Novel Toxins and Receptors in Mucormycosis Pathogenesis and Treatment

毛霉菌病发病机制和治疗中的新型毒素和受体

基本信息

批准号：
10666383
负责人：
ASHRAF S. IBRAHIM
金额：
$ 55.48万
依托单位：
LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-02-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10666383
关键词：
ADP-ribosylation factor 6 Adherens Junction Adrenal Cortex Hormones Angioinvasion Antibodies Antifungal Agents Antifungal Therapy Apoptosis Binding Biochemical Blocking Antibodies Blood Vessels Brain Cell Death Cell Line Cell surface Cells Cessation of life Clinical Cross Reactions Data Diabetic Ketoacidosis Disease Edema Endothelial Cells Endothelium Epidermal Growth Factor Receptor Epithelial Cells Epithelium Epitope Mapping Event Extracellular Matrix FDA approved Funding GRP78 gene Galactose Binding Lectin Galectin 1 Genes Germination Hematogenous Hematopoietic Human Hyphae Immunocompetent Immunocompromised Host In Vitro Incidence Induction of Apoptosis Infection Inhalation Integrin alpha3beta1 Integrins Invaded Iron Knockout Mice Life Lung diseases Methods Molecular Monoclonal Antibodies Monomeric GTP-Binding Proteins Mucorales Mucormycosis Mus Mutation Mycotoxins Names Nasal Epithelium Necrosis Neutropenia Operative Surgical Procedures Orbital Diseases Organ Organ Transplantation Organ failure Pathogenesis Pathway interactions Patients Penetration Pericytes Pharmaceutical Preparations Plants Play Poison Prevalence Prevention strategy Process Production Progress Reports Proteins Receptor Cell Reproduction spores Rhizopus Ribosomes Ricin Ricin B Chain Risk Factors Role Seminal Sequence Homologs Serum Small Interfering RNA Solid TP53 gene Therapeutic Thrombosis Tissues Toxin Treatment Failure Tumor Suppressor Proteins Umbilical vein Vascular Permeabilities Virulence alveolar epithelium base clinically relevant cross reactivity design diabetic efficacy evaluation fungus genetic approach glucose-regulated proteins in vivo inhibiting antibody inhibitor monolayer mortality mouse model nanobodies necrotic tissue new therapeutic target novel novel therapeutic intervention preclinical development prevent receptor treatment strategy virtual wound

项目摘要

PROJECT SUMMARY/ABSTRACT Mucormycosis, caused by Mucorales fungi, is a life-threatening infection that occurs in patients immunocom- promised by diabetic ketoacidosis, neutropenia, corticosteroid use, and/or increased serum iron. Rhizopus species are the most common cause of mucormycosis. Because of the rising prevalence of mucormycosis risk factors, the incidence of the infection has risen. Despite disfiguring surgery and aggressive antifungal therapy, the mortality of mucormycosis remains >40%, and approaches 100% in patients with disseminated disease. Clearly new strategies to prevent and treat mucormycosis are needed. Commonly initiated via inhalation of spores, clinical hallmarks of mucormycosis is the virtually uniform pres- ence of extensive angioinvasion with resultant vessel thrombosis and tissue necrosis. These features highlight the importance of the ability of the fungus to invade alveolar epithelial cells (AECs) to initiate the infection. They also emphasize the significance of penetrating the endothelium during the progression and dissemination of the disease. Finally, the extensive tissue necrosis points to the presence of fungal toxins. During the last funding cycle, we determined that Mucorales initiate infection when the CotH invasins bind to integrins on AECs. This binding triggers the activation of AEC epidermal growth factor receptor (EGFR) to in- duce invasion of germinated spores with an unidentified mechanism. We also discovered that germinated spores disseminate through the pericytes and extracellular matrix to invade endothelial cells via CotH interact- ing with Glucose Regulated Protein 78. We also made the seminal discovery that Mucorales damage host cells by producing a toxin called mucoricin, so named because of its similarities to the plant toxin, ricin. Both CotH invasins and mucoricin are required for pathogenesis and antibodies targeting either protein are protective in mice. Specifically, our preliminary data show that the combination of binding of CotH invasins and subsequent production of mucoricin cause disintegration of AECs (potentially by activating the ADP-ribosylation factor 6 (Arf6)), excessive vascular leak, tissue edema, and organ failure; all of which are hallmarks of mucormycosis and are associated with antifungal therapy failure. Thus, we propose to build on these exciting data and deter- mine the molecular mechanisms by which Mucorales induce disintegration of AECs and vascular leak and de- fine the intracellular events of mucoricin-induced host cell entry and death. We will also evaluate the efficacy of novel therapeutic strategies targeting Arf6, host receptors, mucoricin and mucoricin-induced host cell death pathways in mice. We use a mechanism-based approach to examine two hallmarks of mucormycosis: angioinvasion and tissue necrosis. These studies will lead to novel therapies that target mucoricin, host receptors and host cell- activation pathways. Some of these therapies are FDA-approved drugs with potential to rapidly impact treat- ment of this lethal infection.

