BackgroundBlood group O protects African children against severe malaria and has reached high prevalence in malarious regions. However, its role in malaria in pregnancy is ambiguous. In 839 delivering Ghanaian women, associations of ABO blood groups with Plasmodium falciparum infection were examined.MethodsPlasmodium falciparum infection was diagnosed in placental blood samples by microscopy and PCR assays. Present or past infection was defined as the detection of parasitaemia or haemozoin by microscopy, or a positive PCR result. Blood groups were inferred from genotyping rs8176719 (indicating the O allele) and rs8176746/rs8176747 (distinguishing the B allele from the A allele).ResultsThe majority of women had blood group O (55.4%); present or past P. falciparum infection was seen in 62.3% of all women. Among multiparae, the blood groups had no influence on P. falciparum infection. In contrast, primiparae with blood group O had significantly less present or past infection than women with non-O blood groups (61.5 vs 76.2%, P = 0.007). In multivariate analysis, the odds of present or past placental P. falciparum infection were reduced by 45% in blood group O primiparae (aOR, 0.55 [95% CI, 0.33–0.94]).ConclusionsThe present study shows a clear protective effect of blood group O against malaria in primiparae. This accords with findings in severe malaria and in vitro results. The data underline the relevance of host genetic protection among primiparae, i.e. the high-risk group for malaria in pregnancy, and contribute to the understanding of high O allele frequencies in Africa.

Polymorphisms of ATP2B4 encoding an ubiquitous Ca(2+) pump protect against severe childhood malaria. We assessed the influence of a main polymorphism (rs10900585) on malaria among 834 delivering Ghanaian women. In homozygous primiparae, the odds of placental Plasmodium falciparum infection were reduced by 64%. No influence of the polymorphism on parasite density, low birth weight, or preterm delivery was discernible. However, malarial anemia was greatly reduced in primiparous carriers of the variant allele, paralleling the reduced impact of malaria on hemoglobin levels in this group. A common ATP2B4 polymorphism protects against malaria in pregnancy and related maternal anemia, suggesting ATP2B4 variant associated protection not to be limited to severe childhood malaria.

Abstract. Phagocytosis of malaria pigment (hemozoin) induces increased activity of matrix metalloproteinase (MMP)-9, an endopeptidase involved in cytokine regulation. In this study, we examined whether a common functional MMP-9 promoter polymorphism (rs3918242) affects Plasmodium falciparum infection in pregnancy. Eighteen percent of Ghanaian primiparae carried the minor T allele. It was associated with reduced odds of placental hemozoin and of placental as well as peripheral blood parasitemia. The results indicate that a common MMP-9 polymorphism protects against placental malaria indicating that this endopeptidase is involved in susceptibility to P. falciparum.Pregnant women are a particular risk group for infection with Plasmodium falciparum and malaria. Although commonly asymptomatic at high endemicity, malaria in pregnancy may cause anemia, abortion, stillbirth, low birth weight (LBW), and preterm delivery (PTD), and contributes to high infant mortality. The increased susceptibility of pregnant women, particularly primigravidae, is largely due to parasites expressing specific variants of the P. falciparum erythrocyte membrane protein-1. Parasite adhesion via these variant surface proteins results in the sequestration of infected red blood cells (RBCs) in the placental intervillous space. Sequestration frequently is accompanied by local hemozoin (malaria pigment) deposition and accumulation of inflammatory cells, including monocytes/macrophages. Specific immune mechanisms targeting the pregnancy-associated parasites, particularly parasite-specific antibodies, are low in primigravidae. Only with successive pregnancies, these are acquired, and infection risk and manifestation decrease.

Abstractobjectives Haematological parameters differ between individuals of African and European ancestry. However, respective data of first-generation African migrants are virtually absent. We assessed these in Ghanaian migrants living in Berlin, compared them with reference data from Germany and Ghana, and estimated the role of iron deficiency (ID) and erythrocyte polymorphisms in anaemia.methods A total of 576 Ghanaians (median age, 45 years) were analysed. Blood counts were performed, haemoglobinopathies and glucose-6-phosphate dehydrogenase (G6PD) deficiency were genotyped, and concentrations of ferritin and C-reactive protein were measured to define ID.results Most individuals had resided in Germany for more than a decade (median, 18 years). By WHO definition, anaemia was present in 30.9% of females and 9.4% of males. Median haemoglobin (Hb) levels were lower than among Germans (women, À0.8 g/dl, men, À0.7 g/dl). However, applying reference values from Ghana, only 1.9% of the migrants were considered anaemic. Alphathalassaemia, Hb variants and G6PD deficiency were observed in 33.9%, 28.3% and 23.6%, respectively. ID was highly prevalent in women (32.0%; men, 3.9%). The population fraction of anaemia cases attributable to ID was 29.0% (alpha-thalassaemia, 13.6%; G6PD deficiency, 13.5%). Nevertheless, excluding ID, alpha-thalassaemia, G6PD deficiency and sickle cell disease, anaemia prevalence remained high (women, 18.4%; men, 6.5%), and was also high when applying uncensored thresholds proposed for African Americans (females, 19.3%; males, 7.8%).conclusions Iron deficiency and erythrocyte polymorphisms are common among first-generation Ghanaian migrants but explain only part of the increased prevalence of anaemia. Common Hb thresholds for the definition of anaemia may not be appropriate for this group.

