Anyona Samuel, Cheng Qiuying, Guo Yan, Raballah Evans, Hurwitz Ivy, Onyango Clinton, Seidenberg Philip, Schneider Kristan, Lambert Christophe, McMahon Benjamin, Ouma Collins, Perkins Douglas
Maseno University School of Medicine.
Center for Global Health, University of New Mexico.
Res Sq. 2023 Jul 19:rs.3.rs-3150748. doi: 10.21203/rs.3.rs-3150748/v1.
This study on severe malarial anemia (SMA: Hb < 6.0 g/dL), a leading global cause of childhood morbidity and mortality, analyzed the entire expressed transcriptome in whole blood from children with non-SMA (Hb ≥ 6.0 g/dL, n = 41) and SMA (n = 25). Analyses revealed 3,420 up-regulated and 3,442 down-regulated transcripts, signifying impairments in host inflammasome activation, cell death, innate immune responses, and cellular stress responses in SMA. Immune cell profiling showed a decreased antigenic and immune priming response in children with SMA, favoring polarization toward cellular proliferation and repair. Enrichment analysis further identified altered neutrophil and autophagy-related processes, consistent with neutrophil degranulation and altered ubiquitination and proteasome degradation. Pathway analyses highlighted SMA-related alterations in cellular homeostasis, signaling, response to environmental cues, and cellular and immune stress responses. Validation with a qRT-PCR array showed strong concordance with the sequencing data. These findings identify key molecular themes in SMA pathogenesis, providing potential targets for new malaria therapies.
本研究针对严重疟疾贫血（SMA：血红蛋白<6.0 g/dL）展开，这是全球儿童发病和死亡的主要原因之一。研究分析了非SMA儿童（血红蛋白≥6.0 g/dL，n = 41）和SMA儿童（n = 25）全血中的整个表达转录组。分析发现3420个转录本上调，3442个转录本下调，这表明SMA患者的宿主炎性小体激活、细胞死亡、先天免疫反应和细胞应激反应存在损伤。免疫细胞分析显示，SMA儿童的抗原性和免疫启动反应降低，有利于向细胞增殖和修复方向极化。富集分析进一步确定了中性粒细胞和自噬相关过程的改变，这与中性粒细胞脱颗粒以及泛素化和蛋白酶体降解改变一致。通路分析突出了SMA相关的细胞稳态、信号传导、对环境线索的反应以及细胞和免疫应激反应的改变。用qRT-PCR阵列进行验证显示与测序数据高度一致。这些发现确定了SMA发病机制中的关键分子主题，为新型疟疾治疗提供了潜在靶点。
