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: 10692069
• 负责人: Xinzhuan Su
• 金额: $ 134.84万
• 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/10692069
• 关键词: Affect; Anemia; Antimalarials; Biological; Cell Maturation; Cerebral Malaria; Chromosome Mapping; Collaborations; Development; Disease; Disease susceptibility; Drug resistance; Erythroblasts; Erythrocytes; Genes; Genetic; Genome; Genomics; Goals; IRF3 gene; ITGAM gene; Immune response; Immunity; Immunologics; Immunomodulators; In Vitro; Infection; Interferon Type I; Interferons; International; Interruption; Island; Knockout Mice; Lead; Ligands; MMP3 gene; Malaria; Manuscripts; Methods; Molecular; Mus; Mutation; Odorant Receptors; Parasites; Parasitic infection; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Plasmodium berghei; Plasmodium falciparum; Plasmodium yoelii; Play; Proteins; Publications; Publishing; Receptor Gene; Reporting; Rodent; Role; Signal Pathway; Site; Stimulator of Interferon Genes; Symptoms; TBK1 gene; Ubiquitination; Virulence; Work; Writing; functional genomics; human disease; in vitro activity; in vivo; knock-down; macrophage; malaria infection; malarial anemia; monocyte; mortality; olfactory receptor; overexpression; p38 Mitogen Activated Protein Kinase; pressure; response; small molecule; transmission process; ubiquitin ligase; ubiquitin-protein ligase

During the year 2021-2022, we focused on studying the molecular mechanisms of malaria pathogenesis and signaling pathways using Plasmodium yoelii and Plasmodium berghei parasites. We also have a project studying mechanisms of drug resistance in Plasmodium falciparum. We have made good progress in several projects: 1, Continued from our report last year, now we have identified several small molecules (drugs) that can inhibit or stimulate MARCH1 activity in vitro. We are currently evaluating the candidate compounds in vivo. Some of these compounds are immune modulators that have been used in trials of different human diseases. We hope to use some of the compounds to treat cerebral malaria caused by Plasmodium berghei ANNK and severe malaria by Plasmodium yoelii N67C. Traditional antimalarial drugs kill the parasites directly, but the drug pressures may lead to mutations conferring drug resistance. Host immune modulators can be explored for treating malaria with a reduced chance of drug resistance. 2. We have finished a study on the molecular mechanism of malaria-induced anemia. We have shown that infection with P. yoelii 17XNL inhibits red blood cell (RBC) maturation. We invested the roles of erythroblast island (EBI) macrophages in malaria anemia and showed that EBI macrophages from 17XNL infected mice were defective in supporting erythrocyte maturation in vitro and in vivo. A manuscript from this study was submitted recently. 3. We have shown that over-expression of some Olfr genes could stimulate type I interferon (INF-I) responses and increase phosphorylation levels of IRF3 and TBK1. We have made good progress in the mechanism of how the olfactory receptors (Olfr) regulate INF-I response and identified a putative molecular signaling pathway. Additionally, we have identified a potential ligand that can activate several Olfr proteins. We are writing a manuscript for publication now. 4. We have finished a project on a P. falciparum E3 ubiquitin ligase and its role in protein ubiquitination. We showed that knocking down the E3 ubiquitin ligase gene affected parasite responses to several antimalarial drugs and changed the protein levels of some drug transporters. A manuscript is under revision now. We are working on another E3 ubiquitin ligase and hope to have a second manuscript ready soon. 5. We are still working on another host gene (mmp3) that has been shown to be highly expressed in malaria parasite infections. We have generated mmp3 knockout mice and are studying the functions of MMP3 in host immune response to malaria parasite infections. We have shown that MMP3 can regulate host IFN-I responses and are studying the mechanism of how MMP3 regulates IFN-I responses. 6, We sequenced and assembled the genome of another P. yoelii strain (N67C), an isogenic parasite of N67. We are comparing its genome with that of N67 to identify polymorphic sites that may contribute to the differences in virulence and stimulation of host responses. 7, We also published two invited reviews in 2022. One entitled: Genetic mapping of determinants in drug resistance, virulence, disease susceptibility, and interaction of host-rodent malaria parasites in Parasitol. International. 91 (2022) 102637. A second one is: The origin, isolation, and biological characterization of rodent malaria parasites. Parasitol. International. 91 (2022) 102636. 8, In collaboration with Drs. Rongfu Wand and Xiao Yu, we continued to work on the mechanism of host INF-I responses to malaria parasite infections. We showed that activation of cGAS-STING pathway by P. yoelii N67C infection influences host immunity and mortality by induction of CD11b+Ly6+ proinflammatory monocytes, identifying a previously unrecognized role of cGAS-STING-MyD88-p38 signaling pathway (Adv. Sci. 2022, 9, 2103701).

