Virus host interactions in clinical samples

临床样本中病毒宿主的相互作用

基本信息

批准号：
10702836
负责人：
Joseph Ziegelbauer
金额：
$ 80.37万
依托单位：
DIVISION OF BASIC SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10702836
关键词：
Africa South of the Sahara Area Automobile Driving B-Cell Lymphomas B-Cell NonHodgkins Lymphoma B-Lymphocytes Biological Markers Biopsy Cell Line Characteristics Clinical Collaborations Complex Development Diagnosis Diagnostic Procedure Disease Disease remission Endothelial Cells Environment Etiology FLT4 gene Gastrointestinal tract structure Gene Expression Gene Expression Profile Genes HIV HIV Infections Human Human Herpesvirus 4 Human Herpesvirus 8 Immune Immune response Immunocompromised Host Immunologic Deficiency Syndromes In Vitro Individual Infection Kaposi Sarcoma Laboratory Infection Lesion Life Link Location Lung Lymphatic Endothelial Cells Lymphoproliferative Disorders Lytic Malignant Neoplasms Methods Morbidity - disease rate Multicentric Angiofollicular Lymphoid Hyperplasia Normal tissue morphology Overlapping Genes Participant Pathogenesis Pathologic Patients Pattern Persons Population Primary Infection Prior Therapy Repression Risk Role STC1 gene Sampling Skin Skin Kaposi&apos s Sarcoma Therapeutic Tissues Transcript United States Vascular Endothelial Growth Factor C Vascular Endothelial Growth Factor D Viral Viral Genes Virus angiogenesis cell type chemotherapy clinically relevant co-infection differential expression improved insight interest mortality novel diagnostics organ transplant recipient post-transplant primary effusion lymphoma programs receptor targeted treatment transcriptome sequencing tumor tumorigenesis viral RNA virus host interaction

Africa South of the Sahara Area Automobile Driving B-Cell Lymphomas B-Cell NonHodgkins Lymphoma B-Lymphocytes Biological Markers Biopsy Cell Line Characteristics Clinical Collaborations Complex Development Diagnosis Diagnostic Procedure Disease Disease remission Endothelial Cells Environment Etiology FLT4 gene Gastrointestinal tract structure Gene Expression Gene Expression Profile Genes HIV HIV Infections Human Human Herpesvirus 4 Human Herpesvirus 8 Immune Immune response Immunocompromised Host Immunologic Deficiency Syndromes In Vitro Individual Infection Kaposi Sarcoma Laboratory Infection Lesion Life Link Location Lung Lymphatic Endothelial Cells Lymphoproliferative Disorders Lytic Malignant Neoplasms Methods Morbidity - disease rate Multicentric Angiofollicular Lymphoid Hyperplasia Normal tissue morphology Overlapping Genes Participant Pathogenesis Pathologic Patients Pattern Persons Population Primary Infection Prior Therapy Repression Risk Role STC1 gene Sampling Skin Skin Kaposi&apos s Sarcoma Therapeutic Tissues Transcript United States Vascular Endothelial Growth Factor C Vascular Endothelial Growth Factor D Viral Viral Genes Virus angiogenesis cell type chemotherapy clinically relevant co-infection differential expression improved insight interest mortality novel diagnostics organ transplant recipient post-transplant primary effusion lymphoma programs receptor targeted treatment transcriptome sequencing tumor tumorigenesis viral RNA virus host interaction