A balanced proinflammatory cytokine response to Plasmodium ssp. infection is crucial to control the disease outcome. To elucidate the effect of cytokines and Plasmodium falciparum-infected erythrocytes on the regulation of interleukin (IL)-6 receptor (IL-6R), ciliary neurotrophic factor alpha (CNTFR-α) and glycoprotein (gp)130 in natural killer (NK) cells in the context of malaria, we assessed their gene expression and surface expression in NK92 cells. P. falciparum alone did not alter gene expression of the investigated receptors in NK92 cells. Analysis revealed a low effect of IL-6 on IL-6R surface expression in NK92 cells. However, at transcriptional level, a downregulation of IL-6R was observed following IL-6 stimulation. Thus, IL-6 might act within a negative feedback loop to terminate signal transduction by downregulating IL-6R expression. Additionally, we observed that IL-6R and CNTFR-α surface expression were regulated by a combination of IL-2, 12, and 18, and gp130 was influenced by interferon-α. Our results show that the IL-6 family receptors in NK92 cells are not directly influenced by P. falciparum. However, cytokines usually derived from accessory cells during malaria episodes may regulate IL-6 receptor signaling pathways. This finding encourages future studies in a more physiological context and with primary cells isolated from humans with and without malaria.

Abstract. The p53 protein is a key cell-signaling mediator integrating host responses to various types of stress. A common polymorphism of the encoding TP53 gene (codon 72, Pro Arg, rs1042522) is associated with susceptibility to virus-related and other cancers. The p53 has also been shown to be central for successful Plasmodium liver stage infection. We examined whether the polymorphism is associated with P. falciparum infection in Ghanaian primiparae and Rwandan children. The allele frequency of TP53 codon 72 Arg was 0.30 among 314 Ghanaian primiparae and 0.31 among 545 Rwandan children, respectively, and it was not associated with infection prevalence or parasite density. This does not exclude p53 to be of pathophysiological relevance in malaria but argues against a major respective role of the TP53 codon 72 polymorphism.In view of the ongoing burden of malaria, improved knowledge of pathophysiological mechanisms may provide novel targets for prevention and treatment.1 Recently, the p53 tumor suppressor protein, a central host cell-signaling factor, has been shown to be critical for successful Plasmodium liver stage infection.2 As a transcription factor, p53 responds to various stimuli to induce apoptosis or cell cycle arrest, or to integrate a variety of other host responses.3,4 Plasmodium liver stage parasites suppress p53 thereby promoting survival of the infected hepatocyte. Conversely, increased levels of p53 counterbalance this suppression and reduce liver stage parasite burden. 2The TP53 gene, encoding p53, shows a common single nucleotide polymorphism at codon 72 (proline to arginine, Pro Arg, rs1042522), conferring various functional consequences including the Arg allele being more effective at inducing apoptosis. 5 This allele has been associated with altered susceptibility to several virus-related and other cancers. 4,6 Notably, indirect evidence for a malaria-protective role of the TP53 codon 72 Arg allele is derived from a small study in Sardinia. 7 We, therefore, examined the distribution of the TP53 codon 72 alleles in two African populations with or without P. falciparum infection, i.e., placental P. falciparum infection in Ghanaian primiparae, and largely asymptomatic P. falciparum infection among Rwandan children.Socio-demographic, clinical, and parasitological characteristics of the two cross-sectional studies and the study groups have been reported elsewhere. 8,9 In brief, 314 primiparous pregnant women were recruited in southern Ghana of whom two-thirds (by polymerase chain reaction [PCR]) had largely asymptomatic placental P. falciparum infection (i.e., only 6.3% of these were febrile), which nevertheless was associated with maternal anemia, low birth weight, and preterm delivery. 8 The second group involved 545 children 5 years of age randomly selected from 24 rural villages in southern highland Rwanda of whom 16.1% were P. falciparum infected (by PCR; 2.9% categorized as symptomatic malaria defined as a positive blood film plus fever, or a history of fever within the preceding 48 hours...

In this group we would like to answer the question why people show a different response against certain pathogens. In many infections the course of the disease can range from asymptomatic carriage to the severest forms even death. In the past we have analysed candidate genes and their role in the course of malaria and could detect some polymorphisms influencing infectious diseases in the genes encoding NOS2, MBL2, IFNa, FCN2, and receptors for IFNg and IFNa. Having worked initially mainly on malaria we broadened our spectrum also to other infectious diseases like hepatitis B, Leprosy, schistosomiasis. Here we give a short overview about ongoing projects.