Insights into malaria susceptibility using genome-wide data on 17,000 individuals from Africa, Asia and Oceania

The human genetic factors that affect resistance to infectious disease are poorly understood. Here we report a genome-wide association study in 17,000 severe malaria cases and population controls from 11 countries, informed by sequencing of family trios and by direct typing of candidate loci in an additional 15,000 samples. We identify five replicable associations with genome-wide levels of evidence including a newly implicated variant on chromosome 6. Jointly, these variants account for around one-tenth of the heritability of severe malaria, which we estimate as -23% using genome-wide genotypes. We interrogate available functional data and discover an erythroid-specific transcription start site underlying the known association in ATP2B4, but are unable to identify a likely causal mechanism at the chromosome 6 locus. Previously reported HLA associations do not replicate in these samples. This large dataset will provide a foundation for further research on thegenetic determinants of malaria resistance in diverse populations.Peer reviewe

A mathematical model for malaria involving differential susceptibility, exposedness and infectivity of human host

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Self-assembled biotransesterified cyclodextrins as Artemisinin nanocarriers - I: Formulation, lyoavailability and <i>in vitro</i> antimalarial activity assessment

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IMMUNE RESPONSES TO HELMINTH PARASITE ANTIGENS IN MALARIA ENDEMIC POPULATIONS

Co-infection with P. falciparum and helminths in Sub-Saharan Africa could modulate the immune response towards the parasites as well as the individual susceptibility to clinical forms. Our aim is to investigate the impact of helminth infections on immune responses and susceptibility to malaria in different ethnic groups from Burkina Faso (Modiano et al. PNAS 1996). The objectives of this work are: i) to measure immunoglobulins against helminth parasite antigens in plasma samples (N=288) collected among Mossi, Fulani and Rimaibe rural communities; ii) to assess differences in relation to age, sex, village, ethnic group, infection with P. falciparum; iii) to assess correlation with antibodies against malaria antigens (CSP, MSP1, MSP2, AMA1) and total IgE. Measurements of IgG against Strongyloides, Taenia spp. and filarial infections are ongoing. A custom ELISA protocol was used to measure IgG against Schistosoma haematobium Soluble Egg Antigen (SEA). The prevalence of anti-SEA IgG is 63%, in line with the prevalence of S. haematobium infection reported for the same area of Burkina Faso (55-85%, Traore et al. Medecine d'Afrique Noire 1990). The prevalence is zero in infants, increases during childhood to reach its peak in teens, and decreases from 20 years onwards. Females show a lower prevalence than males (P=0.003). Differences in prevalence are not observed among villages or ethnic groups, but the Fulani show lower levels of anti-SEA IgG (P=0.0001) suggesting that lighter S. haematobium infections occur in the ethnic group known for a marked lower susceptibility to P. falciparum. Individuals infected with P. falciparum show higher levels of anti-SEA IgG (P=0.0002). A positive correlation exist between anti-SEA IgG, total IgE (P<0.0001) and anti-CSP IgG (P=0.009). These results suggest that common host factors may affect susceptibility to P. falciparum and S. haematobium (e.g. age, ethnicity) and warrant further investigation into the immunological cross-talk between the two parasites

Efficacy and safety of the mosquitocidal drug ivermectin to prevent malaria transmission after treatment: a double-blind, randomized, clinical trial

Item does not contain fulltextBACKGROUND: Artemisinin combination therapy effectively clears asexual malaria parasites and immature gametocytes but does not prevent posttreatment malaria transmission. Ivermectin (IVM) may reduce malaria transmission by killing mosquitoes that take blood meals from IVM-treated humans. METHODS: In this double-blind, placebo-controlled trial, 120 asymptomatic Plasmodium falciparum parasite carriers were randomized to receive artemether-lumefantrine (AL) plus placebo or AL plus a single or repeated dose (200 microg/kg) of ivermectin (AL-IVM1 and AL-IVM2, respectively). Mosquito membrane feeding was performed 1, 3, and 7 days after initiation of treatment to determine Anopheles gambiae and Anopheles funestus survival and infection rates. RESULTS: The AL-IVM combination was well tolerated. IVM resulted in a 4- to 7-fold increased mortality in mosquitoes feeding 1 day after IVM (P < .001). Day 7 IVM plasma levels were positively associated with body mass index (r = 0.57, P < .001) and were higher in female participants (P = .003), for whom An. gambiae mosquito mortality was increased until 7 days after a single dose of IVM (hazard rate ratio, 1.34 [95% confidence interval, 1.07-1.69]; P = .012). Although we found no evidence that IVM reduced Plasmodium infection rates among surviving mosquitoes, the mosquitocidal effect of AL-IVM1 and AL-IVM2 resulted in 27% and 35% reductions, respectively, in estimated malaria transmission potential during the first week after initiation of treatment. CONCLUSIONS: We conclude that IVM can be safely given in combination with AL and can reduce the likelihood of malaria transmission by reducing the life span of feeding mosquitoes. CLINICAL TRIALS REGISTRATION: NCT0160325