李建东《细胞》子刊解析疾病分子机制

　　生物通报道：来自罗切斯特大学医学中心（University of Rochester Medical Center），Amgen公司，南加州大学，贝勒医学院，中国复旦大学华山医院等处的研究人员针对ALI（急性肺损伤）及其早期高死亡率的分子机理这一未解之谜，发现了泛素分解酶（deubiquitinating enzyme）cylindromatosis (CYLD)的关键作用。这一研究成果公布在《Immunity》杂志上。

文章的通讯作者是罗切斯特大学医学中心的华人科学家李建东（Jian-Dong Li，音译），同时参予研究的中方人员还有翁心华教授等。

原文摘要：
Immunity, Vol 27, 349-360, 24 August 2007
Tumor Suppressor CYLD Regulates Acute Lung Injury in Lethal Streptococcus pneumoniae Infections
[Abstract]

肺炎链球菌（Streptococcus pneumoniae，S. pneumoniae）是由肺炎球菌或肺炎链球菌所引起，占院外感染肺炎中的半数以上。肺段或肺叶呈急性炎性实变，患者有寒战、高热、胸痛、咳嗽和血痰等症状。近年来由于抗菌药物的广泛应用，临床上症状轻或不典型病较为多见。

肺炎球菌为革兰阳性球菌，常成对（肺炎双球菌）或呈链状排列（肺炎链球菌），这些细菌为上呼吸道正常菌群，只有当免疫力降低时方始致病。发病以冬季和初春为多，吸烟者、痴呆者、充血性心衰、慢性病患者、慢支炎、支气管扩张、以及免疫缺陷病人均易受肺炎球菌侵袭。

肺炎球菌会引起急性肺损伤（Acute Lung injury, ALI），ALI是由于各种原因引起的肺组织结构发生特征性的病理改变而出现的临床综合征。其病理特点为肺泡毛细血管内皮细胞和肺泡上皮细胞损伤，表现为广泛肺水肿和微小肺不张。病理生理改变主要是肺内分流增加和肺顺应性下降。临床上表现为低氧血症、呼吸频速和X线胸片出现双肺弥漫性浸润。ALI有着从轻到重的连续过程，重症ALI即急性呼吸窘迫综合征(ARDS) 

目前有关ALI及其早期高死亡率的分子机理尚不清楚，虽然近期的研究发现泛素分解酶（deubiquitinating enzyme）cylindromatosis (CYLD)是一个关键的T细胞发育、肿瘤细胞增殖、NF-κB转录因子信号中的关键调控子，但是CYLD在细菌诱导的致死性方面的作用，科学家们仍然不清楚。

在这篇文章中，研究人员发现CYLD缺陷型可以保护小鼠免受S. pneumoniae pneumolysin (PLY)诱导引发的ALI和致死性，CYLD可以通过PLY高度诱导，并且也抑制了肺部MKK3-p38激酶依赖性，血纤维蛋白溶酶原（plasminogen）活性抑制子1（PAI-1）。因此研究人员认为CYLD对于宿主存活性是有害的，这就为解开ALI及其早期高死亡率问题提出了一新的分子机制。
（生物通：张迪）

附：
Jian-Dong Li 

Professor of Microbiology & Immunology 
Primary Appointment:
Microbiology & Immunology 

GEBS Cluster Affiliations:
IMV - Immunology, Microbiology, and Virology
E-Mail: [e-mail] 

Research Focus 
Molecular and Cellular Basis of Host-Bacterial Interactions 

Research Overview 
We primarily focus on understanding the molecular and cellular mechanisms by which the bacterial pathogens interact with host cells to cause diseases. 
Bacterial pathogens have evolved many sophisticated ways to subvert normal host cellular responses during infections. Two such subversive pathogens are the Gram-negative nontypeable Haemophilus influenzae (NTHi) and the Gram-positive Streptococcus pneumoniae (S. pneumoniae) that exemplify important, as yet underexplored, human respiratory pathogens in both children and adults. Despite the need for prophylactic measures, the molecular and cellular mechanisms underlying the pathogenesis of NTHi and S. pneumoniae infections remain largely unknown. 

Our long-term objectives are to fully investigate the molecular and cellular mechanisms including the signaling mechanism underlying NTHi and S. pneumoniae infections using multidisciplinary approaches including molecular genetics, cell biology, biochemistry, molecular biology, immunology, functional genomics and proteomics as well as knockout mice. 

