falciparum children receive in malaria-endemic areas, the younger children will seroconvert to VSA. If human erythrocyte polymorphisms were to hamper invasion and/or growth of the parasite or enhance the antibody-dependent control of malarial infection, this should manifest as differences in both mean parasite densities and patterns of age-specific seroconversion to VSA. The frequency of the host polymorphisms +-thalassaemia, CR1, ABO blood group, SAO and G6PD deficiency were determined in a group of children from Papua New Guinea (PNG). Parasitological criteria and levels of antiVSA antibodies were measured in these children in two consecutive surveys, one year apart. The relationship between these genetic polymorphisms, parasite prevalence/density and age-specific antibody seroconversion to VSA was investigated in a malaria endemic region of PNG. Methods Study design and data collection Details of study design and data collection have been reported previously [54]. Briefly, a serial cross-sectional survey was conducted in asymptomatic children living in villages of the Amele region, Madang Province, PNG, where intense year-round malaria transmission occurs [70]. The study took place from November to December of 1999 (...truncated)