Malaria Parasite Development, Drug Resistance, Pathogenesis, and Genomics

疟疾寄生虫的发育、耐药性、发病机制和基因组学

• 批准号: 10014086
• 负责人: Xinzhuan Su
• 金额: $ 164.33万
• 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/10014086
• 关键词: Anemia; Antimalarials; Binding; CRISPR/Cas technology; Carrier Proteins; Cell Line; Cell surface; Collaborations; Communication; Development; Disease; Drug resistance; Erythrocytes; G-Protein-Coupled Receptors; Genes; Genetic; Genomics; Goals; Growth; Hematopoiesis; Immune response; Immunity; Immunologics; Infection; Inflammasome; Interferon Type I; Interferons; Interruption; Knockout Mice; MMP3 gene; Malaria; Manuscripts; Mediating; Methodist Church; Methods; Molecular; Mutation; Nature; Parasites; Parasitic infection; Pathogenesis; Phagocytosis; Phosphoserine; Plasmodium yoelii; Play; Preparation; Proteins; Published Comment; Publishing; Research Institute; Role; Signal Pathway; Signal Transduction; Surface; T cell differentiation; Time; Tyrosine Phosphorylation; Universities; Virulence; Work; base; circumsporozoite protein; disease mechanisms study; disease phenotype; experimental study; functional genomics; gene function; inhibitor/antagonist; malaria infection; mouse model; protein transport; receptor; response; transmission process

During the year of 2018-2019, we focused on studying the molecular mechanisms of malaria pathogenesis and signaling pathways using Plasmodium yoelii/mouse model. 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 infection. We found that PyEBL can regulate host immune response and parasite growth by stimulating a strong type I interferon response and T cell differentiation. A C741Y substitution in the protein trafficking domain changes Band 3 tyrosine phosphorylation and surface phosphoserine (PS) exposure on infected red blood cell (RBC), but not the rate of RBC invasion, leading to increased phagocytosis of infected RBCs. This study provides a paradigm shift in our understanding of parasite-host interaction during malarial parasite infection. A manuscript from this work has been submitted. 2. We have finished a project studying a gene called March1. We found that March1 can regulate host response to infections of multiple parasite strains. A manuscript was submitted to Nature Communications, and we have been working on experiments in response to reviewer's comments in the past few months. At the same time, we are generating cell lines to screen small compound inhibitors for therapy. 3. We are finishing up a project characterizing a gene called receptor transporter protein 4 (RTP4) known to promote cell surface expression of G protein-coupled receptors (GPCRs). Our study discovers a new function for the gene; it can regulate host type I interferon (IFN-I) response during malaria infection. We generated rtp4 knockout mice and characterized its roles during malaria infection. A manuscript is under preparation. 4. In collaboration with Dr. Rongfu Wang of Houston Methodist Research Institute, we showed inflammasome activation during malaria infection can negatively regulate MyD88-IRF7 type I IFN signaling and anti-malaria immunity. This work was published in Nature Communications. 5. In collaboration with Dr. Jian Li and colleagues at Xiamen University, we completed a project of developing a microhomology-mediated end joining (MMEJ) based CRISPR/Cas9 method and used the method to generate size mutations in the central repeat region of Plasmodium yoelii circumsporozoite protein (PyCSP). This work was recently published in Int. J. Parasitol. 6. We continued to work on other projects such as characterizing the function of MMP3 in malaria infection and the mechanism of malaria induced anemia and hematopoiesis.

2018-2019年，我们利用约氏疟原虫/小鼠模型，重点研究疟疾发病的分子机制和信号转导途径。 我们在几个项目上取得了良好的进展： 1.完成了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中的作用机制的多年研究。我们发现，PyEBL可以通过刺激强大的I型干扰素反应和T细胞分化来调节宿主免疫反应和寄生虫的生长。蛋白转运区的C741Y替换改变了感染红细胞(RBC)上带3酪氨酸的磷酸化和表面磷酸丝氨酸(PS)的暴露，但不改变RBC的侵袭速度，导致感染RBC吞噬功能的增加。这项研究为我们对疟疾寄生虫感染过程中寄生虫-宿主相互作用的理解提供了一个范式转变。这部作品的一份手稿已经提交。 2.我们已经完成了一个研究March1基因的项目。我们发现March1可以调节宿主对多种寄生虫株的感染反应。一份手稿被提交给了自然通讯，在过去的几个月里，我们一直在进行实验，以回应评论家的评论。与此同时，我们正在建立细胞系，以筛选用于治疗的小型化合物抑制剂。 3.我们正在完成一个名为受体转运蛋白4(RTP4)的基因的特征研究，该基因可促进G蛋白偶联受体(GPCRs)的细胞表面表达。我们的研究发现了该基因的一个新功能；它可以在疟疾感染过程中调节宿主I型干扰素(IFN-I)的反应。我们建立了rtp4基因敲除小鼠，并研究了它在疟疾感染过程中的作用。一份手稿正在准备中。 4.与休斯顿卫理公会研究所王荣福博士合作发现，疟疾感染过程中炎症小体的激活可以负向调节MyD88-IRF7 I型干扰素信号和抗疟疾免疫。这项研究发表在《自然通讯》杂志上。 5.与厦门大学李健博士及同事合作，建立了一种基于微同源性介导的末端连接(MMEJ)的CRISPR/Cas9方法，并利用该方法产生了约氏疟原虫环子孢子蛋白(PyCSP)中心重复序列的大小突变。这项研究最近在Int上发表。J.Parasitol。 6.我们继续开展其他项目，例如确定MMP3在疟疾感染中的功能，以及疟疾引起贫血和造血的机制。