浙江大学医学院免疫学系特聘教授，浙江大学医学院免疫学研究所所长，第二军医大医学院教授曹雪涛院士继08年岁末在《血液》（Blood）发表免疫学成果后，2009年开年又于《免疫学杂志》（The Journal of Immunology）发表文章。
自然杀伤细胞（Nature Killer Cell，NK）是机体重要的免疫细胞，尤其在抗击肿瘤的过程中发挥重要的作用。来自骨髓的抑制性细胞（myeloid-derived suppressor cells，MDSC），一类表达CD11b+Gr-1+的髓样细胞，在肿瘤发生的过程中出现异常的过度表达现象，大量的MDSC细胞能抑制T细胞和树突状细胞发挥免疫活性，导致肿瘤细胞可逃避免疫系统。然而，MDSC细胞对NK细胞天然免疫功能的调节作用还有待深入调查研究。
在本研究中，曹雪涛院士研究小组对该问题进行研究，将肿瘤移植到动物模型中，结果发现，MDSC细胞对肝脏和脾脏中的NK细胞具有强大的抑制作用，使得NK细胞无法发挥天然免疫功能，这些结果表明，肿瘤损伤肝脏中的NK细胞是一个普遍的现象。研究小组接下来研究肝癌移植小鼠模型，探索肝脏NK细胞如何受到损坏。
结果发现，肝脏和脾脏中的MDSC细胞与NK细胞的关系，当MDSC细胞增多则NK细胞的免疫功能下降。MDSC能抑制NK细胞表达细胞毒性标志NKG2D以及IFN-γ。此外，MDSC细胞抑制Nk细胞的能力由细胞膜表面的TGF-β1来控制。研究还发现，当MDSC细胞减少时，NK细胞的功能可逐步得到恢复，但是调节性T细胞对NK细胞的作用却不因调节性T细胞的减少而得到恢复。
这些研究结果表明，MDSC细胞通过TGF-β1诱导NK细胞失去功能。这也说明，MDSC细胞而不是调节性T细胞是NK细胞的负功能调节因子。研究结果为肿瘤逃避免疫系统提供了新的视野。
该研究项目受到国家自然科学基金资助。（生物谷Bioon.com）
生物谷推荐原始出处：
The Journal of Immunology, 2009, 182: 240-249.
Cancer-Expanded Myeloid-Derived Suppressor Cells Induce Anergy of NK Cells through Membrane-Bound TGF-β11
Hequan Li2,*, Yanmei Han2,, Qiuli Guo, Minggang Zhang and Xuetao Cao3,*,
* Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, and Institute of Immunology and National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai, Peoples Republic of China
NK cells, the important effector of innate immunity, play critical roles in the antitumor immunity. Myeloid-derived suppressor cells (MDSC), a population of CD11b+Gr-1+ myeloid cells expanded dramatically during tumor progression, can inhibit T cells and dendritic cells, contributing to tumor immune escaper. However, regulation of NK cell innate function by MDSC in tumor-bearing host needs to be investigated. In this study, we found that the function of NK cells from liver and spleen was impaired significantly in all tumor-bearing models, indicating the impairment of hepatic NK cell function by tumor is a universal phenomenon. Then we prepared the orthotopic liver cancer-bearing mice as tumor model to investigate how hepatic NK cells are impaired. We show that down-regulation of NK cell function is inversely correlated with the marked increase of MDSC in liver and spleen. MDSC inhibit cytotoxicity, NKG2D expression, and IFN- production of NK cells both in vitro and in vivo. After incubation with MDSC, NK cells could not be activated to produce IFN-. Furthermore, membrane-bound TGF-β1 on MDSC is responsible for MDSC-mediated suppression of NK cells. The impaired function of hepatic NK cells in orthotopic liver cancer-bearing mice could be restored by depletion of MDSC, but not regulatory T cells. Therefore, cancer-expanded MDSC can induce anergy of NK cells via membrane-bound TGF-β1. MDSC, but not regulatory T cells, are main negative regulator of hepatic NK cell function in tumor-bearing host. Our study provides new mechanistic explanations for tumor immune escape.
2009年3月2日星期一
PLoS biology：人类肠道细菌超1000万亿
从细菌多样性程度来说，肠道堪称人体内的热带雨林。日前，发表在美国《公共科学图书馆·生物学》杂志(PLoS biology)上的一篇文章称，人类肠道内的细菌群落数量是原有认识的10倍以上。
单从数量上来说，哺乳动物结肠内的细菌群落密度堪称地球之最。人体内共有细胞约100万亿个(成年人)，细菌数量则是细胞的10倍，超过1000万亿个，而这些细菌大多集中在人类消化道中。
以前，科学家估算人体细菌种类的方法是从肠道中提取细菌，然后在培养皿上培养，待菌落长出后，再进行计数。利用这种方法得到的数据是，人体内大约有500种细菌。但这种方法有个无法弥补的缺陷：只能计算可以在培养皿中生长的常见菌落的数量，对于无法在体外环境中生长的罕见细菌，则无法计数。因此，“人体内有500种细菌”的结论并不准确。
美国斯坦福大学医学院的戴维·雷尔曼(David Relman)和同事一起，利用一种新型技术——焦磷酸测序法(pyrosequencing)，得到了关于人体肠道内菌落数量更为准确的数据。雷尔曼说：“焦磷酸测序法以前是用于评估海底环境中细菌生态系统的丰度，我们首次将这种技术用于评估人体内部的‘生态系统’。”
利用焦磷酸测序法为细菌分类时，研究人员首先要提取大量待检测细菌的DNA片段(这些片段一般编码某些常见分子)，在根据片段上的变异情况，对细菌进行分类。
论文第一作者、雷尔曼实验室的博士后研究人员雷斯·德特雷福森(Les Dethlefsen)说：“比起培养鉴别法，这种新的基因测序技术能检测到更多的细菌种类。”
雷尔曼等人发现，人体肠道内的细菌种类远超人们想象，至少有5600个细菌群落。他们的这项研究得到了美国自然科学基金会和美国国立卫生研究院的资助。
对于人体健康，肠道细菌发挥着重要作用：分解食物、微调免疫系统、分泌维生素K等营养物质、“吞”掉食物残渣……另外，细菌数量多还可以让致病菌没有立足之地。
近些年，医生为病人开的抗生素越来越多。很多科学家担心，人们经常服用抗生素类药物，会使肠道细菌数量减少，甚至可能产生更多的具有耐药性的致病菌。雷尔曼和德特雷福森希望，焦磷酸测序法进一步用于评估抗生素对肠道有益菌和人体健康的影响。（生物谷Bioon.com）
生物谷推荐原始出处：
PLoS biology，doi:10.1371/journal.pbio.0060280，Les Dethlefsen，David A. Relman
The Pervasive Effects of an Antibiotic on the Human Gut Microbiota, as Revealed by Deep 16S rRNA Sequencing
Les Dethlefsen1,2, Sue Huse3, Mitchell L. Sogin3, David A. Relman1,2,4*
1 Department of Microbiology and Immunology, Stanford University, Stanford, California, United States of America, 2 Department of Medicine, Stanford University, Stanford, California, United States of America, 3 Josephine Bay Paul Center for Comparative Molecular Biology and Evolution, Marine Biological Laboratory, Woods Hole, Massachusetts, United States of America, 4 Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States of America
The human intestinal microbiota is essential to the health of the host and plays a role in nutrition, development, metabolism, pathogen resistance, and regulation of immune responses. Antibiotics may disrupt these coevolved interactions, leading to acute or chronic disease in some individuals. Our understanding of antibiotic-associated disturbance of the microbiota has been limited by the poor sensitivity, inadequate resolution, and significant cost of current research methods. The use of pyrosequencing technology to generate large numbers of 16S rDNA sequence tags circumvents these limitations and has been shown to reveal previously unexplored aspects of the “rare biosphere.” We investigated the distal gut bacterial communities of three healthy humans before and after treatment with ciprofloxacin, obtaining more than 7,000 full-length rRNA sequences and over 900,000 pyrosequencing reads from two hypervariable regions of the rRNA gene. A companion paper in PLoS Genetics (see Huse et al., doi: 10.1371/journal.pgen.1000255) shows that the taxonomic information obtained with these methods is concordant. Pyrosequencing of the V6 and V3 variable regions identified 3,300–5,700 taxa that collectively accounted for over 99% of the variable region sequence tags that could be obtained from these samples. Ciprofloxacin treatment influenced the abundance of about a third of the bacterial taxa in the gut, decreasing the taxonomic richness, diversity, and evenness of the community. However, the magnitude of this effect varied among individuals, and some taxa showed interindividual variation in the response to ciprofloxacin. While differences of community composition between individuals were the largest source of variability between samples, we found that two unrelated individuals shared a surprising degree of community similarity. In all three individuals, the taxonomic composition of the community closely resembled its pretreatment state by 4 weeks after the end of treatment, but several taxa failed to recover within 6 months. These pervasive effects of ciprofloxacin on community composition contrast with the reports by participants of normal intestinal function and with prior assumptions of only modest effects of ciprofloxacin on the intestinal microbiota. These observations support the hypothesis of functional redundancy in the human gut microbiota. The rapid return to the pretreatment community composition is indicative of factors promoting community resilience, the nature of which deserves future investigation.
