Suppression of Plasmodium MIF-CD74 signaling protects against severe malaria.
Suppression of Plasmodium MIF-CD74 signaling protects against severe malaria.
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DOI：
10.1096/fj.202101072r
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
疟疾是由疟原虫感染引起的最致命的并发症，脑型疟疾占疟疾死亡人数的大部分。尽管我们对发病的细胞和分子机制的了解还不完全，但最近的研究支持全身和神经炎症是脑水肿和血脑屏障(BBB)功能障碍的原因。所有的疟原虫物种都编码一种天然细胞因子--巨噬细胞移动抑制因子(MIF)的同源基因，这种因子在哺乳动物生物学中起着调节天然反应的作用。疟原虫MIF(PMIF)类似地通过宿主MIF受体CD74发出信号，导致增强的炎症反应。我们利用CD74缺陷(CD74−/−)宿主和PMIF缺陷寄生虫的组合，研究了pMIF-CD74在实验性脑疟疾发病和肝期疟原虫发育中的相互作用。CD74CD8小鼠被发现对细胞外基质有保护作用，这种保护作用与脑微血管不能将寄生虫抗原呈递给隔离的致病的−/−+T细胞有关。感染pMIF缺陷子的WT宿主或感染CD74WT子孢子的CD74WT宿主可影响感染的肝细胞的存活，从而减少血液期相关炎症，有助于保护−/−免受细胞外基质的侵袭。我们用一种新的药理PMIF选择性拮抗剂概括了这些发现，该拮抗剂可以减少PMIF/CD74信号并完全保护小鼠免受ECM的影响。这些发现揭示了疟原虫篡夺宿主CD74信号的保守机制，并为新的药物干预提供了一种易于处理的方法。
The deadliest complication of infection by Plasmodium parasites, cerebral malaria, accounts for the majority of malarial fatalities. Although our understanding of the cellular and molecular mechanisms underlying the pathology remains incomplete, recent studies support the contribution of systemic and neuroinflammation as the cause of cerebral edema and blood-brain barrier (BBB) dysfunction. All Plasmodium species encode an orthologue of the innate cytokine, Macrophage Migration Inhibitory Factor (MIF), which functions in mammalian biology to regulate innate responses. Plasmodium MIF (PMIF) similarly signals through the host MIF receptor CD74, leading to an enhanced inflammatory response. We investigated the PMIF-CD74 interaction in the onset of experimental cerebral malaria (ECM) and liver stage Plasmodium development by using a combination of CD74 deficient (Cd74−/−) hosts and PMIF deficient parasites. Cd74−/− mice were found to be protected from ECM and the protection was associated with the inability of brain microvessels to present parasite antigen to sequestered and pathogenic Plasmodium-specific CD8+ T cells. Infection of WT hosts with PMIF-deficient sporozoites or infection of Cd74−/− hosts with WT sporozoites impacted the survival of infected hepatocytes and subsequently reduced blood-stage associated inflammation, contributing to protection from ECM. We recapitulated these finding with a novel pharmacologic PMIF-selective antagonist that reduced PMIF/CD74 signaling and fully protected mice from ECM. These findings reveal a conserved mechanism for Plasmodium usurpation of host CD74 signaling and suggest a tractable approach for new pharmacologic intervention.
影响因子：
7.3
作者：
Dahlgren, Markus K.;Garcia, Alvaro Baeza;Hare, Alissa A.;Tirado-Rives, Julian;Leng, Lin;Bucala, Richard;Jorgensen, William L.
通讯作者：
Jorgensen, William L.