Genetic susceptibility to malaria getting complex

The evolution of sickle cell disease illustrates the powerful selective pressure of malaria in Africa, and candidate gene association studies have identified more than ten putative susceptibility determinants involving erythrocytes or the immune system. Efforts at present are aimed at understanding the functional basis of known associations, and at developing both linkage- and association-based approaches of genome-wide screening for novel susceptibility factors.     

Safety of chloroquine in chemosuppression of malaria during pregnancy.

A cohort of 169 births to women who were exposed throughout pregnancy to chloroquine 300 mg base once a week for chemosuppression of malaria was studied. The birth defects in this cohort were compared with those in a control group of 454 births to women who were not exposed to chloroquine, most of whom lived in non-malarious areas. The proportion of birth defects in the exposed group was not significantly different from that in the control group. This observation must be considered within the limitations of the study, which could detect only a strong teratogenic effect. It could not exclude risks lower than a 5.7-fold increase in the incidence of birth defects when chloroquine was used. Women using chloroquine during pregnancy for chemosuppression of malaria can be reassured that it is not a strong teratogen, but if it is to be used the risk of developing malaria should be balanced against the lack of data to determine whether it carries a low teratogenic risk.     

Plasmodium falciparum malaria mimicking autoimmune hemolytic anemia during pregnancy.

A 30-year-old woman contracted Plasmodium falciparum malaria in the first trimester of her pregnancy while taking chloroquine for malaria prophylaxis. Her illness was characterized by hemolytic anemia with IgG1 coating of the surface of the erythrocytes and IgG3 in her serum. The hemolysis subsided following treatment of the malaria infection early in the third trimester. She delivered at term an infant who had hypoplasia of the right tibia and fibula and absence of the fifth ray of the right foot. The hemolytic process was attributed to the malaria infection, and the birth defect may have been related to the antimalarial therapy in the first trimester of pregnancy.     

Malaria during pregnancy: a priority area of malaria research and control

More than 2000 million people live in areas where malaria transmission occurs and are therefore at risk of being infected. It follows that 1000 million people are exposed to the risks of malaria when pregnant. Although the special features of malaria during pregnancy have been recognized for nearly a century(1), it is only recently that it is being considered as a priority for malaria research and control, as discussed here by Clara Menendez.     

N-acetylglucosaminyltransferase V-deficiency increases susceptibility to murine malaria

It is considered that several glycoproteins on erythrocytes in mammalian species are involved in malaria parasite infection. To elucidate the role of N-glycans on malaria parasite infection, we induced experimental murine malaria infection (using Plasmodium berghei ANKA) in mice deficient in N-acetylglucosaminyltransferase V (Mgat5), which is one of the enzymes involved in β1,6-GlcNAc N-glycan biosynthesis. After infection, Mgat5^-/- mice showed severe body weight loss and parasitemia compared with wild-type mice. The Mgat5^-/- mice, but not wild-type mice, also showed severe pathology accompanied by marked infiltration of plasma cells into the lungs and liver. These results suggest that β1,6-GlcNAc N-glycans on/in host erythrocytes may interfere with invasion of the parasites and progression to severe malaria.     

Biomarkers for susceptibility to infection and disease severity in human malaria

Malaria remains a major infectious disease that affects millions of people. Once infected with Plasmodium parasites, a host can develop a broad range of clinical presentations, which result from complex interactions between factors derived from the host, the parasite and the environment. Intense research has focused on the identification of reliable predictors for exposure, susceptibility to infection and the development of severe complications during malaria. Although most promising markers are based on the current understanding of malaria immunopathogenesis, some are also focused more broadly on mechanisms of tissue damage and inflammation. Taken together, these markers can help optimise therapeutic strategies and reduce disease burden. Here, we review the recent advances in the identification of malarial biomarkers, focusing on those related to parasite exposure and disease susceptibility. We also discuss priorities for research in biomarkers for severe malaria.     

Glucose tolerance in ewes and susceptibility to pregnancy toxaemia

Intravenous glucose tolerance tests were undertaken on fed twin-pregnant ewes at about 120 days of gestation by injecting 0.4 g glucose per kilogram of live weight, then measuring glucose and insulin concentrations in plasma over the next 2 h. An insulin resistance index was calculated from the product of T1/2 for glucose disappearance and the plasma insulin concentrations integrated over time. Approximately 10 days later, the ewes were starved to induce ovine pregnancy toxaemia. During this period, the course of the hypoglycaemia and ketonaemia were followed by measuring metabolite concentrations in jugular blood samples obtained every 2-3 days. The existence of dehydration, acid-base imbalance and renal failure was also determined from packed cell volumes, serum CO2 content and serum concentrations of urea, creatinine and inorganic phosphate. Ewes that became recumbent and moribund with the disease were classified as susceptible whereas those asymptomatic after 10 days were classified as non-susceptible. Seven susceptible ewes had significantly higher insulin resistance indices (2043 +/- 670 s.d.) than did six non-susceptible ewes (1261 +/- 433 s.d.). It was concluded that poor control of glucose homeostasis may be an important predisposing factor in pathogenesis of the disease.     

