Liu Fang-Fang, Li Ke
Department of Pathology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
School of Life and Health Sciences, Hainan Province Key Laboratory of One Health, Collaborative Innovation Center of One Health, Hainan University, Haikou, Hainan, China.
Front Cell Infect Microbiol. 2025 Sep 5;15:1679337. doi: 10.3389/fcimb.2025.1679337. eCollection 2025.
Malaria associated anemia is increasingly recognized as a consequence not only of red cell destruction but of profound, parasite driven disruption of erythropoiesis within the bone marrow niche. Here, we synthesize recent , ex vivo, clinical and postmortem studies to construct a unified mechanistic framework in which four interlocking pathways converge to produce dyserythropoiesis. First, a cytokine storm dominated by IL-6, TNF-α, IFN-γ and MIF suppresses erythropoietin synthesis, upregulates hepcidin and diverts erythroid progenitors toward myeloid fate via destabilization of GATA-1. Second, hemozoin crystals catalyze Fenton chemistry and lipid peroxidation, generating 4-hydroxynonenal adducts that cripple GATA-1 and trigger mitochondrial apoptosis of erythroblasts. Third, parasites preferentially infect orthochromatic erythroblasts, prolonging a 10-day gametocyte maturation cycle beyond the host's 3-4-day enucleation window and releasing extracellular vesicles that arrest terminal differentiation. Fourth, hemozoin-laden macrophages remodel erythroblastic islands, precipitating local iron restriction and sustained oxidative stress. Together these processes create a "developmental sanctuary" that favors parasite persistence while crippling host erythropoiesis. We also highlight emerging single-cell and spatial-omics technologies, together with 3-D bone-marrow organoids, as platforms for dissecting spatiotemporal parasite-host interactions and for testing niche-targeted therapies aimed at reversing ineffective erythropoiesis.
疟疾相关贫血越来越被认为不仅是红细胞破坏的结果，而且是寄生虫驱动的骨髓微环境中红细胞生成严重紊乱的结果。在此，我们综合了近期的体外、临床和尸检研究，构建了一个统一的机制框架，其中四条相互关联的途径汇聚在一起，导致红细胞生成异常。首先，以IL-6、TNF-α、IFN-γ和MIF为主导的细胞因子风暴抑制促红细胞生成素的合成，上调铁调素，并通过使GATA-1不稳定，将红系祖细胞导向髓系命运。其次，疟原虫色素晶体催化芬顿化学反应和脂质过氧化，生成4-羟基壬烯醛加合物，使GATA-1失活，并触发成红细胞的线粒体凋亡。第三，疟原虫优先感染正染性成红细胞，将10天的配子体成熟周期延长至宿主3-4天的去核窗口之外，并释放细胞外囊泡，从而阻止终末分化。第四，载有疟原虫色素的巨噬细胞重塑成红细胞岛，导致局部铁限制和持续的氧化应激。这些过程共同创造了一个“发育避难所”，有利于疟原虫的持续存在，同时削弱宿主的红细胞生成。我们还强调了新兴的单细胞和空间组学技术，以及三维骨髓类器官，作为剖析时空寄生虫-宿主相互作用以及测试旨在逆转无效红细胞生成的针对微环境的疗法的平台。