单从数量上来说，哺乳动物结肠内的细菌群落密度堪称地球之最。人体内共有细胞约100万亿个(成年人)，细菌数量则是细胞的10倍，超过1000万亿个，而这些细菌大多集中在人类消化道中。
以前，科学家估算人体细菌种类的方法是从肠道中提取细菌，然后在培养皿上培养，待菌落长出后，再进行计数。利用这种方法得到的数据是，人体内大约有500种细菌。但这种方法有个无法弥补的缺陷：只能计算可以在培养皿中生长的常见菌落的数量，对于无法在体外环境中生长的罕见细菌，则无法计数。因此，“人体内有500种细菌”的结论并不准确。
美国斯坦福大学医学院的戴维·雷尔曼(David Relman)和同事一起，利用一种新型技术——焦磷酸测序法(pyrosequencing)，得到了关于人体肠道内菌落数量更为准确的数据。雷尔曼说：“焦磷酸测序法以前是用于评估海底环境中细菌生态系统的丰度，我们首次将这种技术用于评估人体内部的‘生态系统’。”
利用焦磷酸测序法为细菌分类时，研究人员首先要提取大量待检测细菌的DNA片段(这些片段一般编码某些常见分子)，在根据片段上的变异情况，对细菌进行分类。
论文第一作者、雷尔曼实验室的博士后研究人员雷斯·德特雷福森(Les Dethlefsen)说：“比起培养鉴别法，这种新的基因测序技术能检测到更多的细菌种类。”
雷尔曼等人发现，人体肠道内的细菌种类远超人们想象，至少有5600个细菌群落。他们的这项研究得到了美国自然科学基金会和美国国立卫生研究院的资助。
对于人体健康，肠道细菌发挥着重要作用：分解食物、微调免疫系统、分泌维生素K等营养物质、“吞”掉食物残渣……另外，细菌数量多还可以让致病菌没有立足之地。
近些年，医生为病人开的抗生素越来越多。很多科学家担心，人们经常服用抗生素类药物，会使肠道细菌数量减少，甚至可能产生更多的具有耐药性的致病菌。雷尔曼和德特雷福森希望，焦磷酸测序法进一步用于评估抗生素对肠道有益菌和人体健康的影响。（生物谷Bioon.com）
生物谷推荐原始出处：
PLoS biology，doi:10.1371/journal.pbio.0060280，Les Dethlefsen，David A. Relman
The Pervasive Effects of an Antibiotic on the Human Gut Microbiota, as Revealed by Deep 16S rRNA Sequencing
Les Dethlefsen1,2, Sue Huse3, Mitchell L. Sogin3, David A. Relman1,2,4*
1 Department of Microbiology and Immunology, Stanford University, Stanford, California, United States of America, 2 Department of Medicine, Stanford University, Stanford, California, United States of America, 3 Josephine Bay Paul Center for Comparative Molecular Biology and Evolution, Marine Biological Laboratory, Woods Hole, Massachusetts, United States of America, 4 Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States of America
The human intestinal microbiota is essential to the health of the host and plays a role in nutrition, development, metabolism, pathogen resistance, and regulation of immune responses. Antibiotics may disrupt these coevolved interactions, leading to acute or chronic disease in some individuals. Our understanding of antibiotic-associated disturbance of the microbiota has been limited by the poor sensitivity, inadequate resolution, and significant cost of current research methods. The use of pyrosequencing technology to generate large numbers of 16S rDNA sequence tags circumvents these limitations and has been shown to reveal previously unexplored aspects of the “rare biosphere.” We investigated the distal gut bacterial communities of three healthy humans before and after treatment with ciprofloxacin, obtaining more than 7,000 full-length rRNA sequences and over 900,000 pyrosequencing reads from two hypervariable regions of the rRNA gene. A companion paper in PLoS Genetics (see Huse et al., doi: 10.1371/journal.pgen.1000255) shows that the taxonomic information obtained with these methods is concordant. Pyrosequencing of the V6 and V3 variable regions identified 3,300–5,700 taxa that collectively accounted for over 99% of the variable region sequence tags that could be obtained from these samples. Ciprofloxacin treatment influenced the abundance of about a third of the bacterial taxa in the gut, decreasing the taxonomic richness, diversity, and evenness of the community. However, the magnitude of this effect varied among individuals, and some taxa showed interindividual variation in the response to ciprofloxacin. While differences of community composition between individuals were the largest source of variability between samples, we found that two unrelated individuals shared a surprising degree of community similarity. In all three individuals, the taxonomic composition of the community closely resembled its pretreatment state by 4 weeks after the end of treatment, but several taxa failed to recover within 6 months. These pervasive effects of ciprofloxacin on community composition contrast with the reports by participants of normal intestinal function and with prior assumptions of only modest effects of ciprofloxacin on the intestinal microbiota. These observations support the hypothesis of functional redundancy in the human gut microbiota. The rapid return to the pretreatment community composition is indicative of factors promoting community resilience, the nature of which deserves future investigation.
2009年2月27日星期五
JCM：羊水中发现不可培养的细菌
来自凯斯西部保留地大学和耶鲁大学的科学家在理解为何一些孕妇的子宫内部会遭遇无任何感染迹象的炎症问题上有了显著的进展。
利用基因克隆技术，科学家发现存在于患羊膜内炎症的妇女体内的大约60%的细菌被传统的培养测试漏掉了，后者被认为是发现细菌感染的金标准。
这些发现发表在了《临床微生物学杂志》1月号上。
这组科学家利用新的DNA方法追踪细菌的存在，从而首次发现了羊膜内感染的微生物物种的一份详尽名单。为了增加准确性，这组科学家使用了多种分析手段的综合，包括羊水的蛋白质组学结果以及对胎盘的组织学分析，从而证实这种感染和炎症。
凯斯西部保留地大学的牙科医学副教授、该研究的主要作者Yiping Han说，羊膜内炎症已知会导致不到32周的胎儿的自发早产。该研究对46名妇女进行了研究，其中44名妇女经历过早产。Han 此前进行了多个研究项目，检查了口腔细菌和早产之间的联系。
在这项研究中，科学家对来自有早产体征或症状的怀孕妇女的羊水细菌浓度和对照组的没有这类迹象且足月分娩的16名妇女的羊水细菌浓度进行了比较。对照组的羊水来自用于遗传筛查的羊水穿刺或者检查胎儿肺部成熟的分析，甚至DNA方法也没有显示出其中有细菌的迹象。
“由于培养没有发现羊水中的全部细菌，这要求使用新的检测方法，”Han说。“同样重要的是发现哪种细菌造成了导致早产的感染和炎症，从而在这个病理生理学连锁事件的早期使用抗生素。”
利用新的检测过程——该过程为了识别16SrRNA细菌基因序列，扩增了该基因并把它克隆——除了可以发现细菌培养能发现的细菌，这组科学家还有能力发现一些细菌培养无法发现的有害细菌，其中一些细菌此前没有和早产联系起来。
“通过利用基于16s rRNA基因的聚合酶链式反应（PCR）和之后的克隆分析，我们可以确定羊膜内细菌感染和早产发作之间的特征和真正的关系，”Han说。
这组科学家还发现不仅仅是样本中的一种细菌导致了炎症，而是大量的不同种类的细菌，“未被发现的、无法培养的或很难培养的细菌物种可能在导致自发早产方面扮演了一个关键的角色，”Han说。
这些细菌或者通过生殖道到达胎盘，或者通过血液到达胎盘。Han怀疑其中一些细菌源于口腔，口腔中存在成百上千种细菌。这些口腔细菌中的一种是具核梭杆菌（Fusobacterium nucleatum ），它在口腔中普遍存在。然而，一旦它进入了血流中，它就和一些健康问题有了关联。（生物谷Bioon.com）
生物谷推荐原始出处：
Journal of Clinical Microbiology, January 2009, p. 38-47, Vol. 47, No. 1
Uncultivated Bacteria as Etiologic Agents of Intra-Amniotic Inflammation Leading to Preterm Birth
Yiping W. Han,1,2* Tao Shen,1 Peter Chung,1 Irina A. Buhimschi,3 and Catalin S. Buhimschi3
Department of Periodontics, Case Western Reserve University School of Dental Medicine, Cleveland, Ohio 44106,1 Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106,2 Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University, New Haven, Connecticut 065203
Intra-amniotic infection and inflammation are major causes of preterm birth (PTB). However, intra-amniotic inflammation is often detected in the absence of infection. This may partly be due to the culturing methods employed in hospital laboratories, which are unable to detect the uncultivated species. In this study, intra-amniotic microbial infections associated with PTB were examined by both culture and 16S rRNA-based culture-independent methods and were corroborated by the presence of intra-amniotic inflammation. Amniotic fluid (AF) specimens from 46 pregnancies complicated by PTB and 16 asymptomatic women were analyzed. No bacterial DNA was amplified in AF collected from the asymptomatic women. Among the 46 samples associated with PTB, bacterial DNA was amplified from all (16/16) of the culture-positive samples and 17% (5/30) of the culture-negative samples. In the culture-positive group, additional species were detected in more than half (9/16) of the cases by PCR and clone analysis. Altogether, approximately two- thirds of the species detected by the culture-independent methods were not isolated by culture. They included both uncultivated and difficult-to-cultivate species, such as Fusobacterium nucleatum, Leptotrichia (Sneathia) spp., a Bergeyella sp., a Peptostreptococcus sp., Bacteroides spp., and a species of the order Clostridiales. To examine intra-amniotic inflammation, an AF proteomic fingerprint (mass-restricted score) was determined by surface-enhanced laser desorption ionization-time-of-flight mass spectrometry. Inflammation was detected in all five samples which were culture negative but PCR positive. Women who were PCR positive more often had elevated interleukin-6 levels in their AF, histological chorioamnionitis, and funisitis and delivered neonates with early-onset neonatal sepsis. Previously unrecognized, uncultivated, or difficult-to-cultivate species may play a key role in the initiation of PTB.