2021-2022年，我们重点研究了约氏疟原虫和伯氏疟原虫的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。 我们在几个项目上取得了良好的进展： 1、延续我们去年的报道，现在我们已经鉴定出几种可以在体外抑制或刺激MARCH 1活性的小分子（药物）。我们目前正在体内评估候选化合物。其中一些化合物是免疫调节剂，已用于不同人类疾病的试验。我们希望将其中的一些化合物用于治疗伯氏疟原虫ANNK引起的脑型疟疾和约氏疟原虫N67 C引起的重症疟疾。传统的抗疟药物直接杀死寄生虫，但药物压力可能导致产生抗药性的突变。可以探索宿主免疫调节剂用于治疗疟疾，降低抗药性的机会。 2.我们完成了疟疾致贫血的分子机制研究。我们已经表明，感染约氏疟原虫17 XNL抑制红细胞（RBC）成熟。我们研究了成红细胞岛（EBI）巨噬细胞在疟疾贫血中的作用，并表明17 XNL感染小鼠的EBI巨噬细胞在体外和体内支持红细胞成熟方面存在缺陷。最近提交了这项研究的手稿。 3.我们已经表明，一些Olfr基因的过表达可以刺激I型干扰素（INF-1）的反应，并增加IRF 3和TBK 1的磷酸化水平。我们在嗅觉受体（Olfr）调节INF-1反应的机制方面取得了很大进展，并确定了一条可能的分子信号通路。此外，我们已经确定了一个潜在的配体，可以激活几个Olfr蛋白。我们现在正在写稿准备出版。 4.我们已经完成了一个关于恶性疟原虫E3泛素连接酶及其在蛋白质泛素化中的作用的项目。我们发现，敲低E3泛素连接酶基因影响寄生虫对几种抗疟药物的反应，并改变了一些药物转运蛋白的蛋白水平。一份手稿正在修改中.我们正在研究另一种E3泛素连接酶，希望很快能有第二份手稿。 5.我们仍在研究另一种宿主基因（mmp 3），它已被证明在疟疾寄生虫感染中高度表达。我们已经产生了MMP 3基因敲除小鼠，并正在研究MMP 3在宿主对疟原虫感染的免疫应答中的功能。我们已经证明MMP 3可以调节宿主IFN-1应答，并正在研究MMP 3如何调节IFN-1应答的机制。 6、我们对约氏疟原虫N67的同基因株N67 C进行了基因组测序和组装。我们正在将其基因组与N67的基因组进行比较，以确定可能导致毒力和刺激宿主反应差异的多态性位点。 7、我们还在2022年发布了两篇特邀评论。一份题为：Parasitol中宿主-啮齿动物疟原虫的抗药性、毒力、疾病易感性和相互作用决定因素的遗传作图。国际化. 91（2022）102637。第二个是：啮齿动物疟原虫的起源、分离和生物学特性。寄生醇国际化. 91（2022）102636。 8、与Wand Rongfu博士和Xiao Yu博士合作，继续研究宿主INF-1对疟原虫感染的反应机制。我们表明，约氏疟原虫N67 C感染对cGAS-STING途径的激活通过诱导CD 11b + Ly 6+促炎性单核细胞影响宿主免疫力和死亡率，鉴定了cGAS-STING-MyD 88-p38信号传导途径先前未被认识的作用（Adv. Sci. 2022，9，2103701）。