Hemoglobin Genotypes Modulate Inflammatory Response to Plasmodium Infection.

Keri Oxendine Harp,Joshua L Hood,Michael D Wilson,Jonathan K Stiles,Yvonne Dei-Adomakoh,Andrew A Adjei,Adel Driss,Felix Botchway

doi:10.3389/fimmu.2020.593546

Abstract

In 2018, 228 million cases and 405,000 malaria-associated deaths were reported worldwide with a majority being in Africa. A wide range of factors, including parasitemia, host immunity, inflammatory responses to infection, and host hemoglobin genotype, mediate the severity of malaria. Among the hemoglobinopathies, hemoglobin S (HbS) is caused by a single amino acid substitution of Glutamic Acid replaced by Valine at the sixth position of the beta-globin chain (E6V). Hemoglobin C (HbC) on the other hand, involves a single amino acid substitution of Glutamic Acid by a Lysine (E6K), which has received the most attention. These substitutions alter the stability of Hb leading to wide-ranging hematological disorders. The homozygous state of hemoglobin S (HbSS) results in sickle cell anemia (SCA) whereas the heterozygous state (HbAS) results in sickle cell trait (SCT). Both mutations are reported to mediate the reduction in the severity and fatality of Plasmodium falciparum malaria. The mechanism underlying this protection is poorly understood. Since both malaria and sickle cell disease (SCD) are associated with the destruction of erythrocytes and widespread systemic inflammation, identifying which inflammatory factor(s) mediate susceptibility of individuals with different hemoglobin genotypes to Plasmodium infection could result in the discovery of new predictive markers and interventions against malaria or SCD severity. We hypothesized that hemoglobin genotypes modulate the inflammatory response to Plasmodium infection. We conducted a cross-sectional study in Ghana, West Africa, between 2014 and 2019 to ascertain the relationships between blood inflammatory cytokines, Plasmodium infection, and hemoglobin genotype. A total of 923 volunteers were enrolled in the study. A total of 74, age and sex-matched subjects were identified with various genotypes including HbAS, HbAC, HbSS, HbSC, HbCC, or HbAA. Complete blood counts and serum inflammatory cytokine expression levels were assessed. The results indicate that differential expression of CXCL10, TNF-α, CCL2, IL-8, and IL-6 were tightly linked to hemoglobin genotype and severity of Plasmodium infection and that these cytokine levels may be predictive for susceptibility to severe malaria or SCD severity.

Highlights

An estimated 228 million cases and 405,000 deaths associated with malaria worldwide were reported in 2018 with 93% of the cases occurring in Africa [1]
Inflammatory chemokines CXCL10, CCL2, and CCL3 as well as cytokines, tumor necrosis factor alpha (TNF-a), IL-8, and IL-6 were differentially expressed in individuals with different hemoglobin genotypes that were infected or uninfected with malaria parasites (Figures 1, Supplement Figure 1)
CXCL10, CCL3, TNF-a, and IL-6 levels were tightly associated with white blood cells (WBCs), red blood cells (RBCs) counts, and Hb levels (Figure 3, Supplement Tables 4–6)

Summary

Introduction

An estimated 228 million cases and 405,000 deaths associated with malaria worldwide were reported in 2018 with 93% of the cases occurring in Africa [1]. Hemoglobin C (HbC), is associated with a mutation in the same codon GAG!AAG, which causes a single amino acid substitution of Glutamic Acid by a Lysine (E6K) [5, 6]. These mutations alter the stability of Hb resulting in a variety of clinical symptoms. Identifying the inflammatory factor(s) mediating susceptibility of individuals with different hemoglobin genotypes to Plasmodium infection could lead to the discovery of new predictive markers and interventions against malaria or SCD severity [1, 2, 8, 10, 11]

Methods

Results

Conclusion