利用基因克隆技术，科学家发现存在于患羊膜内炎症的妇女体内的大约60%的细菌被传统的培养测试漏掉了，后者被认为是发现细菌感染的金标准。
这些发现发表在了《临床微生物学杂志》1月号上。
这组科学家利用新的DNA方法追踪细菌的存在，从而首次发现了羊膜内感染的微生物物种的一份详尽名单。为了增加准确性，这组科学家使用了多种分析手段的综合，包括羊水的蛋白质组学结果以及对胎盘的组织学分析，从而证实这种感染和炎症。
凯斯西部保留地大学的牙科医学副教授、该研究的主要作者Yiping Han说，羊膜内炎症已知会导致不到32周的胎儿的自发早产。该研究对46名妇女进行了研究，其中44名妇女经历过早产。Han 此前进行了多个研究项目，检查了口腔细菌和早产之间的联系。
在这项研究中，科学家对来自有早产体征或症状的怀孕妇女的羊水细菌浓度和对照组的没有这类迹象且足月分娩的16名妇女的羊水细菌浓度进行了比较。对照组的羊水来自用于遗传筛查的羊水穿刺或者检查胎儿肺部成熟的分析，甚至DNA方法也没有显示出其中有细菌的迹象。
“由于培养没有发现羊水中的全部细菌，这要求使用新的检测方法，”Han说。“同样重要的是发现哪种细菌造成了导致早产的感染和炎症，从而在这个病理生理学连锁事件的早期使用抗生素。”
利用新的检测过程——该过程为了识别16SrRNA细菌基因序列，扩增了该基因并把它克隆——除了可以发现细菌培养能发现的细菌，这组科学家还有能力发现一些细菌培养无法发现的有害细菌，其中一些细菌此前没有和早产联系起来。
“通过利用基于16s rRNA基因的聚合酶链式反应（PCR）和之后的克隆分析，我们可以确定羊膜内细菌感染和早产发作之间的特征和真正的关系，”Han说。
这组科学家还发现不仅仅是样本中的一种细菌导致了炎症，而是大量的不同种类的细菌，“未被发现的、无法培养的或很难培养的细菌物种可能在导致自发早产方面扮演了一个关键的角色，”Han说。
这些细菌或者通过生殖道到达胎盘，或者通过血液到达胎盘。Han怀疑其中一些细菌源于口腔，口腔中存在成百上千种细菌。这些口腔细菌中的一种是具核梭杆菌（Fusobacterium nucleatum ），它在口腔中普遍存在。然而，一旦它进入了血流中，它就和一些健康问题有了关联。（生物谷Bioon.com）
生物谷推荐原始出处：
Journal of Clinical Microbiology, January 2009, p. 38-47, Vol. 47, No. 1
Uncultivated Bacteria as Etiologic Agents of Intra-Amniotic Inflammation Leading to Preterm Birth
Yiping W. Han,1,2* Tao Shen,1 Peter Chung,1 Irina A. Buhimschi,3 and Catalin S. Buhimschi3
Department of Periodontics, Case Western Reserve University School of Dental Medicine, Cleveland, Ohio 44106,1 Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106,2 Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University, New Haven, Connecticut 065203
Intra-amniotic infection and inflammation are major causes of preterm birth (PTB). However, intra-amniotic inflammation is often detected in the absence of infection. This may partly be due to the culturing methods employed in hospital laboratories, which are unable to detect the uncultivated species. In this study, intra-amniotic microbial infections associated with PTB were examined by both culture and 16S rRNA-based culture-independent methods and were corroborated by the presence of intra-amniotic inflammation. Amniotic fluid (AF) specimens from 46 pregnancies complicated by PTB and 16 asymptomatic women were analyzed. No bacterial DNA was amplified in AF collected from the asymptomatic women. Among the 46 samples associated with PTB, bacterial DNA was amplified from all (16/16) of the culture-positive samples and 17% (5/30) of the culture-negative samples. In the culture-positive group, additional species were detected in more than half (9/16) of the cases by PCR and clone analysis. Altogether, approximately two- thirds of the species detected by the culture-independent methods were not isolated by culture. They included both uncultivated and difficult-to-cultivate species, such as Fusobacterium nucleatum, Leptotrichia (Sneathia) spp., a Bergeyella sp., a Peptostreptococcus sp., Bacteroides spp., and a species of the order Clostridiales. To examine intra-amniotic inflammation, an AF proteomic fingerprint (mass-restricted score) was determined by surface-enhanced laser desorption ionization-time-of-flight mass spectrometry. Inflammation was detected in all five samples which were culture negative but PCR positive. Women who were PCR positive more often had elevated interleukin-6 levels in their AF, histological chorioamnionitis, and funisitis and delivered neonates with early-onset neonatal sepsis. Previously unrecognized, uncultivated, or difficult-to-cultivate species may play a key role in the initiation of PTB.
Trends in Immunology：天然免疫反应需要T细胞参与
中科院生物物理所感染免疫中心唐宏研究员和傅阳心教授在2009年月1月刊的《免疫学趋势》（Trends in Immunology）杂志上以Do adaptive immune cells suppress or activate innate immunity?为题，系统阐述了他们近来提出的“天然免疫反应需要T细胞参与” 的新理论。
经典的免疫学理论认为天然免疫反应启动获得性免疫，而获得性免疫随后进一步放大天然免疫效应，二者的合作与平衡才能清除入侵病原，起到免疫保护的作用。该实验室近期的研究结果表明（原文见Nature Medicine, 2007；评述见Nature Medicine, 2007; Nature Reviews in Immunology, 2007; Nature China, 2008），原先关于区分天然免疫和获得性免疫的界限可能并不那么清楚，T细胞其实也参与天然免疫反应并维持其稳态。经典理论认为天然免疫和获得性免疫反应的双重低下是早产儿容易死于急性感染的主要原因。该实验室的研究发现，实际上，在感染早期获得性免疫细胞对于天然免疫反应具有负调控的作用，从而有效的将天然免疫反应的强度控制在一定的水平内而不至对机体造成免疫损伤。新生鼠或早产儿由于获得性免疫低下，天然免疫炎性反应无法得到有效控制，这种“炎性因子风暴”才是致死原因。因此，获得性免疫一方面抑制感染早期的炎症反应，另一方面在感染后期行使病原特异性清除功能，两者缺一不可。
这个新理论对于深入了解病毒性感染的炎症反应和病毒清除机理，控制免疫低下病人（新生儿、老年人、放化疗癌症病人、器官移植患者或艾滋病人）机会性感染具有极高的指导价值。（生物谷Bioon.com）
生物谷推荐原始出处：
Trends in Immunology Volume 30, Issue 1, January 2009,doi:10.1016/j.it.2008.10.003
Do adaptive immune cells suppress or activate innate immunity?
Jie Zhao1, Xuanming Yang1, Sogyong L. Auh2, Kwang Dong Kim3, Hong Tang1, and Yang-Xin Fu1, 2,
1Center for Infection and Immunity and National Key Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Rd, Chaoyang District, Beijing 100101, China2Department of Pathology, Committee of Immunology, University of Chicago, Chicago, IL 60637, USA3Division of Applied Life Science, Gyeongsang National University, Jinju, 660-701, Korea
Current dogma holds that the innate immune system primes the adaptive immune system in response to infection, which in turn amplifies innate responses in a positive loop to effectively control pathogens. Therefore, it is accepted in most cases that T-cell deficient hosts die of acute infection because of the impaired ability of the innate immune system to control pathogens. Recent studies, however, reveal that adaptive immune cells actively dampen initial innate responses. In contrast to current understanding, there is now evidence that an insufficient number of T cells results in loss of control of innate immune responses. This raises new questions regarding the, as of yet underappreciated, role of the adaptive immune system in early infection and inflammation.
