Histidine-rich protein II nanoparticle delivery of heme iron load drives endothelial inflammation in cerebral malaria.
Histidine-rich protein II nanoparticle delivery of heme iron load drives endothelial inflammation in cerebral malaria.
复制标题
DOI：
10.1073/pnas.2306318120
复制
发表时间：
2023-06-27
影响因子：
11.1
通讯作者：
Goldberg, Daniel E.
中科院分区：
文献类型：
--
作者：
Nguyen, Suong T.;Du, Daniel;Wychrij, Daniel;Cain, Matthew D.;Wu, Qingping;Klein, Robyn S.;Russo, Ilaria;Goldberg, Daniel E.
高血浆水平的富组氨酸蛋白II（HRPII），分泌的疟疾蛋白，与严重的疟疾，但HRPII的毒力机制尚未完全建立。我们观察到，分泌HRPII寄生虫培养和血浆中形成大的血红素负载纳米粒子。HRPII的毒力与其向内皮细胞递送数百种血红素有关，导致铁毒性和活性氧物质的产生，并随后激活NLRP 3炎性体。该级联破坏内皮屏障完整性。这些数据定义了HRPII和脑水肿（脑型疟疾的标志）之间的联系。血红素螯合或炎性小体抑制破坏这一过程减轻了HRPII的影响，并可能指导进一步研究严重疟疾的临床治疗。富组氨酸蛋白II（HRPII）是由恶性疟原虫在疟疾感染的血液阶段分泌的。高血浆水平的HRPII与脑型疟疾相关，脑型疟疾是一种严重且高度致命的疟疾并发症。在血脑屏障（BBB）和动物模型中，HRPII已显示出诱导血管渗漏，这是脑型疟疾的标志。我们已经发现了一个重要的机制，血脑屏障中断是由HRPII的独特功能驱动。通过表征来自感染患者的血清和培养物中由恶性疟原虫寄生虫产生的HRPII，我们发现HRPII存在于14种多肽的大的多聚体颗粒中，所述多聚体颗粒富含高达700个血红素/颗粒。HRPII的血红素负载是通过小窝蛋白介导的hCMEC/D3脑微血管内皮细胞内吞作用进行有效结合和内化所必需的。内溶酶体酸化后，三分之二的血红素从酸不稳定结合位点释放，并被血红素加氧酶1代谢，产生三价铁和活性氧。随后NLRP 3炎性体的激活和IL-1β分泌导致内皮渗漏。抑制这些途径与血红素螯合，铁螯合，或抗炎药物保护的完整性BBB培养模型从HRPII：血红素。增加脑血管通透性后，年轻小鼠注射血红素负载HRPII（HRPII：血红素），但没有血红素耗尽HRPII。我们认为在严重的疟疾感染期间，血流中的HRPII：血红素纳米颗粒向内皮细胞提供了压倒性的铁负荷，导致血管炎症和水肿。破坏这一过程是一个机会，有针对性的治疗，以减少脑型疟疾的发病率和死亡率。
High plasma levels of histidine-rich protein II (HRPII), a secreted malaria protein, are associated with severe malaria, but the mechanism of HRPII virulence is not fully established. We observed that secreted HRPII in parasite culture and plasma forms large heme-laden nanoparticles. The virulence of HRPII is tied to its delivery of hundreds of hemes to endothelial cells, leading to iron toxicity and production of reactive oxygen species, and subsequently activating the NLRP3 inflammasome. This cascade disrupts endothelial barrier integrity. These data define the link between HRPII and cerebral edema, a hallmark of cerebral malaria. Disruption of this process by heme sequestration or inflammasome inhibition mitigated the effects of HRPII and may guide further studies into clinical therapies for severe malaria. Histidine-rich protein II (HRPII) is secreted by Plasmodium falciparum during the blood stage of malaria infection. High plasma levels of HRPII are associated with cerebral malaria, a severe and highly fatal complication of malaria. HRPII has been shown to induce vascular leakage, the hallmark of cerebral malaria, in blood–brain barrier (BBB) and animal models. We have discovered an important mechanism for BBB disruption that is driven by unique features of HRPII. By characterizing serum from infected patients and HRPII produced by P. falciparum parasites in culture, we found that HRPII exists in large multimeric particles of 14 polypeptides that are richly laden with up to 700 hemes per particle. Heme loading of HRPII is required for efficient binding and internalization via caveolin-mediated endocytosis in hCMEC/D3 cerebral microvascular endothelial cells. Upon acidification of endolysosomes, two-thirds of the hemes are released from acid-labile binding sites and metabolized by heme oxygenase 1, generating ferric iron and reactive oxygen species. Subsequent activation of the NLRP3 inflammasome and IL-1β secretion resulted in endothelial leakage. Inhibition of these pathways with heme sequestration, iron chelation, or anti-inflammatory drugs protected the integrity of the BBB culture model from HRPII:heme. Increased cerebral vascular permeability was seen after injection of young mice with heme-loaded HRPII (HRPII:heme) but not with heme-depleted HRPII. We propose that during severe malaria infection, HRPII:heme nanoparticles in the bloodstream deliver an overwhelming iron load to endothelial cells to cause vascular inflammation and edema. Disrupting this process is an opportunity for targeted adjunctive therapies to reduce the morbidity and mortality of cerebral malaria.
登录
查看更多内容
DOI：
10.1083/jcb.103.4.1269
发表时间：
1986-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Howard RJ;Uni S;Aikawa M;Aley SB;Leech JH;Lew AM;Wellems TE;Rener J;Taylor DW
通讯作者：
Taylor DW
影响因子：
6.4
作者：
Fox, Lindsay L.;Taylor, Terrie E.;Seydel, Karl B.
通讯作者：
Seydel, Karl B.
影响因子：
15.1
作者：
Franke, Maximilian;Bieber, Michael;Schuhmann, Michael K.
通讯作者：
Schuhmann, Michael K.
影响因子：
11.8
作者：
Bangirana, Paul;Opoka, Robert O.;John, Chandy C.
通讯作者：
John, Chandy C.
影响因子：
3.7
作者：
Liu M;Amodu AS;Pitts S;Patrickson J;Hibbert JM;Battle M;Ofori-Acquah SF;Stiles JK
通讯作者：
Stiles JK