Malaria Parasite Development, Drug Resistance, Pathogenesis, and Genomics

2016-2017年，我们利用约氏疟原虫/小鼠模型，重点研究了疟疾发病的分子机制和信号通路。 我们在多个项目中取得了良好的进展： 1.我们完成了一个研究疟疾感染期间CD 40在调节I型干扰素（IFN-I）反应中的作用的项目。我们发现，CD 40可以增强STING刺激的IFN-Ⅰ反应，并在寄生虫血症控制和宿主生存中发挥作用。我们还表明，寄生虫材料，如DNA和RNA可以刺激CD 40的表达通过TLR信号通路。这项研究揭示了CD 40在先天性IFN-I应答中的一种以前未被认识的功能，并为更好地理解和管理疟疾提供了重要信息。这项工作发表在PLoS Pathogens上。 2.我们还完成了寄生虫E3泛素连接酶在调节寄生虫生长和疾病毒力方面的功能验证。我们使用CRISPR/cas9方法替换了E3泛素连接酶基因的部分编码序列。我们发现改变寄生虫的生长交换后的部分基因序列，这证实了寄生虫的发展和疾病的毒力的基因的作用。一份手稿已被Nature Communications接受。 3.我们继续研究约氏疟原虫感染后炎症反应的分子机制。 我们现在专注于IFN-γ介导的促炎反应，并正在解剖寄生虫感染后导致炎症的分子相互作用和细胞类型。已向《科学报告》提交了一份手稿。 4.我们在其他项目上也取得了良好的进展，包括一个名为March 1的基因。我们发现该基因可以调节宿主对多种寄生虫株感染的反应。我们正在研究该基因如何调节宿主免疫反应的分子机制。 5.此外，与休斯顿卫理公会研究所的科学家合作，我们已经确定了pDC中IFN-I信号传导的关键调节机制和免疫细胞在产生针对致命疟疾感染的有效免疫力中的阶段特异性功能，该研究发表在Immunity上。 6.在第二个合作项目中，我们发现了转录因子FOSL 1在调节IFN-I反应中的一个先前未知的作用。我们发现FOSL 1可以通过阻断TBK 1和TRAF 3/TRIF相互作用来抑制IFN-I对疟疾和病毒感染的反应。这项工作发表在mBio上。 7.我们与宾夕法尼亚州立大学的科学家合作，使用全基因组关联分析来鉴定从中缅边境收集的恶性疟原虫寄生虫中与多种抗疟药物耐药性相关的遗传位点。这项工作发表在Scientific Reports上。 8.我们与厦门大学的科学家合作，继续研究中国南方鸟类寄生虫（萨氏白细胞虫）的流行情况。我们还测试了几种三环化合物对寄生虫的配子体。这项工作发表在PLoS ONE上。 9.在第二个合作项目中，我们开发了一种CRISPR/Cas9方法，可以对约氏疟原虫基因进行序列编辑，该方法发表在《分子和生物化学寄生虫学》上。

During the year of 2016-2017, we focused on studying molecular mechanisms of malaria pathogenesis and signaling pathways using Plasmodium yoelii/mouse model. We have made good progresses in several projects: 1. We finished a project studying the role of CD40 in regulating type I interferon (IFN-I) response during malaria infection. We showed that CD40 could enhance STING-stimulated IFN-I response and played a role in parasitemia control and host survival. We also showed that parasite materials such as DNA and RNA could stimulate CD40 expression through TLR signaling pathways. This study reveals a previously unrecognized function of CD40 in innate IFN-I responses and provides important information for better understanding and management of malaria. This work was published in PLoS Pathogens. 2. We have also finished functional verification of a parasite E3 ubiquitin ligase in regulating parasite growth and disease virulence. We replaced partial coding sequences of the E3 ubiquitin liagse gene using the CRISPR/cas9 method. We showed changed parasite growth after exchange of partial gene sequences, which confirms a role of the gene in parasite development and disease virulence. A manuscript has been accepted by Nature Communications. 3. We continued to study the molecular mechanism of inflammatory responses after P. yoelii infection. We are now focusing on pro-inflammatory responses mediated by IFN-gamma and are dissecting the molecular interactions and cell types contributing to inflammation after parasite infection. A manuscript has been submitted to Scientific Reports. 4. We have made good progresses on other projects, including a gene called March1. We found that this gene can regulate host response to infections of multiple parasite strains. We are investigating the molecular mechanism of how this gene regulates host immune response. 5. Additionally, in collaboration with scientists at Houston Methodist Research Institute, Houston, we have identified a critical regulatory mechanism of IFN-I signaling in pDCs and stage-specific function of immune cells in generating potent immunity against a lethal malaria infection, which was published in Immunity. 6. In a second collaborative project, we discovered a previously unknown role of the transcription factor FOSL1 in regulating IFN-I response. We showed that FOSL1 could inhibit IFN-I responses to malaria and viral infections by blocking TBK1 and TRAF3/TRIF Interactions. This work was published in mBio. 7. In collaboration with scientists at Penn State University, we used genome-wide association analysis to identify genetic loci associated with resistance to multiple antimalarials in Plasmodium falciparum parasites collected from China-Myanmar border. This work was published in Scientific Reports. 8. In collaboration with scientists at Xiamen University, we continued to study prevalence of a bird parasite (Leucocytozoon sabrazesi) in Southern China. We also tested several tricyclic compounds against the gametocyte of the parasite. The work was published in PLoS ONE. 9. In a second collaborative project, we developed a CRISPR/Cas9 method that allows sequential editing of Plasmodium yoelii genes, which was published in Molecular and Biochemical Parasitology.