经典的免疫学理论认为天然免疫反应启动获得性免疫，而获得性免疫随后进一步放大天然免疫效应，二者的合作与平衡才能清除入侵病原，起到免疫保护的作用。该实验室近期的研究结果表明（原文见Nature Medicine, 2007；评述见Nature Medicine, 2007; Nature Reviews in Immunology, 2007; Nature China, 2008），原先关于区分天然免疫和获得性免疫的界限可能并不那么清楚，T细胞其实也参与天然免疫反应并维持其稳态。经典理论认为天然免疫和获得性免疫反应的双重低下是早产儿容易死于急性感染的主要原因。该实验室的研究发现，实际上，在感染早期获得性免疫细胞对于天然免疫反应具有负调控的作用，从而有效的将天然免疫反应的强度控制在一定的水平内而不至对机体造成免疫损伤。新生鼠或早产儿由于获得性免疫低下，天然免疫炎性反应无法得到有效控制，这种“炎性因子风暴”才是致死原因。因此，获得性免疫一方面抑制感染早期的炎症反应，另一方面在感染后期行使病原特异性清除功能，两者缺一不可。
这个新理论对于深入了解病毒性感染的炎症反应和病毒清除机理，控制免疫低下病人（新生儿、老年人、放化疗癌症病人、器官移植患者或艾滋病人）机会性感染具有极高的指导价值。（生物谷Bioon.com）
生物谷推荐原始出处：
Trends in Immunology Volume 30, Issue 1, January 2009,doi:10.1016/j.it.2008.10.003
Do adaptive immune cells suppress or activate innate immunity?
Jie Zhao1, Xuanming Yang1, Sogyong L. Auh2, Kwang Dong Kim3, Hong Tang1, and Yang-Xin Fu1, 2,
1Center for Infection and Immunity and National Key Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Rd, Chaoyang District, Beijing 100101, China2Department of Pathology, Committee of Immunology, University of Chicago, Chicago, IL 60637, USA3Division of Applied Life Science, Gyeongsang National University, Jinju, 660-701, Korea
Current dogma holds that the innate immune system primes the adaptive immune system in response to infection, which in turn amplifies innate responses in a positive loop to effectively control pathogens. Therefore, it is accepted in most cases that T-cell deficient hosts die of acute infection because of the impaired ability of the innate immune system to control pathogens. Recent studies, however, reveal that adaptive immune cells actively dampen initial innate responses. In contrast to current understanding, there is now evidence that an insufficient number of T cells results in loss of control of innate immune responses. This raises new questions regarding the, as of yet underappreciated, role of the adaptive immune system in early infection and inflammation.
Cell：microRNA调控免疫系统
哈佛大学医学院免疫疾病研究所的科学家Klaus Rajewsky教授在最新一期的Cell杂志发表综述文章，对microRNA控制免疫系统的基本原则问题进行了归纳总结。
对microRNA的调控研究发现，microRNA（miRNA）对哺乳动物免疫系统具有重要的调控意义。研究者发现用遗传技术敲除某一miRNA或是消减某一miRNA基因的功能（与免疫功能相关的miRNA），对免疫系统的发育会造成重大的破坏作用，导致机体发生疾病，比如说，可能引发自体免疫疾病甚至是癌症。尽管，单个的miRNA就能调节上百个靶位基因影响蛋白表达，一旦影响蛋白的表达就会对生物体的正常生理功能造成影响，也许某些关键蛋白表达量的降低会招来恶果，导致细胞功能异常，甚至产生疾病。（生物谷Bioon.com）
生物谷推荐原始出处：
Cell,9 January 2009 doi:10.1016/j.cell.2008.12.027
MicroRNA Control in the Immune System: Basic Principles
Changchun Xiao1,2andKlaus Rajewsky1,,
1 Immune Disease Institute, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA2 Present address: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
MicroRNA (miRNA) control has emerged as a critical regulatory principle in the mammalian immune system. Genetic ablation of the miRNA machinery, as well as loss or deregulation of certain individual miRNAs, severely compromises immune development and response and can lead to immune disorders like autoimmunity and cancer. Although individual miRNAs modulate protein output from hundreds of target genes, they may impact physiological processes by regulating the concentrations of just a few key cellular proteins that may be components of a single or of functionally interrelated pathways in a given cellular context.
Nature：哺乳动物宿主CD8+ T细胞数量的适应性变化
反复暴露于病原体及以杀死病原体为使命的记忆性CD8+ T-细胞的生成，被认为会导致事先存在的记忆性T-细胞存量的消耗，以保持记忆腔的总体大小不变。但用小鼠进行的新的研究工作表明，记忆性CD8+ T-细胞腔的大小在免疫之后会增加，而且新的记忆性CD8+ T-细胞的生成并不会显著减少事先存在的记忆性CD8+ T-细胞的数量。关于哺乳动物宿主CD8+ T-细胞数量能根据免疫经验发生适应性变化的发现，对于疫苗的生产可能具有重要意义，因为我们也许有可能大量引入特异性CD8+ T-细胞，而不会影响以前就有的、针对其他感染的免疫能力。（生物谷Bioon.com）
生物谷推荐原始出处：
Nature 457, 196-199 (8 January 2009) doi:10.1038/nature07486
Memory CD8 T-cell compartment grows in size with immunological experience
Vaiva Vezys1,2,4, Andrew Yates3,4, Kerry A. Casey1, Gibson Lanier2, Rafi Ahmed2, Rustom Antia3 & David Masopust1,2
1 Department of Microbiology and Center for Immunology, University of Minnesota, Minneapolis, Minnesota 55455, USA2 Emory Vaccine Center, Emory University School of Medicine, and,3 Department of Biology, Emory University, Atlanta, Georgia 30322, USA4 These authors contributed equally to this work.
Memory CD8 T cells, generated by natural pathogen exposure or intentional vaccination, protect the host against specific viral infections1. It has long been proposed that the number of memory CD8 T cells in the host is inflexible, and that individual cells are constantly competing for limited space2, 3. Consequently, vaccines that introduce over-abundant quantities of memory CD8 T cells specific for an agent of interest could have catastrophic consequences for the host by displacing memory CD8 T cells specific for all previous infections4, 5, 6. To test this paradigm, we developed a vaccination regimen in mice that introduced as many new long-lived memory CD8 T cells specific for a single vaccine antigen as there were memory CD8 T cells in the host before vaccination. Here we show that, in contrast to expectations, the size of the memory CD8 T-cell compartment doubled to accommodate these new cells, a change due solely to the addition of effector memory CD8 T cells. This increase did not affect the number of CD4 T cells, B cells or naive CD8 T cells, and pre-existing memory CD8 T cells specific for a previously encountered infection were largely preserved. Thus, the number of effector memory CD8 T cells in the mammalian host adapts according to immunological experience. Developing vaccines that abundantly introduce new memory CD8 T cells should not necessarily ablate pre-existing immunity to other infections.
生物谷推荐原始出处：
Nature 457, 196-199 (8 January 2009) doi:10.1038/nature07486
Memory CD8 T-cell compartment grows in size with immunological experience
Vaiva Vezys1,2,4, Andrew Yates3,4, Kerry A. Casey1, Gibson Lanier2, Rafi Ahmed2, Rustom Antia3 & David Masopust1,2
1 Department of Microbiology and Center for Immunology, University of Minnesota, Minneapolis, Minnesota 55455, USA2 Emory Vaccine Center, Emory University School of Medicine, and,3 Department of Biology, Emory University, Atlanta, Georgia 30322, USA4 These authors contributed equally to this work.
Memory CD8 T cells, generated by natural pathogen exposure or intentional vaccination, protect the host against specific viral infections1. It has long been proposed that the number of memory CD8 T cells in the host is inflexible, and that individual cells are constantly competing for limited space2, 3. Consequently, vaccines that introduce over-abundant quantities of memory CD8 T cells specific for an agent of interest could have catastrophic consequences for the host by displacing memory CD8 T cells specific for all previous infections4, 5, 6. To test this paradigm, we developed a vaccination regimen in mice that introduced as many new long-lived memory CD8 T cells specific for a single vaccine antigen as there were memory CD8 T cells in the host before vaccination. Here we show that, in contrast to expectations, the size of the memory CD8 T-cell compartment doubled to accommodate these new cells, a change due solely to the addition of effector memory CD8 T cells. This increase did not affect the number of CD4 T cells, B cells or naive CD8 T cells, and pre-existing memory CD8 T cells specific for a previously encountered infection were largely preserved. Thus, the number of effector memory CD8 T cells in the mammalian host adapts according to immunological experience. Developing vaccines that abundantly introduce new memory CD8 T cells should not necessarily ablate pre-existing immunity to other infections.
