Love/hate relationships of Achromobacter species and human macrophages

无色杆菌属与人类巨噬细胞的爱/恨关系

• 批准号: BB/Y00440X/1
• 负责人: Miguel Valvano
• 金额: $ 68.59万
• 依托单位: Queen's University Belfast
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FY00440X%2F1
• 关键词: Love; hate; relationships; Achromobacter; species

The success of pathogenic microbes depends on their ability to overcome immune barriers in the host including survival in host cells designed to kill pathogens (e.g., macrophages), which gobbled up microbes and trap them in membrane-bound vacuoles known as phagosomes. Engulfed pathogenic microbes, however, can disarm macrophages and counteract immune defenses by deploying proteins called effectors. When infections occur in healthy people, pathogens also elicit inflammatory responses that help the host to clear the infection. In contrast, susceptible people, such as those with cystic fibrosis, immunosuppressive therapies, diabetes, elderly, or undergoing major surgery, cannot readily overcome pathogens. Moreover, susceptible people can be infected by opportunistic bacteria that rarely cause infection in healthy people and often display high-level multidrug antibiotic resistance, which makes treatment more difficult. For example, my research group has discovered that cystic fibrosis (CF) gene-defective macrophages cannot destroy engulfed bacteria and play a central role in maintaining the chronic inflammation state associated with infections by opportunistic bacteria. The interplay between the host and the pathogen in these cases whereby the host is permissive to infection is not well understood, and emerging opportunistic pathogens, in general, are not well established as infection models. We think that intracellular pathogens engulfed by macrophages, combined with host underlying defects (e.g., CF mutations), induce a highly proinflammatory state that becomes deleterious to susceptible people with CF. To explore this idea, we first need to establish a relevant model system; we propose to use the emerging bacterium Achromobacter as a novel opportunistic pathogen and to compare Achromobacter's survival mechanisms in normal and CF-defective human macrophages, as non-susceptible and susceptible host cell models, respectively.Achromobacter bacteria are increasingly becoming the dominant microbes recovered from people with cystic fibrosis (PWCF) including those with end-stage lung disease. Very little is known on the pathogenesis of Achromobacter sp. However, we have recently discovered that Achromobacter bacteria isolated from PWCF can survive and divide intracellularly in human macrophages, ultimately destroying these cells by stimulating heightened inflammation. For this, we have also found that Achromobacter deploys bacterial toxins in the host cells and represses anti-inflammatory responses. In this research proposal we aim to define: (i) the bacterial properties associated with intracellular survival, and (ii) the macrophage cellular responses upon infection by comparing macrophages from healthy and CF people. We anticipate these studies will allow us to identify new ways to treat the infection in these people that may be applicable to other situations where the host is more susceptible due to diseases or medical treatments.

致病性微生物的成功取决于其克服宿主中免疫屏障的能力，包括旨在杀死病原体（例如巨噬细胞）的宿主细胞中的存活，这些宿主细胞（例如巨噬细胞）吞噬了微生物并将其捕获在被称为吞噬体的膜结合的液泡中。但是，吞没的致病微生物可以通过部署称为效应子的蛋白质来解除巨噬细胞和抵抗免疫防御的措施。当健康人中感染时，病原体还会引起炎症反应，帮助宿主清除感染。相比之下，易感人物，例如患有囊性纤维化，免疫抑制疗法，糖尿病，老年人或接受重大手术的人，无法轻易克服病原体。此外，易感人物可能会受到机会性细菌的感染，这些细菌很少引起健康人的感染，并且经常表现出高级多药抗生素耐药性，从而使治疗更加困难。例如，我的研究小组发现，囊性纤维化（CF）基因缺陷巨噬细胞不能破坏被吞噬的细菌，并且在维持与机会性细菌相关的慢性炎症状态方面起着核心作用。在这种情况下，宿主与病原体之间的相互作用允许宿主感染尚未得到充分了解，并且通常将新兴的机会性病原体确定为感染模型。我们认为，巨噬细胞吞没的细胞内病原体与宿主的潜在缺陷（例如CF突变）相结合，诱导了一种高度促进的疾病，该状态变得有害于易感CF的人。为了探索这个想法，我们首先需要建立相关的模型系统。我们建议将新兴细菌作为一种新型的机会性病原体，并将Achromobacter的生存机制比较正常和CF缺陷的人类巨噬细胞中的生存机制，分别是不易易感性和易感性宿主细胞模型，因为近卵细菌逐渐从cy fibres中恢复了cyStick，cy fibrise（Pwc cyst ics cyst ics）都在cy夫人中恢复过来。关于Achromobacter sp的发病机理，知之甚少。但是，我们最近发现，从pwcf中分离出来的细菌可以在人类巨噬细胞中生存和细胞内分裂，最终通过刺激增强的炎症来破坏这些细胞。为此，我们还发现，阿克罗莫杆菌在宿主细胞中部署细菌毒素并抑制抗炎反应。在这项研究建议中，我们旨在定义：（i）与细胞内存活相关的细菌特性，以及（ii）通过比较健康和CF人的巨噬细胞感染后巨噬细胞反应。我们预计这些研究将使我们能够确定这些人的感染方法，这些方法可能适用于其他情况，因为宿主由于疾病或药物治疗而更容易受到影响。