Our short-term goals are to elucidate the signaling mechanisms involved in NTHi and S. pneumoniae infections. Because NTHi and S. pneumoniae infections, like most other respiratory bacterial infections, are characterized by inflammation and mucus overproduction, we particularly focus on investigating the signaling pathways including the bacterial factors, host epithelial surface receptors, intracellular signaling pathways and transcription factors involved in NTHi- and S. pneumoniae-induced inflammatory and immune responses as well as mucin up-regulation, a primary innate defensive response for mammalian airways. 

Four major research areas we are currently focusing on are as follows: 

Regulation of Inflammation in Bacterial Infections: Inflammation is a hallmark of respiratory bacterial infections. The molecular mechanisms underlying bacteria-induced inflammation remain largely undefined. Given that, in in vivo situations, multiple factors are existing simultaneously, we hypothesize that NF-κB, the key regulator of inflammation, is synergistically regulated by multiple pathogenic inducers via activation of multiple signaling pathways in the pathogenesis of respiratory bacterial infections. Indeed, we recently showed that NTHi and S. pneumoniae or NTHi and TNF-α synergistically activate NF-κB and cytokine production via multiple signaling pathways involving IκBα, p38 MAPK and MEKK1. We currently focus on identifying the bacterial factors and their host receptors as well as the molecular basis for the cross-talk between NF-κB and p38 MAP kinase pathways underlying the synergistic regulation of inflammation in respiratory bacterial infections. In addition, the signaling mechanisms underlying the synergistic activation of inflammation will also be investigated in vivo using knock-out mice. 

Regulation of Mucin in Bacterial Infections: Mucus overproduction, a hallmark of airway infections, is a primary innate defensive response for mammalian airways. The molecular mechanisms underlying mucin overproduction are largely unknown. Mucins protect and lubricate the epithelial surface and trap particles, including bacteria and viruses, for mucociliary clearance. In infections, excessive production of mucin occurs, overwhelming the normal mucociliary clearance mechanisms. As mucus levels increase, they contribute significantly to airway obstruction in airway infections and conductive hearing loss in middle ear infections. We currently focus on the molecular characterization of the novel bacterial virulence factors, the host receptor and its downstream positive and negative signaling pathways as well as the transcription factors involved in mucin transcription. Moreover we also explore the functional mimicry of host activities by NTHi because preliminary evidences have suggested that NTHi may manipulate the host signaling pathways possibly using some molecules similarly to host growth factors. 

Regulation of Toll-like Receptor by Bacteria in Airway Infections: The recognition of invading microbes followed by the induction of effective innate immune response is crucial for host survival. Human surface epithelial cells are situated at host-environment boundaries, and thus act as the first line of host defense against invading microbes. They recognize the microbial ligands via Toll-like receptors (TLRs) expressed on the surface of epithelial cells. As the immune system needs to constantly strive a balance between activation and inhibition to avoid detrimental and inappropriate inflammatory responses, TLR signaling must be tightly regulated. We currently focus on investigating how TLR signaling is negatively regulated. We are particularly interested in understanding the inducible negative regulation during bacterial infections. 
Regulation of Host Survival in S. pneumoniae Infections: Streptococcus pneumoniae (S. pneumoniae) is a major cause of morbidity and mortality worldwide. It causes invasive diseases such as pneumonia. Pneumolysin, a pore-forming hemolysin, is a key virulence factor in S. pneumoniae infections. It plays an important role in inducing acute lung hemorrhage and lethality. Despite the importance of pneumolysin in pneumococcal diseases, little is known about the molecular mechanisms by which pneumolysin-induced hemorrhage and lethality is regulated. The Long-term Objective is to fully understand the molecular mechanisms by which S. pneumoniae pneumolysin-induced hemorrhage and lethality is regulated in S. pneumoniae infections so that potential therapeutic targets can be identified for treating these infections. 

翁心华

男, 1938年９月生, 1962年毕业于上海医科大学。现任上海医科大学附属华山医院抗生素所副所长，传染病学教研室副主任、 传染病科主任、教授、博士生导师。兼任上海内科学会副主任委员；上海传染病寄生虫学会主任委员；中华内科学会常委；中华传染病学会常委；中华热带病学会理事；新药与临床编委；实用内科杂志编委；中华传染病杂志副总编；上海医科大学学报编委。

主要的临床课题研究有四个方面：长期不明发热的病因诊断；脑囊虫病的临床研究；感染性疾病快速诊断的研讨；日本血吸虫的免疫学诊断，发表有关论文50余篇。主编过“现代感染病学”(即将出版)“内科学进展讲座”“内科疾病诊断标准”。参与“医学百科全书”“实用内科学（第九版）”等10余本专业书籍的编写，目前担任“实用内科学（第十版）”的副主编。