A high throughput model of Cryptococcus Infection and Cell Biology In Vivo for identifying host and pathogen disease determinants and new therapeutics

体内隐球菌感染和细胞生物学的高通量模型，用于识别宿主和病原体疾病决定因素和新疗法

• 批准号: MR/J009156/1
• 负责人: Simon Johnston
• 金额: $ 128.48万
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FJ009156%2F1
• 关键词: throughput; model; Cryptococcus; Infection; Cell

I am interested in how our immune system is and is not able to remove micro-organisms that can cause disease. An example of where the immune system is not able to work properly is when a person is infected with HIV (the virus that causes AIDS). Other examples include cancer, during and after organ transplantation and during treatment for rheumatoid arthritis. When the immune system is not working properly we may become ill with a micro-organism that normally would not cause a significant problem. One such micro-organism is the fungus Cryptococcus.Infections with Cryptococcus are very unusual in those with a normal immune system but in individuals with, for example, severe HIV infection, Cryptococcus is much more common and very serious. The AIDS epidemic has resulted in a large group of people who are susceptible to Cryptococcus and it has been estimated that there are as many as 1 million cases and 600, 000 deaths due to Cryptococcus each year. Fungi that cause disease in humans are uncommon and those that cause serious disease are very rare. Fungi that cause serious disease in humans are difficult to treat because the drugs we have are often quite harmful to us as well.As well as the Cryptococcus that causes serious disease in those with immune systems that are not working, there is a second type that has been found to cause disease in people who have apparently normal immune systems. This second type is mainly found around the equator but there have been increasing numbers outside this area.My research is trying to understand these different areas of why Cryptococcus causes disease so that we can find better treatments. The questions I am asking in my research are: What happens to the immune system that means we are seriously infected with Cryptococcus? What makes infection with some types of Cryptococcus more severe (virulent)? Are there any new drugs that we can use to improve the way we treat Cryptococcus?I will explore these questions using a model of Cryptococcus infection I have developed in the zebrafish. The zebrafish has a similar immune system to our own and I can observe the immune cells of living animals and see what happens during the infection. I am also going to use this model to test possible new drugs. My hope is that through this research we will have a greater understanding of how and why Cryptococcus causes disease and that this will lead to new treatments.

我感兴趣的是我们的免疫系统是如何和无法消除微生物，可以导致疾病。免疫系统不能正常工作的一个例子是当一个人感染了艾滋病毒（导致艾滋病的病毒）。其他例子包括癌症，在器官移植期间和之后以及在类风湿性关节炎的治疗期间。当免疫系统不能正常工作时，我们可能会感染一种通常不会引起重大问题的微生物。隐球菌属的感染在免疫系统正常的人中是非常罕见的，但在患有严重艾滋病病毒感染的人中，隐球菌属的感染要常见得多，而且非常严重。艾滋病的流行导致大量人群易感染隐球菌，据估计，每年有多达100万例隐球菌感染病例和60万例隐球菌死亡。导致人类疾病的真菌并不常见，而导致严重疾病的真菌则非常罕见。导致人类严重疾病的真菌很难治疗，因为我们使用的药物通常对我们也很有害。除了隐球菌会导致免疫系统不起作用的人患上严重疾病外，还有第二种类型的隐球菌会导致免疫系统正常的人患病。第二种隐球菌主要分布在赤道附近，但在赤道以外的地区也有越来越多的隐球菌。我的研究试图了解这些不同的地区为什么隐球菌会引起疾病，以便我们能够找到更好的治疗方法。我在研究中提出的问题是：免疫系统发生了什么，这意味着我们严重感染了隐球菌？是什么使某些类型的隐球菌感染更严重（毒性）？有没有什么新药可以用来改善我们治疗隐球菌的方法？我将使用我在斑马鱼中开发的隐球菌感染模型来探索这些问题。斑马鱼的免疫系统与我们的相似，我可以观察活体动物的免疫细胞，看看在感染过程中会发生什么。我也将用这个模型来测试可能的新药。我希望通过这项研究，我们将更好地了解隐球菌如何以及为什么会引起疾病，这将导致新的治疗方法。

项目成果

CD4-Transgenic Zebrafish Reveal Tissue-Resident Th2- and Regulatory T Cell-like Populations and Diverse Mononuclear Phagocytes.

• DOI: 10.4049/jimmunol.1600959
• 发表时间: 2016-11-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Dee CT;Nagaraju RT;Athanasiadis EI;Gray C;Fernandez Del Ama L;Johnston SA;Secombes CJ;Cvejic A;Hurlstone AF
• 通讯作者: Hurlstone AF

Mycophenolate mofetil increases inflammation resolution in zebrafish via neutrophil apoptosis

吗替麦考酚酯通过中性粒细胞凋亡增加斑马鱼炎症消退

• DOI: 10.1101/145359
• 发表时间: 2017
• 作者: Bojarczuk A

Using Flow Cytometry to Analyze Cryptococcus Infection of Macrophages.

使用流式细胞术分析巨噬细胞的隐球菌感染。

• DOI: 10.1007/978-1-4939-6581-6_24
• 发表时间: 2017
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Evans RJ

PPAR-gamma Fun(gi) With Prostaglandin.

• DOI: 10.1177/1550762919899641
• 发表时间: 2020
• 期刊: Nuclear receptor signaling

Cryptococcus neoformans Intracellular Proliferation and Capsule Size Determines Early Macrophage Control of Infection.

• DOI: 10.1038/srep21489
• 发表时间: 2016-02-18
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Bojarczuk A;Miller KA;Hotham R;Lewis A;Ogryzko NV;Kamuyango AA;Frost H;Gibson RH;Stillman E;May RC;Renshaw SA;Johnston SA
• 通讯作者: Johnston SA