项目摘要/摘要由粘膜真菌引起的粘膜菌病是一种威胁生命的感染，发生在患者中。由糖尿病性酮症酸中毒，中性粒细胞减少症，皮质类固醇使用和/或血清铁增加的承诺。根茎物种是粘膜菌病的最常见原因。由于粘膜菌病风险的患病率上升因素，感染的发生率上升。尽管手术和侵略性抗真菌疗法毁容，但粘膜细胞增多的死亡率仍然> 40％，在传播疾病的患者中接近100％。显然，需要采取新的预防和治疗粘膜菌病的策略。通常是通过吸入孢子引发的，粘膜细胞增多的临床标志是几乎均匀的前提广泛的血管浸润，导致血管血栓形成和组织坏死。这些功能突出显示真菌侵入肺泡上皮细胞（AEC）启动感染的能力的重要性。他们还强调了在进展和传播过程中穿透内皮的重要性疾病。最后，广泛的组织坏死表明存在真菌毒素。在最后一个资金周期中，我们确定当Coth Invasins结合到 AEC的整合素。这种结合触发了AEC表皮生长因子受体（EGFR）的激活用身份不明的机制对发芽孢子的浸润。我们还发现发芽孢子通过周细胞和细胞外基质传播，通过Coth相互作用侵入内皮细胞 - 用葡萄糖调节的蛋白质78。通过产生一种称为粘蛋白的毒素，因此命名是因为它与植物毒素Ricin相似。两者都有发病机理需要侵入蛋白和粘蛋白，靶向任何一种蛋白质的抗体在老鼠。具体而言，我们的初步数据表明，Coth Invasins的结合与随后的结合粘蛋白的产生会导致AEC分解（可能通过激活ADP-核糖基化因子6 （ARF6）），过度的血管泄漏，组织水肿和器官衰竭；所有这些都是粘膜细胞增多的标志并与抗真菌治疗衰竭有关。因此，我们建议以这些令人兴奋的数据为基础，并确定矿山粘液诱导AEC崩解以及血管泄漏和de-的分子机制细细胞内粘蛋白诱导的宿主细胞进入和死亡的细胞内事件。我们还将评估靶向ARF6，宿主受体，粘膜素和粘膜蛋白诱导的宿主细胞死亡的新型治疗策略小鼠的途径。我们使用一种基于机制的方法来检查粘膜菌病的两个标志：血管侵袭和组织坏死。这些研究将导致靶向粘蛋白，宿主受体和宿主细胞的新型疗法 - 激活途径。其中一些疗法是FDA批准的药物，可能会迅速影响治疗 - 这种致命感染。

项目成果

期刊论文数量（29）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Evaluation of Sex Differences in Murine Diabetic Ketoacidosis and Neutropenic Models of Invasive Mucormycosis.

DOI：
10.3390/jof7040313
发表时间：
2021-04-18
期刊：
Journal of fungi (Basel, Switzerland)
影响因子：
0
作者：
Gebremariam T;Alkhazraji S;Alqarihi A;Wiederhold NP;Najvar LK;Patterson TF;Filler SG;Ibrahim AS
通讯作者：
Ibrahim AS

A bacterial endosymbiont of the fungus Rhizopus microsporus drives phagocyte evasion and opportunistic virulence.

DOI：
10.1016/j.cub.2022.01.028
发表时间：
2022-03-14
期刊：
Current biology : CB
影响因子：
0
作者：
Itabangi H;Sephton-Clark PCS;Tamayo DP;Zhou X;Starling GP;Mahamoud Z;Insua I;Probert M;Correia J;Moynihan PJ;Gebremariam T;Gu Y;Ibrahim AS;Brown GD;King JS;Ballou ER;Voelz K
通讯作者：
Voelz K

Combination Therapy for Mucormycosis: Why, What, and How?

DOI：
10.1093/cid/cir885
发表时间：
2012-02-01
期刊：
CLINICAL INFECTIOUS DISEASES
影响因子：
11.8
作者：
Spellberg, Brad;Ibrahim, Ashraf;Walsh, Thomas J.
通讯作者：
Walsh, Thomas J.

Combination treatment of liposomal amphotericin B and isavuconazole is synergistic in treating experimental mucormycosis.

DOI：
10.1093/jac/dkab233
发表时间：
2021-09-15
期刊：
The Journal of antimicrobial chemotherapy
影响因子：
0
作者：
Gebremariam T;Gu Y;Singh S;Kitt TM;Ibrahim AS
通讯作者：
Ibrahim AS

Calli Essential Oils Synergize with Lawsone against Multidrug Resistant Pathogens.

DOI：
10.3390/molecules22122223
发表时间：
2017-12-20
期刊：
Molecules (Basel, Switzerland)
影响因子：
0
作者：
Soliman SSM;Alsaadi AI;Youssef EG;Khitrov G;Noreddin AM;Husseiny MI;Ibrahim AS
通讯作者：
Ibrahim AS