Malaria Parasite Genomics, Development, Drug Resistance, Pathogenesis, and host-parasite interaction

疟原虫基因组学、发育、耐药性、发病机制和宿主-寄生虫相互作用

• 批准号: 10272084
• 负责人: Xinzhuan Su
• 金额: $ 152.56万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10272084
• 关键词: Affect; Anemia; Antimalarials; Binding; Brain; Carrier Proteins; Cell Line; Cell Maturation; Clone Cells; Development; Disease; Drug resistance; Erythrocytes; Genes; Genetic; Genomics; Goals; Immunologics; Infection; Inflammation; Interferon Type I; Interferons; Interruption; Luciferases; MMP3 gene; Malaria; Manuscripts; Mediating; Methods; Molecular; Parasites; Pathogenesis; Pharmaceutical Preparations; Plasmodium; Plasmodium falciparum; Plasmodium yoelii; Play; Proteins; Publications; Publishing; Receptor Gene; Role; Signal Pathway; Symptoms; T-Cell Activation; Virulence; West Nile viral infection; Work; disease mechanisms study; experimental study; functional genomics; inhibitor/antagonist; knock-down; malaria infection; mouse model; olfactory receptor; receptor; response; screening; transmission process; ubiquitin-protein ligase

During the year of 2019-2020, we focused on studying the molecular mechanisms of malaria pathogenesis and signaling pathways using Plasmodium yoelii/mouse model. We also have a project studying mechanisms of drug resistance in Plasmodium falciparum. We have made good progresses in several projects: 1. We have completed a multi-year project dissecting the mechanism of Plasmodium yoelii erythrocyte binding-like protein (PyEBL) in regulating host innate response to malaria infections. This work was finally published in mBio after additional experiments and revision (mBio. 2020, 11:e02995-19). 2. We have finished another project studying a gene called March1 and published the work in Proc Natl Acad Sci U S A (2020, doi: 10.1073/pnas.2006492117) after extensive revision. This work shows MARCH1 is an important molecule that can regulate host type I interferon (IFN-I) response and T cell activation during malaria infections. Additionally, we have generated and cloned cell lines expressing luciferases, MAVS, and MARCH1 for screening small compound inhibitors. 3. Similarly, we have finished and published the work on receptor transporter protein 4 (RTP4). We show that RTP4 can regulate host IFN-I response during P. yoelii infections. Our work also suggests that RTP4 plays a critical role in brain pathogenesis during malaria parasite and West Nile virus infections. This work was again published in Proc Natl Acad Sci U S A recently (2020, doi: 10.1073/pnas.2006492117). 4. We continued to work on characterization of MMP3 function in malaria infections. MMP3 is highly up-regulated during infections of some P. yoelii strains. We are dissecting the mechanism of MMP3 in mediating inflammation in malaria. 5. We have been studying the molecular mechanism of malaria induced anemia. We have shown that infections with certain P. yoelii strains inhibit red blood cell (RBC) maturation. We are performing the last few experiments to complete a manuscript for publication. 6. We initiated a project investigating the functions of selected olfactory receptors (ORs) in malaria infections. We have identified 40 OR genes that may play a role in P. yoelii infections. 7. We have tagged several P. falciparum E3 ubiquitin ligases and showed that knocking-down some of the genes affects parasite responses to anti-malarial drugs. 8, Working with colleagues, I wrote an invited review on Plasmodium genomics and genetics that was published in Clin Microbiol Rev (2019 Jul 31;32(4). pii: e00019-19. doi: 10.1128/CMR.00019-19).

在2019-2020年期间，我们利用约氏疟原虫/小鼠模型重点研究了疟疾发病机制和信号通路的分子机制。我们还有一个研究恶性疟原虫抗药性机制的项目。 我们在多个项目中取得了良好的进展： 1.我们已经完成了一个多年的项目解剖约氏疟原虫红细胞结合样蛋白（PyEBL）在调节宿主对疟疾感染的先天反应的机制。经过额外的实验和修订，这项工作最终发表在mBio上（mBio. 2020，11：e02995-19）。 2.我们已经完成了另一个研究March 1基因的项目，并在广泛修订后发表在Proc Natl Acad Sci U S A（2020，doi：10.1073/pnas.2006492117）上。这项工作表明MARCH 1是一种重要的分子，可以调节疟疾感染期间宿主I型干扰素（IFN-I）反应和T细胞活化。此外，我们已经产生并克隆了细胞系，表达p53酶，MAVS，和MARCH 1筛选小化合物抑制剂。 3.同样，我们已经完成并发表了受体转运蛋白4（RTP 4）的工作。我们表明，RTP 4可以调节宿主IFN-I反应在约氏疟原虫感染。我们的工作还表明，RTP 4在疟疾寄生虫和西尼罗河病毒感染期间的脑发病机制中起着关键作用。这项工作最近再次发表在Proc Natl Acad Sci U S A上（2020，doi：10.1073/pnas.2006492117）。 4.我们继续研究MMP 3在疟疾感染中的功能特征。MMP 3在一些约氏疟原虫菌株感染期间高度上调。我们正在剖析MMP 3介导疟疾炎症的机制。 5.我们一直在研究疟疾引起贫血的分子机制。我们已经表明，感染某些约氏疟原虫菌株会抑制红细胞（RBC）成熟。我们正在进行最后几个实验，以完成一个手稿出版。 6.我们启动了一个项目，调查选定的嗅觉受体（OR）在疟疾感染中的功能。我们已经确定了40个可能在约氏疟原虫感染中起作用的OR基因。 7.我们已经标记了几种恶性疟原虫E3泛素连接酶，并表明敲低一些基因会影响寄生虫对抗疟疾药物的反应。 8，与同事合作，我写了一篇关于疟原虫基因组学和遗传学的特邀评论，发表在Clin Microbiol Rev（2019年7月31日;32（4）。pii：e00019-19。doi：10.1128/CMR.00019-19）。