Nature Immunology：肿瘤可能通过特殊机制逃避免疫
健康的细胞会表达出一种小RNA，帮助它们回避来自免疫系统不必要的识别和进攻。在8月出版的《自然—免疫学》期刊上，研究人员对这一机制进行了解释，并推测肿瘤可能也利用了同样的机制来逃逸检测。
在遇到病毒感染等压力状况时，两种蛋白质MICA和MICB会被免疫细胞上表达的受体NKG2D所识别。对这些由压力诱导的蛋白质的探测会触发一种可去除压力源的免疫反应。而病毒则会使用一种名为小RNA的短链RNA来抑制MICA和MICB的表达，从而逃避相应的免疫反应。
以色列希伯来大学Ofer Mandelboim和同事指出，类似于这种病毒，健康的非压力型人类细胞也能表达出抑制MICA和MICB表达的小RNA，因此，健康细胞能逃避免疫系统的探测。与健康组织相比，人类的许多肿瘤组织也表达出过量的这类小RNA，从而让它们逃过免疫系统的识别，这就是问题的严重性所在。 （生物谷Bioon.com）
生物谷推荐原始出处：
Nature Immunology，doi:10.1038/ni.1642，Noam Stern-Ginossar，Ofer Mandelboim
Human microRNAs regulate stress-induced immune responses mediated by the receptor NKG2D
Noam Stern-Ginossar1, Chamutal Gur1, Moshe Biton1, Elad Horwitz1, Moran Elboim1, Noa Stanietsky1, Michal Mandelboim2 & Ofer Mandelboim1
Abstract
MICA and MICB are stress-induced ligands recognized by the activating receptor NKG2D. A microRNA encoded by human cytomegalovirus downregulates MICB expression by targeting a specific site in the MICB 3' untranslated region. As this site is conserved among different MICB alleles and a similar site exists in the MICA 3' untranslated region, we speculated that these sites are targeted by cellular microRNAs. Here we identified microRNAs that bound to these MICA and MICB 3' untranslated region sequences and obtained data suggesting that these microRNAs maintain expression of MICA and MICB protein under a certain threshold and facilitate acute upregulation of MICA and MICB during cellular stress. These microRNAs were overexpressed in various tumors and we demonstrate here that they aided tumor avoidance of immune recognition.
1 Lautenberg Center for General and Tumor Immunology, The Hebrew University, The BioMedical Research Institute, Hadassah Medical School, Jerusalem 91120, Israel.2 Clinical Virology Unit, Tel-Hashomer, Ramat Gan 52621, Israel.
在遇到病毒感染等压力状况时，两种蛋白质MICA和MICB会被免疫细胞上表达的受体NKG2D所识别。对这些由压力诱导的蛋白质的探测会触发一种可去除压力源的免疫反应。而病毒则会使用一种名为小RNA的短链RNA来抑制MICA和MICB的表达，从而逃避相应的免疫反应。
以色列希伯来大学Ofer Mandelboim和同事指出，类似于这种病毒，健康的非压力型人类细胞也能表达出抑制MICA和MICB表达的小RNA，因此，健康细胞能逃避免疫系统的探测。与健康组织相比，人类的许多肿瘤组织也表达出过量的这类小RNA，从而让它们逃过免疫系统的识别，这就是问题的严重性所在。 （生物谷Bioon.com）
生物谷推荐原始出处：
Nature Immunology，doi:10.1038/ni.1642，Noam Stern-Ginossar，Ofer Mandelboim
Human microRNAs regulate stress-induced immune responses mediated by the receptor NKG2D
Noam Stern-Ginossar1, Chamutal Gur1, Moshe Biton1, Elad Horwitz1, Moran Elboim1, Noa Stanietsky1, Michal Mandelboim2 & Ofer Mandelboim1
Abstract
MICA and MICB are stress-induced ligands recognized by the activating receptor NKG2D. A microRNA encoded by human cytomegalovirus downregulates MICB expression by targeting a specific site in the MICB 3' untranslated region. As this site is conserved among different MICB alleles and a similar site exists in the MICA 3' untranslated region, we speculated that these sites are targeted by cellular microRNAs. Here we identified microRNAs that bound to these MICA and MICB 3' untranslated region sequences and obtained data suggesting that these microRNAs maintain expression of MICA and MICB protein under a certain threshold and facilitate acute upregulation of MICA and MICB during cellular stress. These microRNAs were overexpressed in various tumors and we demonstrate here that they aided tumor avoidance of immune recognition.
1 Lautenberg Center for General and Tumor Immunology, The Hebrew University, The BioMedical Research Institute, Hadassah Medical School, Jerusalem 91120, Israel.2 Clinical Virology Unit, Tel-Hashomer, Ramat Gan 52621, Israel.
2009年2月26日星期四
Nature Immunology：肺部组织通过免疫调控保护自己
在7月出版的《自然—免疫学》期刊上，科学家们揭示了一个秘密：肺部组织在对付空气中的刺激物或感染物时，如何避免让自己受到过度损害。对因呼吸道感染而发生并发症的患者来说，新发现非常有助于开发新治疗方法。
肺是非常精致的组织，常常会暴露在通过呼吸进入的各种微生物和微颗粒中。过度的免疫反应会导致疤痕，影响肺气体交换功能。
英国伦敦帝国理工学院Tracy Hussell和同事报告说，一种名为CD200R的分子会向停留在肺部的特定免疫分子施加一种抑制作用，提高肺部需要免疫细胞的门槛。一旦这种反应被启动后，CD200R就会减少肺部的感染，缓解对肺组织的损伤。在受到流感病毒感染时，缺乏CD200R的小鼠的存活率更低。死亡原因是不受限制的免疫细胞对间接组织造成了过度损伤。（生物谷Bioon.com）
生物谷推荐原始出处：
Nature Immunology，doi : 10.1038/ni.1637，Robert J Snelgrove，Tracy Hussell
A critical function for CD200 in lung immune homeostasis and the severity of influenza infection
Robert J Snelgrove1, John Goulding1, Arnaud M Didierlaurent1, Daphne Lyonga1, Seema Vekaria1, Lorna Edwards1, Emily Gwyer1, Jonathon D Sedgwick2, A Neil Barclay3 & Tracy Hussell1
AbstractThe lung must maintain a high threshold of immune 'ignorance' to innocuous antigens to avoid inflammatory disease that depends on the balance of positive inflammatory signals and repressor pathways. We demonstrate here that airway macrophages had higher expression of the negative regulator CD200 receptor (CD200R) than did their systemic counterparts. Lung macrophages were restrained by CD200 expressed on airway epithelium. Mice lacking CD200 had more macrophage activity and enhanced sensitivity to influenza infection, which led to delayed resolution of inflammation and, ultimately, death. The administration of agonists that bind CD200R, however, prevented inflammatory lung disease. Thus, CD200R is critical for lung macrophage immune homeostasis in the resting state and limits inflammatory amplitude and duration during pulmonary influenza infection.
1 Imperial College London, Kennedy Institute, London, W6 8LH, UK.2 Eli Lilly, Indianapolis 46285, USA.3 Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.
肺是非常精致的组织，常常会暴露在通过呼吸进入的各种微生物和微颗粒中。过度的免疫反应会导致疤痕，影响肺气体交换功能。
英国伦敦帝国理工学院Tracy Hussell和同事报告说，一种名为CD200R的分子会向停留在肺部的特定免疫分子施加一种抑制作用，提高肺部需要免疫细胞的门槛。一旦这种反应被启动后，CD200R就会减少肺部的感染，缓解对肺组织的损伤。在受到流感病毒感染时，缺乏CD200R的小鼠的存活率更低。死亡原因是不受限制的免疫细胞对间接组织造成了过度损伤。（生物谷Bioon.com）
生物谷推荐原始出处：
Nature Immunology，doi : 10.1038/ni.1637，Robert J Snelgrove，Tracy Hussell
A critical function for CD200 in lung immune homeostasis and the severity of influenza infection
Robert J Snelgrove1, John Goulding1, Arnaud M Didierlaurent1, Daphne Lyonga1, Seema Vekaria1, Lorna Edwards1, Emily Gwyer1, Jonathon D Sedgwick2, A Neil Barclay3 & Tracy Hussell1
AbstractThe lung must maintain a high threshold of immune 'ignorance' to innocuous antigens to avoid inflammatory disease that depends on the balance of positive inflammatory signals and repressor pathways. We demonstrate here that airway macrophages had higher expression of the negative regulator CD200 receptor (CD200R) than did their systemic counterparts. Lung macrophages were restrained by CD200 expressed on airway epithelium. Mice lacking CD200 had more macrophage activity and enhanced sensitivity to influenza infection, which led to delayed resolution of inflammation and, ultimately, death. The administration of agonists that bind CD200R, however, prevented inflammatory lung disease. Thus, CD200R is critical for lung macrophage immune homeostasis in the resting state and limits inflammatory amplitude and duration during pulmonary influenza infection.
1 Imperial College London, Kennedy Institute, London, W6 8LH, UK.2 Eli Lilly, Indianapolis 46285, USA.3 Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.