Neurocognitive outcomes in Malawian children exposed to malaria during pregnancy: An observational birth cohort study

BackgroundAnnually 125 million pregnancies are at risk of malaria infection. However, the impact of exposure to malaria in pregnancy on neurodevelopment in children is not well understood. We hypothesized that malaria in pregnancy and associated maternal immune activation result in neurodevelopmental delay in exposed offspring.Methods and findingsBetween April 2014 and April 2015, we followed 421 Malawian mother–baby dyads (median [IQR] maternal age: 21 [19, 28] years) who were previously enrolled (median [IQR] gestational age at enrollment: 19.7 [17.9, 22.1] weeks) in a randomized controlled malaria prevention trial with 5 or 6 scheduled assessments of antenatal malaria infection by PCR. Children were evaluated at 12, 18, and/or 24 months of age with cognitive tests previously validated in Malawi: the Malawi Developmental Assessment Tool (MDAT) and the MacArthur–Bates Communicative Development Inventories (MCAB-CDI). We assessed the impact of antenatal malaria (n [%] positive: 240 [57.3]), placental malaria (n [%] positive: 112 [29.6]), and maternal immune activation on neurocognitive development in children. Linear mixed-effects analysis showed that children exposed to antenatal malaria between 33 and 37 weeks gestation had delayed language development across the 2-year follow-up, as measured by MCAB-CDI (adjusted beta estimate [95% CI], −7.53 [−13.04, −2.02], p = 0.008). Maternal immune activation, characterized by increased maternal sTNFRII concentration, between 33 and 37 weeks was associated with lower MCAB-CDI language score (adjusted beta estimate [95% CI], −8.57 [−13.09, −4.06], p < 0.001). Main limitations of this study include a relatively short length of follow-up and a potential for residual confounding that is characteristic of observational studies.ConclusionsThis mother–baby cohort presents evidence of a relationship between malaria in pregnancy and neurodevelopmental delay in offspring. Malaria in pregnancy may be a modifiable risk factor for neurodevelopmental injury independent of birth weight or prematurity. Successful interventions to prevent malaria during pregnancy may reduce the risk of neurocognitive delay in children.

Andrea Weckman and co-workers study associations between children’s neurodevelopmental outcomes and malaria in pregnancy.     

Host response to malaria during pregnancy: placental monocyte recruitment is associated with elevated beta chemokine expression

Malaria during pregnancy is associated with poor birth outcomes, particularly low birth weight. Recently, monocyte infiltration into the placental intervillous space has been identified as a key risk factor for low birth weight. However, the malaria-induced chemokines involved in recruiting and activating placental monocytes have not been identified. In this study, we determined which chemokines are elevated during placental malaria infection and the association between chemokine expression and placental monocyte infiltration. Placental malaria infection was associated with elevations in mRNA expression of three beta chemokines, macrophage-inflammatory protein 1 (MIP-1) alpha (CCL3), monocyte chemoattractant protein 1 (MCP-1; CCL2), and I-309 (CCL1), and one alpha chemokine, IL-8 (CXCL8); all correlated with monocyte density in the placental intervillous space. Placental plasma concentrations of MIP-1 alpha and IL-8 were increased in women with placental malaria and were associated with placental monocyte infiltration. By immunohistochemistry, we localized placental chemokine production in malaria-infected placentas: some but not all hemozoin-laden maternal macrophages produced MIP-1 beta and MCP-1, and fetal stromal cells produced MCP-1. In sum, local placental production of chemokines is increased in malaria, and may be an important trigger for monocyte accumulation in the placenta.     

Fcgamma receptor IIA and IIIB polymorphisms are associated with susceptibility to cerebral malaria

Human FcgammaRIIA and FcgammaRIIIB exhibit genetic polymorphisms, FcgammaRIIA-131H/R and FcgammaRIIIB-NA1/NA2, coding for different capacities for IgG binding and phagocytosis. Recently, FcgammaRIIA-131R was reported to be associated with protection against high-density Plasmodium falciparum infection in Kenya. Furthermore, FcgammaRIIIB-NA1/NA2 polymorphism was shown to influence FcgammaRIIA function in an allele-specific manner. In this study, we examined a possible association of FcgammaRIIA-131H/R and FcgammaRIIIB-NA1/NA2 polymorphisms with malaria severity in 107 cerebral malaria patients, 157 non-cerebral severe malaria patients, and 202 mild malaria controls living in northwest Thailand. This study reveals that, with the FcgammaRIIIB-NA2 allele, the FcgammaRIIA-131H/H genotype is associated with susceptibility to cerebral malaria (OR 1.85, 95% CI 1.14-3.01; P=0.012), although these polymorphisms are not individually involved in the disease severity. Our results suggest that FcgammaRIIA-131H/R and FcgammaRIIIB-NA1/NA2 polymorphisms have an interactive effect on host defense against malaria infection.     

Predictors of asymptomatic malaria in pregnancy

A number of studies have described malaria parasitaemia in pregnancy as mostly an asymptomatic condition, however information about predictors of asymptomatic malaria is largely lacking. We investigated the prevalence of symptoms and potential predictors of asymptomatic malaria in pregnant women attending Ante-Natal Clinic (ANC) of two public maternity hospitals in Ibadan, Southwest-Nigeria. Demographic data, history of previous and present pregnancy were obtained from the subjects and blood smears were examined for malaria diagnosis by light microscopy. Seventy - seven parasitaemic pregnant women attending antenatal clinic were evaluated for presence or absence of symptoms that may be associated with malaria. Thirty-seven women (48%) were asymptomatic whereas 40 (52%) presented with symptoms such as weakness, headache and general body ache and fever. Parasite density was significantly higher in symptomatic patients (P = 0.042), while asymptomatic patients had low level parasitaemia but significantly higher gametocyte carriage (P = 0.035). In conclusion, parasitaemic pregnant women resident in hyper- or holo-endemic malaria region are likely to be symptomatic with increasing density of the parasitaemia.