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项目摘要

In collaboration with Drs. Yarchoan, Ramaswami, Lurain, and Krug in HAMB, we have been investigating human and viral gene expression patterns in normal tissue, in Kaposi sarcoma (KS), and other KSHV-infected pathological tissues. Little is known about cellular and viral RNA transcripts in KS lesions and how these factors are influenced by prior therapy, concurrent KSHV-associated diseases, or the tissue location of KS lesions. We sought to understand how human gene expression and viral transcripts are altered in KS as compared to normal tissue using matched patient samples. In this study of participants with well-annotated clinical characteristics, we also investigated both skin and GI KS to determine differences in the viral and host transcripts between these lesions. We determined whether there were differences in immune environment by the location of the KS lesion or clinical characteristics. Specific cellular genes of interest that were linked to pathogenesis of KS or KSHV infection were investigated with in vitro studies using lymphatic endothelial cells (LECs) infected with KSHV to study and determine the significance of these findings from patient samples. We compared the cellular and KSHV gene expression signatures of skin and GI KS lesions. Skin and GI KS were compared to normal matched samples using bulk RNA sequencing. Twenty-two paired samples of KS and normal tissue were obtained (skin (10 pairs) and GI (12 pairs)) from 19 patients with KS of whom 17 had concurrent HIV infection. Seven paired samples were from patients who had received prior KS therapy. Three patients provided both skin and GI samples at the same timepoint. These analyses identified 370 differentially expressed genes unique to cutaneous KS and 58 DEGs unique to GI KS compared to normal skin or GI tissues. Twenty-six differentially expressed genes overlapped between skin and GI KS, which included FLT4, which encodes for a VEGF-C and VEGF-D receptor, and STC1. KSHV infection of primary lymphatic endothelial cells (LECs) resulted in increased angiogenesis, and repression of STC1 or FLT4 inhibited angiogenesis. The analyses of KSHV expression from KS lesions identified certain lytic genes, specifically ORF75, that were consistently expressed, and these expression patterns differed from laboratory infection of LECs with KSHV and KSHV gene expression in PEL cell lines. This study demonstrates that complex patterns of gene expression are found in KS tissue that differ from the canonical latent/lytic programs seen in KSHV cell lines and also demonstrates differences in viral gene and clinically relevant host gene expression in skin and GI KS that may offer insights into the pathogenesis of these forms of KS.

与Drs合作。 Yarchoan，Ramaswami，Lurain和Krug在汉堡中，我们一直在正常组织，Kaposi Sarmoma（KS）和其他KSHV感染的病理组织中研究人类和病毒基因表达模式。关于KS病变中的细胞和病毒RNA转录本知之甚少，以及这些因素如何受到先前治疗，并发的KSHV相关疾病或KS病变的组织位置的影响。我们试图了解使用匹配的患者样品与正常组织相比，KS中的人类基因表达和病毒转录本如何改变。在这项对具有良好临床特征的参与者的研究中，我们还研究了皮肤和GI KS，以确定这些病变之间的病毒和宿主转录本的差异。我们确定免疫环境的差异是通过KS病变或临床特征的位置存在差异。研究了与KSHV感染的淋巴内皮细胞（LEC）研究并确定患者样品中这些发现的重要性的特定细胞基因，该特定的与KS或KSHV感染有关的发病机理与KS或KSHV感染有关。我们比较了皮肤和GI KS病变的细胞和KSHV基因表达特征。使用散装RNA测序将皮肤和GI KS与正常匹配的样品进行比较。从19例KS患者中获得了22个KS和正常组织的配对样品（皮肤（10对）和GI（12对）），其中17例同时患有HIV感染。来自接受过KS治疗的患者的七个配对样品。三名患者在同一时间点提供了皮肤和GI样品。这些分析确定了与正常皮肤或GI组织相比，鉴定出370个差异表达的基因和GI KS独有的58度。 26个差异表达的基因在皮肤和GI KS之间重叠，其中包括FLT4，该基因编码为VEGF-C和VEGF-D受体，以及STC1。原发性淋巴内皮细胞（LEC）的KSHV感染导致血管生成增加，STC1或FLT4的抑制抑制了血管生成。来自KS病变的KSHV表达的分析鉴定出始终表达的某些裂解基因，特别是ORF75，这些表达模式与PEL细胞系中具有KSHV和KSHV基因表达的LEC的实验室感染不同。这项研究表明，在KS组织中发现了基因表达的复杂模式，这些模式与KSHV细胞系中的规范潜在/裂解程序有所不同，还显示了病毒基因的差异以及在皮肤和GI KS中与临床相关的宿主基因表达的差异，这些宿主基因表达可能会提供对这些KS形式的发病机理的见解。