Love/hate relationships of Achromobacter species and human macrophages

病原微生物的成功取决于它们克服宿主免疫屏障的能力，包括在宿主细胞中生存，这些宿主细胞旨在杀死病原体(例如巨噬细胞)，后者吞噬微生物并将其困在被称为吞噬小体的膜结合的空泡中。然而，被吞噬的病原微生物可以解除巨噬细胞的武装，并通过部署称为效应器的蛋白质来抵消免疫防御。当感染发生在健康人身上时，病原体也会引发炎症反应，帮助宿主清除感染。相比之下，易感人群，如囊性纤维化、免疫抑制疗法、糖尿病、老年人或正在接受大手术的人，不容易克服病原体。此外，易感人群可能会被机会性细菌感染，这些细菌很少会在健康人中造成感染，而且往往表现出高水平的多药耐药性，这使得治疗更加困难。例如，我的研究小组发现囊性纤维化(CF)基因缺陷的巨噬细胞无法摧毁被吞噬的细菌，并在维持与机会性细菌感染相关的慢性炎症状态方面发挥核心作用。在这些宿主允许感染的情况下，宿主和病原体之间的相互作用尚不清楚，通常情况下，新出现的机会性病原体也没有很好地被建立为感染模型。我们认为，被巨噬细胞吞噬的细胞内病原体，与宿主潜在的缺陷(例如，CF突变)结合在一起，会诱导高度促炎状态，对CF易感人群变得有害。为了探索这个想法，我们首先需要建立一个相关的模型系统；我们建议使用新兴的细菌Achromobacter作为一种新的机会致病菌，并比较Achromobacter在正常和CF缺陷的人巨噬细胞中的生存机制，分别作为非敏感和易感宿主细胞模型。Achromobacter细菌越来越成为囊性纤维化(PWCF)患者包括终末期肺部疾病患者的主要微生物。目前对Achromobacter sp.的致病机理知之甚少。然而，我们最近发现，从PWCF中分离出来的Achromobacter细菌可以在人的巨噬细胞内存活和分裂，最终通过刺激炎症加剧来破坏这些细胞。为此，我们还发现，Achromobacter在宿主细胞中部署细菌毒素，并抑制抗炎反应。在这项研究方案中，我们的目标是定义：(I)与细胞内生存相关的细菌特性，以及(Ii)巨噬细胞对感染的反应，通过比较健康人和慢性粒细胞白血病患者的巨噬细胞。我们预计，这些研究将使我们能够找到治疗这些人感染的新方法，这些方法可能适用于宿主因疾病或治疗而更容易受到影响的其他情况。

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.