Plasmodium falciparum-associated severe malarial anemia [SMA, hemoglobin (Hb)<5.0g/dL] is a leading cause of morbidity and mortality in African children. Examination of the host immune response and underlying genotypic traits that condition SMA can offer an improved understanding of malaria pathogenesis. Previous investigations have suggested that SMA in high transmission regions is due to impaired erythropoiesis hemolysis and erythrocyte destruction. In the holoendemic transmission region of western Kenya our studies have shown that dyserythropoiesis drives and conditions SMA through poorly understood molecular pathways. Pediatric studies have shown that early erythroid cell populations as well as reticulocyte production is greatly reduced in children with SMA. The driving force of malaria pathogenesis is multifaceted and the mechanisms that promote erythropoietic dysfunction are still being understood. We hypothesize that SMA is conditioned by the immune response through underlying genetic factors that influence erythropoiesis resulting in a exacerbated disease state. To that end the studies described in this manuscript focus on the inflammatory chemokines, monokine induced by gamma (MIG) and interferon gamma-induced protein (IP10) as well as the hemoglobin-coding gene, hemoglobin alpha 2 (HBA2) in the context of SMA and dyserythropoiesis. The first study described herein, identified MIG and IP10 as important mediators associated with SMA. In this study we examined circulating MIG and I10 profiles in non-SMA and SMA children and then genotyped and constructed haplotypes between 5 individual polymorphic variants within the promoter regions for the MIG and IP10 for the entire study cohort (n=1,600). The second study described in this manuscript, utilized a global approach where genome wide association studies as well as whole-genome transcriptomics identified novel molecular pathways between non-SMA and SMA children. These analyses revealed that the expression of the hemoglobin-coding gene, HBA2 is significantly modulated between populations. We then examined these findings closer and genotyped a larger population for 2 promoter variants with the same approach described in the first study. Regression analysis of genotype and haplotype data for both studies revealed significant findings where several variant haplotypes correlated with SMA outcomes and erythropoietic response. Lastly, we used an in vitro model of erythropoiesis to determine if recombinant human MIG and IP10 as well as pediatric study serum (non-SMA and SMA) influence erythroid function. Our results from these studies revealed that pediatric serum from children with SMA influenced cell viability as well as erythroid lineage when we examined cell surface erythroid markers. A similar result was also seen in cell populations that were treated with the inflammatory mediators, MIG, and IP10 which reflected our proposal that serum from children with SMA and inflammatory mediators (MIG and IP10) infringe upon erythroid cell maturation and viability in vivo. Together the results from these studies independently verify the influence of biomolecular markers and mediators on SMA outcomes.
malaria anemia pediatric infectious disease
Level of Degree
Biomedical Sciences Graduate Program
First Committee Member (Chair)
Second Committee Member
Third Committee Member
Karim, Zachary. "Biomolecular signatures of severe malarial anemia." (2016). https://digitalrepository.unm.edu/biom_etds/131