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The role of spleen tyrosine kinase (syk) in neutrophil responses to pathogenic fungi.

脾酪氨酸激酶（syk）在中性粒细胞对病原真菌反应中的作用。

基本信息

批准号：
10208687
负责人：
Michael K Mansour
金额：
$ 40.07万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-16 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10208687
关键词：
Address Admission activity Area Attention Autoimmune Diseases Binding Blood Vessels CRISPR/Cas technology Candida Carbohydrates Cell Wall Cells Cellular Structures Chemotaxis Clinical Complement Complex Coupled Development Disease Embryo Fungal Components Generations Genome Glucans Goals Homing Immune Immunity Immunocompromised Host Immunomodulators Immunosuppression In Vitro Industrial fungicide Infection Inflammation Inflammatory Intensive Care Units Kinetics Lectin Receptors Life Ligands Longevity Malignant Neoplasms Medicine Modernization Molecular Mus Mycoses Natural Immunity Neutropenia Organ Pathogenesis Pathway interactions Patients Pattern recognition receptor Phagocytosis Phagosomes Phenotype Physicians Population Process Production Role SYK gene Shapes Signal Transduction Site Stem cell transplant Stimulus Surface System Therapeutic Transcriptional Activation Transplantation Up-Regulation Work Yeasts base chemokine cytokine dectin 1 extracellular first responder genetic manipulation high risk improved in vivo macrophage microbial mortality mouse model myeloblast neutrophil novel oxidation particle pathogenic fungus protein transport receptor reconstitution response self-renewal side effect stem cells transcription factor

项目摘要

Project Summary: Invasive fungal infections (IFI) constitute a rising threat to patients in the current practice of medicine. The modern physician uses potent immunomodulatory therapeutics to intervene on complex illnesses such as autoimmune disorders, malignancy and transplantation. While the impact of these therapeutics have resulted in major clinical breakthroughs, their immune inhibitory effects have profound side effects, often leaving patients at high risk for life-threatening infectious complications including IFI. To address this growing unmet need, we have turned attention to neutrophils, a critical first-responder innate immune cell required for rapid fungal elimination. In fact, patients with insufficient or dysfunctional neutrophils are at the highest risk for IFI. In macrophages, another innate immune cell, the recognition of the complex multi-layered carbohydrate fungal cell wall is performed, in part, through the lectin receptor, Dectin-1, which binds to β-1,3- glucan and activates spleen tyrosine kinase (syk) resulting in upregulation of pro-inflammatory cytokine production. While syk activity is essential for fungicidal activity in macrophages, its role in neutrophils has yet to be defined. Several issues present major impediments towards defining the role of syk in neutrophils. First, neutrophils are short lived cells (<24hrs) and second, genetic manipulation is difficult owing to their terminal differentiation. Moreover, the generation of syk-deficient mice is not possible given syk contribution to embryonic vascular development. Despite these challenges, we sought to define the role of syk in neutrophil- fungal interactions through the following key observations. First, we address the longevity of neutrophils by using conditional activation of the transcription factor, HoxB8. Through expression of HoxB8, precursor stem cells or myeloblasts remain indefinitely dividing, and following HoxB8 inactivation, myeloblasts differentiate permitting generation of unlimited neutrophils. Second, we demonstrate that the HoxB8 system is amenable to CRISPR/Cas9 editing allowing generation of syk-deficient neutrophils. Third, in order to deconvolute the complex fungal surface, we developed fungal-like particles using purified fungal carbohydrates to probe specific neutrophil responses. Fourth, we demonstrate that HoxB8 neutrophils complement in vivo neutrophil function in a mouse model of neutropenia and Candida infection. To determine the molecular mechanism of syk in fungal innate immunity in neutrophils, we propose three independent specific aims: (1) Determine the in vitro response of syk-deficient HoxB8 neutrophils to defined microbial stimuli, (2) Define the role of syk in neutrophil effector function in response to yeast morphotype, and (3) Delineate the contribution of syk to neutrophil-fungal immunity in vivo. At the conclusion of our studies, we will clarify the subcellular mechanisms responsible for neutrophil-fungal pathogenesis with the hope to develop improved fungicidal strategies to address the growing clinical burden of invasive fungal disease, especially in the highest risk patients. !

