The impact of type 2 immunity on haematopoiesis and consequences for host immune function

2 型免疫对造血的影响及其对宿主免疫功能的影响

• 批准号: MR/W018578/1
• 负责人: James Hewitson
• 金额: $ 78.26万
• 依托单位: University of York
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW018578%2F1
• 关键词: impact; type; immunity; haematopoiesis; consequences

Our bone marrow constantly produces new immune cells to fight against infection. These originate from blood stem cells called haematopoietic stem cells (HSC). HSCs can respond to chemical signals (cytokines) that are produced following infection and this stimulates increased production of immune cells to kill the pathogen. This is beneficial against acute infections like certain bacteria and viruses but can also cause tissue damage in long-lasting diseases. Our research is focused on understanding how we respond to a class of pathogen that represent a very different challenge to our immune system - parasitic worms (helminths). Helminth parasites are much larger than bacteria and viruses and so are controlled by a different type of immune response (type 2 immunity). Type 2 immune responses also cause allergic disease. Around one quarter of the global population are infected with a helminth and these are extremely long-lived infections as the parasite can survive for years or even decades in an infected person. We are researching parasitic worms called which causes the disease schistosomiasis. More than 200 million people are infected with schistosomes and at least 800M people are at risk of infection, mostly in sub-Saharan Africa. There is no vaccine to this infection and treatment relies on a single drug (praziquantel) that does not stop people becoming immediately reinfected. Schistosomes are well known for their ability to manipulate our immune system and this allows them to turn-off immune responses that could otherwise kill them. This has spill over effects on other immune responses and these infections have been shown to reduce our response to other infections and even to vaccines. We have found that one way schistosomes can do this is by altering immune cell development in the bone marrow. We have little understanding of how the type 2 immune responses induced by parasitic worms alters bone marrow cells such as HSCs. Importantly, these changes caused by infection seem to even persist after the parasite is killed by drugs. This means that people who have been successfully cured of their worm infection may still respond to other infections or vaccines in a different or less robust manner to people who have never been infected. To better understand this, we will study how schistosome infection alters HSCs and immune cell function in both laboratory mice and by using blood cells from naturally infected people. We will test how infection alters immune cells, how long these effects persist for after parasite clearance, and how these changes alter immune responses to both the worm itself and also vaccines. This research will reveal how changes to bone marrow cells in schistosome infection broadly alter how our immune system functions and is an essential first step in understanding how we can reverse these changes. This has obvious importance for ongoing vaccine programmes against many different diseases, especially as weaker responses could potentially allow pathogens to mutate and becoming resistant to these vaccines.

我们的骨髓不断产生新的免疫细胞来对抗感染。造血干细胞（HSC）是造血干细胞的一种。HSC可以对感染后产生的化学信号（细胞因子）做出反应，这刺激免疫细胞的产生增加以杀死病原体。这对某些细菌和病毒等急性感染有益，但也可能导致长期疾病的组织损伤。我们的研究重点是了解我们如何应对一类病原体，这类病原体对我们的免疫系统构成了非常不同的挑战-寄生虫（蠕虫）。蠕虫寄生虫比细菌和病毒大得多，因此由不同类型的免疫反应（2型免疫）控制。2型免疫反应也会引起过敏性疾病。全球约有四分之一的人口感染了蠕虫，这些是非常长寿的感染，因为寄生虫可以在感染者体内存活数年甚至数十年。我们正在研究引起血吸虫病的寄生蠕虫。超过2亿人感染了埃博拉病毒，至少有8亿人面临感染风险，其中大部分在撒哈拉以南非洲。这种感染没有疫苗，治疗依赖于单一药物（吡喹酮），不能阻止人们立即再次感染。血吸虫以其操纵我们免疫系统的能力而闻名，这使得它们能够关闭可能杀死它们的免疫反应。这对其他免疫反应产生了溢出效应，这些感染已被证明会降低我们对其他感染甚至疫苗的反应。我们已经发现，染色体可以做到这一点的一种方式是通过改变骨髓中的免疫细胞发育。我们对寄生蠕虫诱导的2型免疫反应如何改变骨髓细胞（如HSC）知之甚少。重要的是，这些由感染引起的变化似乎在寄生虫被药物杀死后仍然存在。这意味着已经成功治愈蠕虫感染的人仍然可能以与从未感染过的人不同或不那么强烈的方式对其他感染或疫苗作出反应。为了更好地理解这一点，我们将研究嗜酸性粒细胞感染如何改变实验室小鼠的HSC和免疫细胞功能，并使用自然感染者的血细胞。我们将测试感染如何改变免疫细胞，这些影响在寄生虫清除后持续多久，以及这些变化如何改变对蠕虫本身和疫苗的免疫反应。这项研究将揭示骨髓细胞在病毒感染中的变化如何广泛地改变我们的免疫系统功能，并且是了解我们如何逆转这些变化的重要第一步。这对正在进行的针对许多不同疾病的疫苗计划具有明显的重要性，特别是因为较弱的反应可能会使病原体发生突变并对这些疫苗产生抗药性。