Harp Keri Oxendine, Botchway Felix, Dei-Adomakoh Yvonne, Wilson Michael D, Hood Joshua L, Adjei Andrew A, Stiles Jonathan K, Driss Adel
Department of Physiology, Morehouse School of Medicine, Atlanta, GA, United States.
Department of Pathology, Korle-Bu Teaching Hospital, University of Ghana Medical School, Accra, Ghana.
Front Immunol. 2020 Dec 23;11:593546. doi: 10.3389/fimmu.2020.593546. eCollection 2020.
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 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 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 infection. We conducted a cross-sectional study in Ghana, West Africa, between 2014 and 2019 to ascertain the relationships between blood inflammatory cytokines, 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 infection and that these cytokine levels may be predictive for susceptibility to severe malaria or SCD severity.
2018年，全球报告了2.28亿例疟疾病例和40.5万例与疟疾相关的死亡，其中大部分发生在非洲。多种因素，包括寄生虫血症、宿主免疫力、对感染的炎症反应以及宿主血红蛋白基因型，介导了疟疾的严重程度。在血红蛋白病中，血红蛋白S（HbS）是由β珠蛋白链第六位的谷氨酸被缬氨酸单氨基酸取代（E6V）引起的。另一方面，血红蛋白C（HbC）涉及谷氨酸被赖氨酸单氨基酸取代（E6K），这受到了最多关注。这些取代改变了Hb的稳定性，导致广泛的血液学紊乱。血红蛋白S的纯合状态（HbSS）导致镰状细胞贫血（SCA），而杂合状态（HbAS）导致镰状细胞性状（SCT）。据报道，这两种突变都介导了疟疾严重程度和死亡率的降低。这种保护的潜在机制尚不清楚。由于疟疾和镰状细胞病（SCD）都与红细胞破坏和广泛的全身炎症有关，确定哪些炎症因子介导不同血红蛋白基因型个体对感染的易感性，可能会发现针对疟疾或SCD严重程度的新预测标志物和干预措施。我们假设血红蛋白基因型调节对感染的炎症反应。我们于2014年至2019年在西非加纳进行了一项横断面研究，以确定血液炎症细胞因子、感染和血红蛋白基因型之间的关系。共有923名志愿者参与了该研究。总共确定了74名年龄和性别匹配的受试者，他们具有各种基因型，包括HbAS、HbAC、HbSS、HbSC、HbCC或HbAA。评估了全血细胞计数和血清炎症细胞因子表达水平。结果表明，CXCL10、TNF-α、CCL2、IL-8和IL-6的差异表达与血红蛋白基因型和感染严重程度紧密相关，并且这些细胞因子水平可能预测对严重疟疾或SCD严重程度的易感性。
