Pathogenic and nonpathogenic hantaviruses differentially regulate endothelial cell responses
Pathogenic and nonpathogenic hantaviruses differentially regulate endothelial cell responses
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DOI：
10.1073/pnas.192298899
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发表时间：
2002-10-15
影响因子：
11.1
通讯作者：
Mackow, ER
中科院分区：
文献类型：
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作者：
Geimonen, E;Neff, S;Mackow, ER
汉他病毒引起两种人类疾病：肾综合征出血热（HFRS）和汉他病毒肺综合征（HPS）。汉他病毒感染人内皮细胞，但对受感染的内皮细胞几乎不造成损害。我们用Affyscore DNA阵列（Santa Clara，CA）分析了由与HPS相关的汉坦病毒[纽约-1病毒（NY-1V）]、HFRS [汉坦病毒（HTNV）]或与人类疾病无关的汉坦病毒[前景希尔病毒（PHV）]指导的内皮细胞转录应答。汉坦病毒感染诱导了117个细胞基因，并在感染后4天（p.i）抑制了25个基因，抑制倍数>3倍。尽管在感染后1天>80%的细胞被每种病毒感染，PHV诱导或抑制67个基因在这个早期的时间相比，三个基因改变HTNV或NY-1V。早期高水平诱导的24个干扰素刺激的基因PHV（4至229倍）代表了一个根本性的差异，在时间调节细胞反应的致病性和非致病性汉坦病毒。因为所有汉坦病毒在感染后晚期诱导>23个IFN刺激基因，致病性汉他病毒似乎抑制由非致病性汉他病毒激活的早期细胞IFN应答。在P.I.后期，其中13个基因被HTNV和NY-1V共同诱导表达，而PHV不诱导表达。与NY-1V相反，HTNV独特地诱导多种趋化因子和细胞粘附分子（即，IL-8、IL-6、GRO-β、ICAM），以及两种可能与HFRS疾病的免疫成分有关的补体级联相关因子。NY-1V不能诱导大多数由HTNV（3/14）指导的细胞趋化因子或主要由NF-κ B激活的基因。然而，NY-1V独特地诱导β 3整合素连接的钾通道，这可能在HPS相关的血管通透性中发挥作用。这些研究提供了对汉他病毒介导的细胞反应的基本了解，这些反应可能区分致病性和非致病性汉他病毒，有助于HFRS和HPS的发病机制，并提供了对疾病机制和潜在治疗干预措施的深入了解。
Hantavinuses cause two human diseases: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Hantavinuses infect human endothelial cells but cause little or no damage to the infected endothelium. We analyzed with Affymetrix DNA Arrays (Santa Clara, CA) the endothelial cell transcriptional responses directed by hantaviruses associated with HPS [New York-1 virus (NY-1V)], HFRS [Hantaan virus (HTNV)], or by a hantavirus not associated with human disease [Prospect Hill virus (PHV)]. Hantavirus infections induced 117 cellular genes and repressed 25 genes by >3-fold, 4 days postinfection (p.i). Although >80% of cells were infected by each virus 1 day p.i., PHV induced or repressed 67 genes at this early time compared with three genes altered by HTNV or NY-1V. The early high-level induction of 24 IFN-stimulated genes by PHV (4- to 229-fold) represents a fundamental difference in the temporal regulation of cellular responses by pathogenic and nonpathogenic hantaviruses. Because all hantaviruses induced >23 IFN-stimulated genes at late times p.i., pathogenic hantaviruses appearto suppress early cellular IFN responses that are activated by nonpathogenic hantaviruses. At late times p.i., 13 genes were commonly induced by HTNV and NY-1V that were not induced by PHV. In contrast to NY-1V, HTNV uniquely induced a variety of chemokines and cell adhesion molecules (i.e., IL-8, IL-6, GRO-beta, ICAM), as well as two complement cascade-associated factors that may contribute to immune components of HFRS disease. NY-1V failed to induce most cellular chemokines directed by HTNV (3/14) or genes primarily activated by NF-kappaB. However, NY-1V uniquely induced beta3 integrin-linked potassium channels, which could play a role in HPS-associated vascular permeability. These studies provide a basic understanding of hantavirus-directed cellular responses that are likely to differentiate pathogenic and nonpathogenic hantaviruses, contribute to HFRS and HPS pathogenesis, and provide insight into disease mechanisms and potential therapeutic interventions.