2009年2月25日星期三
Science：解码感冒病毒
专题： Science报道
据2月13日的《科学》杂志报道说，研究人员构建了一个引起普通感冒的致病原鼻病毒的系谱图。
据2月13日的《科学》杂志报道说，研究人员构建了一个引起普通感冒的致病原鼻病毒的系谱图。
人类鼻病毒外壳结构
该系谱图可以帮助药物开发商通过将哪些病毒株作为标靶而找到治疗感冒的方法。 普通感冒长期以来一直是一个很大的谜团，其主要原因是因为造成感冒的致病原并非只有一种感冒病毒。科学家们已经发现了99种已知的鼻病毒株，他们相信还有更多的鼻病毒没有被发现。在某些病例中，感冒症状轻微；而在另外一些病例中，它们会导致耳朵和肺部的继发感染，甚或引起哮喘。以往有几次研发感冒药物的尝试失败了，其原因可能是因为这些药物对有些感染某些病毒株的人有效，但对其他人却无效。为了解决不同病毒株的问题，Stephen Liggett及其同僚现在已经完成了对所有已知鼻病毒及某些新近发现的新病毒株的 基因组 序列分析。
他们接着通过比较基因序列以及每一种病毒的不同物理特征而制作了一个鼻病毒的系谱图。他们除了发现2个已知的主要集群之外还在该系谱图上发现了新的分枝。他们证明，关系疏远的病毒可以通过重组而产生新的病毒株。这些发现还提示，鼻病毒序列中有一个特殊片断特别易变并可能会影响该病毒的毒性，这就像人们已知的在灰髓炎病毒中有一个相应的片断也具有同样的性质。除了能够帮助人们研发药物之外，这些发现还将为研究人员研究鼻病毒的演变、多样性和耐药性打下基层。（ 生物谷 Bioon.com）
生物谷推荐原始出处：
Science DOI: 10.1126/science.1165557
Sequencing and Analyses of All Known Human Rhinovirus Genomes Reveals Structure and Evolution
Ann C. Palmenberg 1, David Spiro 2, Ryan Kuzmickas 2, Shiliang Wang 2, Appolinaire Djikeng 2, Jennifer A. Rathe 3, Claire M. Fraser-Liggett 4, Stephen B. Liggett 3*
1 Institute for Molecular Virology, University of Wisconsin, Madison, WI 53706, USA.2 J. Craig Venter Institute, Rockville, MD 20850, USA.3 Cardiopulmonary Genomics Program, University of Maryland School of Medicine, Baltimore, MD 21201, USA.4 Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Infection by human rhinoviruses (HRVs) is a major cause of upper and lower respiratory tract disease worldwide and displays significant phenotypic variation. We examined diversity by completing the genome sequences for all known serotypes (n = 99). Superimposition of capsid crystal structure and optimal-energy RNA configurations established alignments and phylogeny. These revealed conserved motifs, clade-specific diversity including a potential new species (HRV-D), mutations in field isolates, and recombination. In analogy with poliovirus, a hypervariable 5'UTR tract may affect virulence. A configuration consistent with nonscanning internal ribosome entry was found in all HRVs and may account for rapid translation. The data density from complete sequences of the reference HRVs provided high resolution for this degree of modeling and serves as a platform for full genome-based epidemiologic studies and antiviral or vaccine development.
该系谱图可以帮助药物开发商通过将哪些病毒株作为标靶而找到治疗感冒的方法。 普通感冒长期以来一直是一个很大的谜团，其主要原因是因为造成感冒的致病原并非只有一种感冒病毒。科学家们已经发现了99种已知的鼻病毒株，他们相信还有更多的鼻病毒没有被发现。在某些病例中，感冒症状轻微；而在另外一些病例中，它们会导致耳朵和肺部的继发感染，甚或引起哮喘。以往有几次研发感冒药物的尝试失败了，其原因可能是因为这些药物对有些感染某些病毒株的人有效，但对其他人却无效。为了解决不同病毒株的问题，Stephen Liggett及其同僚现在已经完成了对所有已知鼻病毒及某些新近发现的新病毒株的 基因组 序列分析。
他们接着通过比较基因序列以及每一种病毒的不同物理特征而制作了一个鼻病毒的系谱图。他们除了发现2个已知的主要集群之外还在该系谱图上发现了新的分枝。他们证明，关系疏远的病毒可以通过重组而产生新的病毒株。这些发现还提示，鼻病毒序列中有一个特殊片断特别易变并可能会影响该病毒的毒性，这就像人们已知的在灰髓炎病毒中有一个相应的片断也具有同样的性质。除了能够帮助人们研发药物之外，这些发现还将为研究人员研究鼻病毒的演变、多样性和耐药性打下基层。（ 生物谷 Bioon.com）
生物谷推荐原始出处：
Science DOI: 10.1126/science.1165557
Sequencing and Analyses of All Known Human Rhinovirus Genomes Reveals Structure and Evolution
Ann C. Palmenberg 1, David Spiro 2, Ryan Kuzmickas 2, Shiliang Wang 2, Appolinaire Djikeng 2, Jennifer A. Rathe 3, Claire M. Fraser-Liggett 4, Stephen B. Liggett 3*
1 Institute for Molecular Virology, University of Wisconsin, Madison, WI 53706, USA.2 J. Craig Venter Institute, Rockville, MD 20850, USA.3 Cardiopulmonary Genomics Program, University of Maryland School of Medicine, Baltimore, MD 21201, USA.4 Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Infection by human rhinoviruses (HRVs) is a major cause of upper and lower respiratory tract disease worldwide and displays significant phenotypic variation. We examined diversity by completing the genome sequences for all known serotypes (n = 99). Superimposition of capsid crystal structure and optimal-energy RNA configurations established alignments and phylogeny. These revealed conserved motifs, clade-specific diversity including a potential new species (HRV-D), mutations in field isolates, and recombination. In analogy with poliovirus, a hypervariable 5'UTR tract may affect virulence. A configuration consistent with nonscanning internal ribosome entry was found in all HRVs and may account for rapid translation. The data density from complete sequences of the reference HRVs provided high resolution for this degree of modeling and serves as a platform for full genome-based epidemiologic studies and antiviral or vaccine development.
Nature：发现大肠杆菌粘附肠壁新机制
大肠杆菌利用鞭毛附着在肠壁上
肠毒性大肠杆菌是发展中国家最常见的腹泻原因，也是旅行者腹泻的主要原因。粘附到宿主细胞上是这种及很多其他种细菌病原体致病所必需的。
现在，研究人员发现了大肠杆菌的一个新的粘附机制，该机制依赖于体内分泌的蛋白EtpA。该蛋白与细菌鞭毛顶端的鞭毛蛋白分子的保留区域发生相互作用，在那里它形成细菌与宿主细胞之间的一个粘附分子桥。这一发现是证明EtpA（以及保留下来的鞭毛蛋白配体）有可能是针对大肠杆菌及其他运动病原体（motile pathogen）的疫苗的有效抗原目标的又一个证据。（生物谷Bioon.com）
Bioon推荐原始出处：
Nature 457, 594-598 (29 January 2009) doi:10.1038/nature07568
Enterotoxigenic Escherichia coli EtpA mediates adhesion between flagella and host cells
Koushik Roy1, George M. Hilliard2, David J. Hamilton3, Jiwen Luo1, Marguerite M. Ostmann4 & James M. Fleckenstein1,2,5
1 Department of Medicine,2 Department of Molecular Sciences,3 Department of Comparative Medicine, University of Tennessee Health Science Center, 956 Court Avenue, Memphis, Tennessee 38163, Tennessee, USA
Adhesion to epithelial cells1 and flagella-mediated motility are critical virulence traits for many Gram-negative pathogens, including enterotoxigenic Escherichia coli (ETEC)2, a major cause of diarrhoea in travellers and children in developing countries3, 4. Many flagellated pathogens export putative adhesins belonging to the two-partner secretion (TPS) family5. However, the actual function of these adhesins remains largely undefined. Here we demonstrate that EtpA, a TPS exoprotein adhesin of enterotoxigenic E. coli 6, mimics and interacts with highly conserved regions of flagellin, the major subunit of flagella, and that these interactions are critical for adherence and intestinal colonization. Although conserved regions of flagellin are mostly buried in the flagellar shaft7, our results suggest that they are at least transiently exposed at the tips of flagella where they capture EtpA adhesin molecules for presentation to eukaryotic receptors. Similarity of EtpA to molecules encoded by other motile pathogens suggests a potential common pattern for bacterial adhesion, whereas participation of conserved regions of flagellin in adherence has implications for development of vaccines for Gram-negative pathogens.
Nature：沙眼衣原体获取类脂机制
沙眼衣原体（Chlamydia trachomatis）感染为眼科最常见的细菌性疾病。沙眼衣原体可引起沙眼、结膜炎、肺炎、泌尿生殖道感染及性病淋巴肉芽肿等。同很多其他细胞内病原体一样，沙眼衣原体也依赖于宿主的类脂来生长。日前，德国研究人员在被感染的HeLa上皮细胞中发现了沙眼衣原体获取其类脂的一个机制。
在正常细胞中，高尔基体的作用是，修饰新合成的蛋白和类脂，供在细胞内或细胞外分配。沙眼衣原体的细胞内复制触发高尔基体分解，通过基质蛋白golgin-84的解理产生功能完好的高尔基体小堆栈。这些高尔基体小堆栈（它们在细菌内含物周围排列）似乎可提供一个渠道，病原体通过该渠道可获得类脂的供应。
这项工作表明，炎性“半胱天冬酶”（caspases）和“钙激活酶”（calpains）在机制上是有所参与的，它们也许可用作抗衣原体药物的新颖的分子目标。（生物谷Bioon.com）
生物谷推荐原始出处：
Nature 457, 731-735 (5 February 2009) doi:10.1038/nature07578
Chlamydia causes fragmentation of the Golgi compartment to ensure reproduction
Dagmar Heuer1, Anette Rejman Lipinski1, Nikolaus Machuy1, Alexander Karlas1, Andrea Wehrens1, Frank Siedler3, Volker Brinkmann2 & Thomas F. Meyer1
1 Department of Molecular Biology,2 Microscopy Core Facility, Max Planck Institute for Infection Biology, Charitéplatz 1, 10117 Berlin, Germany3 Department of Membrane Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany
The obligate intracellular bacterium Chlamydia trachomatis survives and replicates within a membrane-bound vacuole, termed the inclusion, which intercepts host exocytic pathways to obtain nutrients1, 2, 3. Like many other intracellular pathogens, C. trachomatis has a marked requirement for host cell lipids, such as sphingolipids and cholesterol, produced in the endoplasmic reticulum and the Golgi apparatus4, 5, 6. However, the mechanisms by which intracellular pathogens acquire host cell lipids are not well understood1, 2, 3. In particular, no host cell protein responsible for transporting Golgi-derived lipids to the chlamydial inclusions has yet been identified. Here we show that Chlamydia infection in human epithelial cells induces Golgi fragmentation to generate Golgi ministacks surrounding the bacterial inclusion. Ministack formation is triggered by the proteolytic cleavage of the Golgi matrix protein golgin-84. Inhibition of golgin-84 truncation prevents Golgi fragmentation, causing a block in lipid acquisition and maturation of C. trachomatis. Golgi fragmentation by means of RNA-interference-mediated knockdown of distinct Golgi matrix proteins before infection enhances bacterial maturation. Our data functionally connect bacteria-induced golgin-84 cleavage, Golgi ministack formation, lipid acquisition and intracellular pathogen growth. We show that C. trachomatis subverts the structure and function of an entire host cell organelle for its own advantage.