项目概述：侵袭性真菌感染（IFI）在目前的实践中对患者构成了日益严重的威胁，药现代医生使用有效的免疫调节疗法来干预复杂的自身免疫性疾病、恶性肿瘤和移植等疾病。虽然这些影响治疗方法取得重大临床突破，其免疫抑制作用具有深刻的一面这些药物的副作用，往往使患者处于危及生命的感染性并发症的高风险中，包括IFI。解决为了满足日益增长的未满足的需求，我们将注意力转向了中性粒细胞，一种关键的第一反应先天免疫细胞需要快速清除真菌。事实上，中性粒细胞不足或功能障碍的患者在风险最大的是IFL。在巨噬细胞，另一种先天免疫细胞，识别复杂的多层碳水化合物真菌细胞壁的作用部分是通过凝集素受体Dectin-1进行的，Dectin-1与β-1，3- 葡聚糖和激活脾酪氨酸激酶（syk），导致促炎细胞因子的上调生产尽管syk活性对于巨噬细胞中的杀真菌活性是必需的，但它在中性粒细胞中的作用还没有被证实。被定义。目前有几个问题是确定中性粒细胞中syk作用的主要障碍。第一、嗜中性粒细胞是短寿命细胞（<24小时），其次，由于其终末细胞，遗传操作是困难的。分化此外，鉴于syk对以下的贡献，syk缺陷小鼠的产生是不可能的：胚胎血管发育尽管有这些挑战，我们试图确定syk在中性粒细胞中的作用- 真菌的相互作用通过以下关键观察。首先，我们通过以下方式解决中性粒细胞的寿命问题：使用转录因子HoxB 8的条件激活。通过表达HoxB 8，细胞或成髓细胞保持无限分裂，在HoxB 8失活后，成髓细胞分化允许产生无限的嗜中性粒细胞。其次，我们证明了HoxB 8系统适合 CRISPR/Cas9编辑允许产生syk缺陷型中性粒细胞。第三，为了消除复杂的真菌表面，我们开发了真菌样颗粒使用纯化的真菌碳水化合物来探测特异性中性粒细胞反应。第四，我们证明了HoxB 8中性粒细胞补充体内中性粒细胞，在中性粒细胞减少症和念珠菌感染的小鼠模型中的功能。为了确定 syk在中性粒细胞真菌先天免疫中的作用，我们提出了三个独立的具体目标：（1）确定在中性粒细胞真菌先天免疫中， Syk缺陷型HoxB 8中性粒细胞对确定的微生物刺激的体外反应，（2）确定Syk在中性粒细胞效应子功能对酵母形态型的反应，以及（3）描述syk对体内嗜酸菌-真菌免疫。在我们的研究结论中，我们将阐明亚细胞机制负责嗜热真菌的致病机理，希望开发出改进的杀真菌策略，解决侵袭性真菌病日益增加的临床负担，特别是在高危患者中。 !

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Malakoplakia in Thoracic Transplant Recipients.

胸腔移植受者的软斑。

DOI：
10.1016/j.transproceed.2018.11.008
发表时间：
2019
期刊：
Transplantation proceedings
影响因子：
0.9
作者：
Lane,RJ;Kradin,R;Xia,D;Buchan,CA;Turbett,S;Kotton,CN;Mansour,MK
通讯作者：
Mansour,MK

A Case Report of Fatal Mucormycosis in a 30-Year-Old Patient with Autoimmune Polyendocrine Syndrome Type 1.

1 例 30 岁自身免疫性多内分泌综合征 1 型患者致命性毛霉菌病病例报告。

DOI：
10.1007/s10875-022-01226-4
发表时间：
2022
期刊：
Journal of clinical immunology
影响因子：
9.1
作者：
Rosenberg,JacobM;Villalba,JulianA;Ferrè,EliseMN;Mansour,MichaelK;Lionakis,MichailS
通讯作者：
Lionakis,MichailS

Rapid Quantum Magnetic IL-6 Point-of-Care Assay in Patients Hospitalized with COVID-19.

DOI：
10.3390/diagnostics12051164
发表时间：
2022-05-07
期刊：
Diagnostics (Basel, Switzerland)
影响因子：
0
作者：
通讯作者：

Novel Host Response-Based Diagnostics to Differentiate the Etiology of Fever in Patients Presenting to the Emergency Department.

DOI：
10.3390/diagnostics13050953
发表时间：
2023-03-02
期刊：
DIAGNOSTICS
影响因子：
3.6
作者：
Atallah, Johnny;Ghebremichael, Musie;Timmer, Kyle D. D.;Warren, Hailey M. M.;Mallinger, Ella;Wallace, Ellen;Strouts, Fiona R. R.;Persing, David H. H.;Mansour, Michael K. K.
通讯作者：
Mansour, Michael K. K.

Baseline procalcitonin as a predictor of bacterial infection and clinical outcomes in COVID-19: A case-control study.

DOI：
10.1371/journal.pone.0262342
发表时间：
2022
期刊：
PloS one
影响因子：
3.7
作者：
Atallah NJ;Warren HM;Roberts MB;Elshaboury RH;Bidell MR;Gandhi RG;Adamsick M;Ibrahim MK;Sood R;Bou Zein Eddine S;Cobler-Lichter MJ;Alexander NJ;Timmer KD;Atallah CJ;Viens AL;Panossian VS;Scherer AK;Proctor T;Smartt S;Letourneau AR;Paras ML;Johannes S;Wiemer J;Mansour MK
通讯作者：
Mansour MK