Robust Phagocyte Recruitment Controls the Opportunistic Fungal Pathogen Mucor circinelloides in Innate Granulomas In Vivo.
Robust Phagocyte Recruitment Controls the Opportunistic Fungal Pathogen Mucor circinelloides in Innate Granulomas In Vivo.
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DOI：
10.1128/mbio.02010-17
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发表时间：
2018-03-27
期刊：
影响因子：
6.4
通讯作者：
Voelz K
中科院分区：
文献类型：
--
作者：
Inglesfield S;Jasiulewicz A;Hopwood M;Tyrrell J;Youlden G;Mazon-Moya M;Millington OR;Mostowy S;Jabbari S;Voelz K
毛霉菌病是一种新出现的真菌感染，其病死率极高，患者的先天免疫反应缺陷，尤其是吞噬细胞介导的功能缺陷。然而，我们目前对这些先天免疫效应器和毛霉菌孢子在早期免疫反应中的分子和细胞相互作用的了解有限。在这里，用计算机模拟方法和实时活体显微镜相结合的方法模拟了由卷状毛霉孢子感染所引起的先天免疫招募的早期事件。在斑马鱼毛霉病幼体模型中，吞噬细胞被迅速招募到感染部位。这种强有力的早期招募可以防止疾病在体内发作。在硅胶分析中发现，保护取决于感染部位的吞噬细胞的数量，而不是招募的速度。数学模型强调了促炎信号对吞噬细胞募集的作用，以及抑制孢子萌发对预防活动性真菌疾病的重要性。在硅胶数据中，这些都得到了体内缺乏真菌孢子杀灭和缺乏活性氧爆发的支持，这两者共同导致了潜在的真菌感染。在感染的潜伏期，孢子在体内的先天肉芽肿中得到控制。免疫抑制可以使疾病重新活跃起来。总而言之，这些数据代表了第一次在体内实时分析真菌感染早期先天肉芽肿的形成。这一结果突出了毛霉病的潜在潜伏期，应紧急考虑用于患者的临床治疗。毛霉病是一种戏剧性的真菌感染，经常导致患者死亡。我们对引起这种感染的真菌的免疫反应知之甚少，尽管有证据表明感染后早期免疫事件存在缺陷。在这里，我们剖析了对感染性真菌孢子的早期免疫反应。我们发现，特殊的白细胞(吞噬细胞)对这些孢子迅速做出反应，并在真菌周围积聚。然而，我们证明了使吞噬细胞杀死真菌的机制失败了，允许孢子存活。相反，在孢子周围形成一簇类似于早期肉芽肿的吞噬细胞，以控制潜伏感染。这项研究是对真菌感染期间早期肉芽肿形成的第一次详细分析，强调了临床治疗患者需要考虑的潜伏期。
Mucormycosis is an emerging fungal infection with extremely high mortality rates in patients with defects in their innate immune response, specifically in functions mediated through phagocytes. However, we currently have a limited understanding of the molecular and cellular interactions between these innate immune effectors and mucormycete spores during the early immune response. Here, the early events of innate immune recruitment in response to infection by Mucor circinelloides spores are modeled by a combined in silico modeling approach and real-time in vivo microscopy. Phagocytes are rapidly recruited to the site of infection in a zebrafish larval model of mucormycosis. This robust early recruitment protects from disease onset in vivo. In silico analysis identified that protection is dependent on the number of phagocytes at the infection site, but not the speed of recruitment. The mathematical model highlights the role of proinflammatory signals for phagocyte recruitment and the importance of inhibition of spore germination for protection from active fungal disease. These in silico data are supported by an in vivo lack of fungal spore killing and lack of reactive oxygen burst, which together result in latent fungal infection. During this latent stage of infection, spores are controlled in innate granulomas in vivo. Disease can be reactivated by immunosuppression. Together, these data represent the first in vivo real-time analysis of innate granuloma formation during the early stages of a fungal infection. The results highlight a potential latent stage during mucormycosis that should urgently be considered for clinical management of patients. Mucormycosis is a dramatic fungal infection frequently leading to the death of patients. We know little about the immune response to the fungus causing this infection, although evidence points toward defects in early immune events after infection. Here, we dissect this early immune response to infectious fungal spores. We show that specialized white blood cells (phagocytes) rapidly respond to these spores and accumulate around the fungus. However, we demonstrate that the mechanisms that enable phagocytes to kill the fungus fail, allowing for survival of spores. Instead a cluster of phagocytes resembling an early granuloma is formed around spores to control the latent infection. This study is the first detailed analysis of early granuloma formation during a fungal infection highlighting a latent stage that needs to be considered for clinical management of patients.