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Elucidating the mechanism of macrophage death during infection with the AIDS-associated opportunistic pathogen Histoplasma capsulatum

Elucidating the mechanism of macrophage death during infection with the AIDS-associated opportunistic pathogen Histoplasma capsulatum
阐明艾滋病相关机会病原体荚膜组织胞浆菌感染期间巨噬细胞死亡的机制
批准号:
10177850
负责人:
Anita Sil
金额:
$55.33万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-07-10 至 2022-06-30

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中文摘要
翻译
项目摘要 摘要组织胞浆菌(Hc)是一种未被充分研究的真菌病原体,可引起人类致命的疾病。 免疫功能受损的艾滋病患者。我们的长期研究目标是深入了解 HC用来杀死受感染的免疫细胞的机制,最终导致对 艾滋病毒感染者的丙型肝炎病毒感染的治疗。HC是中西部特有的一种土壤真菌 美国、中南美洲、非洲和世界其他地区。它被引入到 哺乳动物通过吸入寄主,随后被巨噬细胞吞噬。与大多数微生物不同,HC 在巨噬细胞吞噬体内存活和复制。吞噬小体内HC的强劲增殖是 随后宿主细胞死亡,从而使活的真菌细胞从巨噬细胞中逃脱并经历 随后的几轮吞噬和细胞内增殖。缺乏细胞免疫的个体 应答者更有可能发展为严重的播散性疾病,而感染丙型肝炎的艾滋病患者 接受长期的,有时是终生的抗真菌治疗。 我们最近发现,HC利用分泌的效应物Cbp1来触发整合的应激 宿主巨噬细胞的应答(ISR),导致细胞内真菌复制后宿主细胞死亡。ISR 是触发翻译延长的α亚单位磷酸化的细胞内信号级联 因子eIF2以及诱导促凋亡转录因子CHOP对多种 压力。我们已经证明CHOP在宿主对HC感染的敏感性中是必需的。 感染。这些数据现已在《公共科学图书馆·病原体》杂志上发表。据我们所知,这些是第一批 在宿主对真菌病原体的反应中牵涉到ISR。然而,我们对此仍然知之甚少 Cbp1如何诱导ISR。在这里,我们建议以稳健的初步数据为基础来定义机制和 丙型肝炎病毒感染期间Cbp1依赖的ISR诱导的后果。我们将:(1)研究其发病机制 Cbp1是如何诱导ISR的;(2)阐明在HC感染过程中Cbp1是否单独作用而诱导ISR和/或宿主- 细胞死亡,或是否参与其他HC效应;以及(3)确定eIF2α的机制和作用 磷酸化,启动ISR的中央信号事件,以响应HC感染。这些研究 将探索真核病原体用来控制巨噬细胞活性的新策略,最终 发展我们对细胞内微生物病原体触发的一般原理的理解 细胞应激并导致疾病。鉴于艾滋病患者对多种细胞内病毒的易感性 关于病原体,这些一般原则的确立可能在以下背景下特别相关 制定治疗策略(如抑制ISR)以治疗与艾滋病相关的机会性感染 其他类似的病原体。
英文摘要
Project Summary Histoplasma capsulatum (Hc) is an understudied fungal pathogen that causes fatal disease in immunocompromised individuals with AIDS. Our long-term research goal is to gain insight into the pathogenic mechanisms used by Hc to kill infected immune cells, ultimately resulting in improved understanding and treatment of Hc infections in HIV-infected individuals. Hc is a soil fungus that is endemic in the Midwestern United States, Central and South America, Africa, and other regions of the world. It is introduced into mammalian hosts by inhalation and is subsequently phagocytosed by macrophages. Unlike most microbes, Hc survives and replicates within the macrophage phagosome. Robust proliferation of Hc within the phagosome is followed by host-cell death, thus allowing live fungal cells to escape from the macrophage and undergo subsequent rounds of phagocytosis and intracellular proliferation. Individuals who lack a cell-mediated immune response are more likely to develop severe disseminated disease, and AIDS patients with Hc infection are subjected to prolonged, sometimes lifelong, anti-fungal therapy. We recently discovered that Hc utilizes the secreted effector Cbp1 to trigger an integrated stress response (ISR) in host macrophages, resulting in host cell death after intracellular fungal replication. The ISR is an intracellular signaling cascade that triggers phosphorylation of the α-subunit of the translation elongation factor eIF2 as well as induction of the pro-apoptotic transcription factor CHOP in response to a variety of stresses. We have shown that CHOP is required for host sensitivity to Hc infection in the mouse model of infection. These data are now in press at PLoS Pathogens. To our knowledge, these are the first data that implicate the ISR in the host response to fungal pathogens. However, we still have very little understanding of how Cbp1 induces the ISR. Here we propose to build on robust preliminary data to define the mechanism and consequences of Cbp1-dependent ISR induction during Hc infection. We will: (1) investigate the mechanism of how Cbp1 induces the ISR; (2) elucidate if Cbp1 acts alone during Hc infection to induce the ISR and/or host- cell death, or whether other Hc effectors are involved; and (3) determine the mechanism and role of eIF2α phosphorylation, the central signaling event that initiates the ISR, in response to Hc infection. These studies will explore new strategies used by eukaryotic pathogens to control the viability of macrophages, ultimately developing our understanding of general principles deployed by intracellular microbial pathogens to trigger cellular stress and cause disease. Given the susceptibility of AIDS patients to a variety of intracellular pathogens, the establishment of these general principles may be particular relevant in the context of developing therapeutic strategies (such as ISR inhibition) for AIDS-related opportunistic infections with Hc and other like pathogens.
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Role of secreted cystine-knot proteins in Histoplasma-host interactions
Virulence gene discovery in Coccidioides
Molecular and cellular analysis of host response to Cocci
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