Harbuzariu Adriana, Nti Annette, Harp Keri Oxendine, Cespedes Juan C, Driss Adel, Stiles Jonathan K
Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA.
iScience. 2022 May 14;25(6):104407. doi: 10.1016/j.isci.2022.104407. eCollection 2022 Jun 17.
Human cerebral malaria (HCM) is a severe complication of infection that is characterized by capillary occlusions, rupture of the blood-brain barrier (BBB), perivascular cellular injury, and brain swelling. histidine-rich protein 2 (HRP2), a byproduct of parasitized red blood cell (pRBC) lysis, crosses the BBB when compromised to cause brain injury. We hypothesized that HRP2-induced neuronal damage can be attenuated by Neuregulin-1 (NRG1), an anti-inflammatory neuroprotective factor. Using brain cortical organoids, we determined that HRP2 upregulated cell death and inflammatory markers and disorganized brain organoid tissue. We identified toll-like receptors (TLR1 and 2) as potential mediators of HRP2-induced cellular damage and inflammation. Exogenous acute treatment of organoids with NRG1 attenuated HRP2 effects. The results indicate that HRP2 mediates malaria-associated HRP2-induced brain injury and inflammation and that NRG1 may be an effective therapy against HRP2 effects in the brain.
人类脑型疟疾（HCM）是一种严重的感染并发症，其特征为毛细血管闭塞、血脑屏障（BBB）破裂、血管周围细胞损伤和脑肿胀。富含组氨酸的蛋白2（HRP2）是被寄生红细胞（pRBC）裂解的副产物，在血脑屏障受损时会穿过血脑屏障导致脑损伤。我们推测，抗炎神经保护因子神经调节蛋白-1（NRG1）可以减轻HRP2诱导的神经元损伤。利用脑皮质类器官，我们确定HRP2上调了细胞死亡和炎症标志物，并使脑类器官组织紊乱。我们确定Toll样受体（TLR1和2）是HRP2诱导的细胞损伤和炎症的潜在介质。用NRG1对类器官进行外源性急性处理可减轻HRP2的作用。结果表明，HRP2介导了疟疾相关的HRP2诱导的脑损伤和炎症，并且NRG1可能是对抗HRP2对脑影响的有效疗法。