Nature：基于T细胞的HIV-1疫苗开发策略仍有可行性
专题： Nature报道
最近遭受的挫折促使人们对 艾滋病疫苗 领域进行一次重大的重新评估。人们一直问的一个问题是，是否继续基于T-细胞的HIV-1疫苗的开发。现在，用一种新疫苗在患有“猴免疫缺陷综合症”（SIV）的猴子身上所进行的一项研究表明，基于T-细胞的策略仍然是有潜在可行性的。该疫苗利用两种表达SIV Gag蛋白的腺病毒 载体 (rAd26 prime/rAd5 boost)制成。它能诱发强效T-细胞免疫反应，并使猴子在病毒感染方面受到一定保护。这些发现为用于防治HIV-1的新一代基于T-细胞的疫苗候选药物的设计提供了线索。（ 生物谷 Bioon.com）
生物谷 推荐原始出处：
Nature 457, 87-91 (1 January 2009) doi:10.1038/nature07469
Immune control of an SIV challenge by a T-cell-based vaccine in rhesus monkeys
Jinyan Liu1, Kara L. O'Brien1, Diana M. Lynch1, Nathaniel L. Simmons1, Annalena La Porte1, Ambryice M. Riggs1, Peter Abbink1, Rory T. Coffey1, Lauren E. Grandpre1, Michael S. Seaman1, Gary Landucci2, Donald N. Forthal2, David C. Montefiori3, Angela Carville4, Keith G. Mansfield4, Menzo J. Havenga5, Maria G. Pau6, Jaap Goudsmit6 & Dan H. Barouch1
1 Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA2 University of California, Irvine School of Medicine, Irvine, California 92697, USA3 Duke University Medical Center, Durham, North Carolina 27710, USA4 New England Primate Research Center, Southborough, Massachusetts 01772, USA5 TNO Biosciences, 2301 CE, Leiden, The Netherlands6 Crucell Holland BV, 2301 CA, Leiden, The Netherlands
A recombinant adenovirus serotype 5 (rAd5) vector-based vaccine for HIV-1 has recently failed in a phase 2b efficacy study in humans1, 2. Consistent with these results, preclinical studies have demonstrated that rAd5 vectors expressing simian immunodeficiency virus (SIV) Gag failed to reduce peak or setpoint viral loads after SIV challenge of rhesus monkeys (Macaca mulatta) that lacked the protective MHC class I allele Mamu-A*01 (ref. 3). Here we show that an improved T-cell-based vaccine regimen using two serologically distinct adenovirus vectors afforded substantially improved protective efficacy in this challenge model. In particular, a heterologous rAd26 prime/rAd5 boost vaccine regimen expressing SIV Gag elicited cellular immune responses with augmented magnitude, breadth and polyfunctionality as compared with the homologous rAd5 regimen. After SIVMAC251 challenge, monkeys vaccinated with the rAd26/rAd5 regimen showed a 1.4 log reduction of peak and a 2.4 log reduction of setpoint viral loads as well as decreased AIDS-related mortality as compared with control animals. These data demonstrate that durable partial immune control of a pathogenic SIV challenge for more than 500 days can be achieved by a T-cell-based vaccine in Mamu-A*01-negative rhesus monkeys in the absence of a homologous Env antigen. These findings have important implications for the development of next-generation T-cell-based vaccine candidates for HIV-1.
最近遭受的挫折促使人们对 艾滋病疫苗 领域进行一次重大的重新评估。人们一直问的一个问题是，是否继续基于T-细胞的HIV-1疫苗的开发。现在，用一种新疫苗在患有“猴免疫缺陷综合症”（SIV）的猴子身上所进行的一项研究表明，基于T-细胞的策略仍然是有潜在可行性的。该疫苗利用两种表达SIV Gag蛋白的腺病毒 载体 (rAd26 prime/rAd5 boost)制成。它能诱发强效T-细胞免疫反应，并使猴子在病毒感染方面受到一定保护。这些发现为用于防治HIV-1的新一代基于T-细胞的疫苗候选药物的设计提供了线索。（ 生物谷 Bioon.com）
生物谷 推荐原始出处：
Nature 457, 87-91 (1 January 2009) doi:10.1038/nature07469
Immune control of an SIV challenge by a T-cell-based vaccine in rhesus monkeys
Jinyan Liu1, Kara L. O'Brien1, Diana M. Lynch1, Nathaniel L. Simmons1, Annalena La Porte1, Ambryice M. Riggs1, Peter Abbink1, Rory T. Coffey1, Lauren E. Grandpre1, Michael S. Seaman1, Gary Landucci2, Donald N. Forthal2, David C. Montefiori3, Angela Carville4, Keith G. Mansfield4, Menzo J. Havenga5, Maria G. Pau6, Jaap Goudsmit6 & Dan H. Barouch1
1 Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA2 University of California, Irvine School of Medicine, Irvine, California 92697, USA3 Duke University Medical Center, Durham, North Carolina 27710, USA4 New England Primate Research Center, Southborough, Massachusetts 01772, USA5 TNO Biosciences, 2301 CE, Leiden, The Netherlands6 Crucell Holland BV, 2301 CA, Leiden, The Netherlands
A recombinant adenovirus serotype 5 (rAd5) vector-based vaccine for HIV-1 has recently failed in a phase 2b efficacy study in humans1, 2. Consistent with these results, preclinical studies have demonstrated that rAd5 vectors expressing simian immunodeficiency virus (SIV) Gag failed to reduce peak or setpoint viral loads after SIV challenge of rhesus monkeys (Macaca mulatta) that lacked the protective MHC class I allele Mamu-A*01 (ref. 3). Here we show that an improved T-cell-based vaccine regimen using two serologically distinct adenovirus vectors afforded substantially improved protective efficacy in this challenge model. In particular, a heterologous rAd26 prime/rAd5 boost vaccine regimen expressing SIV Gag elicited cellular immune responses with augmented magnitude, breadth and polyfunctionality as compared with the homologous rAd5 regimen. After SIVMAC251 challenge, monkeys vaccinated with the rAd26/rAd5 regimen showed a 1.4 log reduction of peak and a 2.4 log reduction of setpoint viral loads as well as decreased AIDS-related mortality as compared with control animals. These data demonstrate that durable partial immune control of a pathogenic SIV challenge for more than 500 days can be achieved by a T-cell-based vaccine in Mamu-A*01-negative rhesus monkeys in the absence of a homologous Env antigen. These findings have important implications for the development of next-generation T-cell-based vaccine candidates for HIV-1.
