Malaria Pathogenesis in young children and vaccine discovery

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

In FY21, we reported human and animal studies to investigate malaria immunology and pathogenesis. Highlighted in this years summary are results from our publications. 1. Kabyemela ER, Fried M, Kurtis JD, Moses G, Gorres JP, Muehlenbachs A, Duffy PE: Fetal Cytokine Balance, Erythropoietin and Thalassemia but Not Placental Malaria Contribute to Fetal Anemia Risk in Tanzania. Front Immunol 2021, 12:624136. In a Tanzanian birth cohort study designed to elucidate the pathogenesis of severe malaria in young infants, we performed a cross-sectional analysis of risk factors for fetal anemia. We determined PM status, newborn red cell abnormalities, and maternal and cord blood levels of iron regulatory proteins, erythropoietin (EPO), cytokines and cytokine receptors. We examined the relationship between these factors and fetal anemia. This study from an area of high malaria transmission provided evidence that 1) fetal alpha(+)-thalassemia and cytokine balance, but not PM at delivery, are related to fetal anemia; 2) maternal iron deficiency increases the risk that other factors may cause fetal anemia; and 3) fetal anemia has a multifactorial etiology that may require a variety of interventions, although measures that reduce maternal iron deficiency may be generally beneficial. 2. Muriuki JM, Mentzer AJ, Mitchell R, Webb EL, Etyang AO, Kyobutungi C, Morovat A, Kimita W, Ndungu FM, Macharia AW, et al: Malaria is a cause of iron deficiency in African children. Nat Med 2021, 27:653-658. Malaria and iron deficiency (ID) are common and interrelated public health problems in African children. Observational data suggest that interrupting malaria transmission reduces the prevalence of ID(1). To test the hypothesis that malaria might cause ID, we used sickle cell trait (HbAS, rs334 ), a genetic variant that confers specific protection against malaria(2), as an instrumental variable in Mendelian randomization analyses. HbAS was associated with a 30% reduction in ID among children living in malaria-endemic countries in Africa (n = 7,453), but not among individuals living in malaria-free areas (n = 3,818). Genetically predicted malaria risk was associated with an odds ratio of 2.65 for ID per unit increase in the log incidence rate of malaria. This suggests that an intervention that halves the risk of malaria episodes would reduce the prevalence of ID in African children by 49%. 3. Prokunina-Olsson L, Morrison RD, Obajemu A, Mahamar A, Kim S, Attaher O, Florez-Vargas O, Sidibe Y, Onabajo OO, Hutchinson AA, et al: IFN-lambda4 is associated with increased risk and earlier occurrence of several common infections in African children. Genes Immun 2021, 22:44-55. Genetic polymorphisms within the IFNL3/IFNL4 genomic region, which encodes type III interferons, have been strongly associated with clearance of hepatitis C virus. We hypothesized that type III interferons might be important for the immune response to other pathogens as well. In a cohort of 914 Malian children, we genotyped functional variants IFNL4-rs368234815, IFNL4-rs117648444, and IFNL3-rs4803217 and analyzed episodes of malaria, gastrointestinal, and respiratory infections recorded at 30,626 clinic visits from birth up to 5 years of age. Our results implicate IFN-lambda4 and not IFN-lambda3 as the primary functional cause of genetic associations with increased overall risk and younger age at first clinical episodes but not with recurrence or intensity of several common pediatric infections.