PNAS：揭开新生隐球菌自我保护机制
美国耶什华大学阿尔伯特爱因斯坦医学院的研究人员称，他们发现了新生隐球菌如何躲过人类免疫系统并导致疾病的过程，该发现有助于开发针对新生隐球菌感染的疫苗。相关研究报告发表在近期出版的美国《国家科学院院刊》（PNAS）上。
该研究负责人苏珊娜·佛瑞丝瓦哈尔表示，这些真菌最易感染免疫系统受损的患者，特别是艾滋病患者和因器官移植而必须采取终身免疫抑制治疗的患者。据估计，全球每年因真菌感染导致的死亡人数高达100万，而其中撒哈拉以南地区就有近60万。
新生隐球菌首先通过肺部感染侵入人体，而后蔓延至包括大脑在内的其他各处器官，被称为隐球菌病，可导致胸痛、干咳、腹部肿胀、头痛、视力模糊等症状。如未及时得到抗真菌药物的治疗，隐球菌病可以致命。
研究人员发现，新生隐球菌外表有一层类似胶囊一样的薄膜在其感染人体过程中起着重要的作用。当真菌进入人体后，其外膜便开始增大。当真菌的外膜增大到一定程度，人体免疫系统中负责清除病毒的巨噬细胞便无法将其吞噬。但研究人员现在还没有理解导致真菌外膜增大的机制。
经过分析，研究人员发现新生隐球菌保护外膜的主要成分是多聚糖，有较长的糖分子链。佛瑞丝瓦哈尔和同事通过利用一种被称为动态散射的技术发现，真菌外膜会将越来越多的糖类聚集在外膜的边缘，从而形成巨大的分子，使外膜沿着轴线向外扩张。
该发现将为药物介入治疗开创新的研究方向，并将为基础多聚糖生物学开创新的研究领域。目前人们对多聚糖还理解甚少，科学家们之前认为多聚糖只是简单增长到一个特定长度，并没有什么研究价值，但这项新研究暗示多聚糖中似乎存在一套人们还不知晓的复杂机制。（生物谷Bioon.com）
生物谷推荐原始出处：
PNAS，doi: 10.1073/pnas.0808995106，Susana Frases， Arturo Casadevall
Capsule of Cryptococcus neoformans grows by enlargement of polysaccharide molecules
Susana Frasesa, Bruno Pontesb, Leonardo Nimrichterc, Nathan B. Vianabd, Marcio L. Rodriguesc and Arturo Casadevallae1
aDepartment of Microbiology and Immunology andeDivision of Infectious Diseases of the Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461;bLaboratório de Pin?as óticas-Coordena??o de Programas de Estudos Avan?ados, Instituto de Ciências Biomédicas, andcLaboratório de Estudos Integrados em Bioquímica Microbiana, Instituto de Microbiologia Professor Paulo de Góes,Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, Brazil; anddInstituto de Física, Universidade Federal do Rio de Janeiro, 21941-972, Rio de Janeiro, Brazil
Abstract
The human pathogenic fungus Cryptococcus neoformans has a distinctive polysaccharide (PS) capsule that enlarges during infection. The capsule is essential for virulence, but the mechanism for capsular growth is unknown. In the present study, we used dynamic light scattering (LS) analysis of capsular PS and optical tweezers (OT) to explore the architecture of the capsule. Analysis of capsular PS from cells with small and large capsules by dynamic LS revealed a linear correlation between PS effective diameter and microscopic capsular diameter. This result implied that capsule growth was achieved by the addition of molecules with larger effective diameter, such that some molecules can span the entire diameter of the capsule. Measurement of polystyrene bead penetration of C. neoformans capsules by using OT techniques revealed that the outer regions were penetrable, but not the inner regions. Our results provide a mechanism for capsular enlargement based on the axial lengthening of PS molecules and suggest a model for the architecture of a eukaryotic microbial capsule.
该研究负责人苏珊娜·佛瑞丝瓦哈尔表示，这些真菌最易感染免疫系统受损的患者，特别是艾滋病患者和因器官移植而必须采取终身免疫抑制治疗的患者。据估计，全球每年因真菌感染导致的死亡人数高达100万，而其中撒哈拉以南地区就有近60万。
新生隐球菌首先通过肺部感染侵入人体，而后蔓延至包括大脑在内的其他各处器官，被称为隐球菌病，可导致胸痛、干咳、腹部肿胀、头痛、视力模糊等症状。如未及时得到抗真菌药物的治疗，隐球菌病可以致命。
研究人员发现，新生隐球菌外表有一层类似胶囊一样的薄膜在其感染人体过程中起着重要的作用。当真菌进入人体后，其外膜便开始增大。当真菌的外膜增大到一定程度，人体免疫系统中负责清除病毒的巨噬细胞便无法将其吞噬。但研究人员现在还没有理解导致真菌外膜增大的机制。
经过分析，研究人员发现新生隐球菌保护外膜的主要成分是多聚糖，有较长的糖分子链。佛瑞丝瓦哈尔和同事通过利用一种被称为动态散射的技术发现，真菌外膜会将越来越多的糖类聚集在外膜的边缘，从而形成巨大的分子，使外膜沿着轴线向外扩张。
该发现将为药物介入治疗开创新的研究方向，并将为基础多聚糖生物学开创新的研究领域。目前人们对多聚糖还理解甚少，科学家们之前认为多聚糖只是简单增长到一个特定长度，并没有什么研究价值，但这项新研究暗示多聚糖中似乎存在一套人们还不知晓的复杂机制。（生物谷Bioon.com）
生物谷推荐原始出处：
PNAS，doi: 10.1073/pnas.0808995106，Susana Frases， Arturo Casadevall
Capsule of Cryptococcus neoformans grows by enlargement of polysaccharide molecules
Susana Frasesa, Bruno Pontesb, Leonardo Nimrichterc, Nathan B. Vianabd, Marcio L. Rodriguesc and Arturo Casadevallae1
aDepartment of Microbiology and Immunology andeDivision of Infectious Diseases of the Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461;bLaboratório de Pin?as óticas-Coordena??o de Programas de Estudos Avan?ados, Instituto de Ciências Biomédicas, andcLaboratório de Estudos Integrados em Bioquímica Microbiana, Instituto de Microbiologia Professor Paulo de Góes,Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, Brazil; anddInstituto de Física, Universidade Federal do Rio de Janeiro, 21941-972, Rio de Janeiro, Brazil
Abstract
The human pathogenic fungus Cryptococcus neoformans has a distinctive polysaccharide (PS) capsule that enlarges during infection. The capsule is essential for virulence, but the mechanism for capsular growth is unknown. In the present study, we used dynamic light scattering (LS) analysis of capsular PS and optical tweezers (OT) to explore the architecture of the capsule. Analysis of capsular PS from cells with small and large capsules by dynamic LS revealed a linear correlation between PS effective diameter and microscopic capsular diameter. This result implied that capsule growth was achieved by the addition of molecules with larger effective diameter, such that some molecules can span the entire diameter of the capsule. Measurement of polystyrene bead penetration of C. neoformans capsules by using OT techniques revealed that the outer regions were penetrable, but not the inner regions. Our results provide a mechanism for capsular enlargement based on the axial lengthening of PS molecules and suggest a model for the architecture of a eukaryotic microbial capsule.
微生物 免疫学
澳大利亚国立大学医学研究所，化学研究所的科学家发现新的免疫理论，相关成果公布在最新一期的Immunity上，并列为封面文章。
众所周知，B细胞具有记忆性，一般来说B细胞的记忆性的形成与DNA序列的改变有联系，B细胞通过改变DNA序列来维持细胞的记忆性。但是，免疫细胞的记忆性机制研究比较多的是B细胞，相比之下，T细胞研究的比较少。
研究小组发现，记忆性T细胞的分化过程中， RNA重排起重要作用。研究小组以小鼠的研究模型，通过沉默一个记忆性T细胞分化的关键基因ptprc（是产生记忆性T细胞CD45RO的重要基因），结果发现记忆性T细胞的比例发生改变。并且RNA结合蛋白hnRNALL发生改变，会导致RNA的识别区域变得不稳定。
研究者发现hnrpll突变会导致T细胞不在外周淋巴结聚集，但不影响增殖。对这些突变细胞进行外显子检测分析，结果发现记忆性T细胞的mRNA接过程发生的广泛的改变。并且相同的变化还出现在神经组织中，这可能是引发记忆性T细胞发生变化的原因。（生物谷Bioon.com）
生物谷推荐原始出处：
Immunity,19 December 2008 doi:10.1016/j.immuni.2008.11.004
Memory T Cell RNA Rearrangement Programmed by Heterogeneous Nuclear Ribonucleoprotein hnRNPLL
Zuopeng Wu1,Xinying Jia2,Laura de la Cruz2,Xun-Cheng Su2,Bruz Marzolf3,Pamela Troisch3,Daniel Zak3,Adam Hamilton1,Belinda Whittle1,Di Yu1,Daniel Sheahan1,Edward Bertram1,Alan Aderem3,Gottfried Otting2,Christopher C. Goodnow1,4,,andGerard F. Hoyne1,4
1 John Curtin School of Medical Research, Australian Phenomics Facility, Australian National University, Canberra ACT 0200, Australia2 Research School of Chemistry, Australian National University, Canberra ACT 0200, Australia3 Institute for Systems Biology, 1441 North 34th St., Seattle, WA 98103-9804, USACorresponding author4 These authors contributed equally
Summary
Differentiation of memory cells involves DNA-sequence changes in B lymphocytes but is less clearly defined in Tcells. RNA rearrangement is identified here as a key event in memory Tcell differentiation by analysis of a mouse mutation that altered the proportions of naive and memory Tcells and crippled the process of Ptprc exon silencing needed to generate CD45RO in memory Tcells. A single substitution ina memory-induced RNA-binding protein, hnRNPLL, destabilized an RNA-recognition domain that bound with micromolar affinity to RNA containing the Ptprc exon-silencing sequence. Hnrpll mutation selectively diminished Tcell accumulation in peripheral lymphoid tissues but not proliferation. Exon-array analysis of Hnrpll mutant naive and memory Tcells revealed an extensive program of alternative mRNA splicing in memory Tcells, coordinated by hnRNPLL. A remarkable overlap with alternative splicing in neural tissues may reflect a co-opted strategy for diversifying memory Tcells.
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