Cellular Determinants of Hantavirus Pathogenesis

汉坦病毒引起两种高度致命的人类疾病，即肾综合征出血热（HFRS）和汉坦病毒肺综合征（HPS），并有可能被用作生物恐怖主义制剂。汉坦病毒主要在内皮细胞中复制，但对受感染的内皮细胞无明显损伤。非致病性汉坦病毒也感染人内皮细胞，表明细胞内事件决定了汉坦病毒引起疾病的能力。利用DNA阵列，我们发现非致病性汉坦病毒Prospect Hill病毒（PHV）在内皮细胞内迅速诱导干扰素（IFN）反应，而致病性汉坦病毒（HTNV） （HFRS）或纽约-1病毒（NY-1V） （HPS）无法诱导干扰素（IFN）反应。因此，当HTNV和NY-1V在人内皮细胞内复制时，PHV的复制受到抑制。此外，PHV和NY-1V的共同感染降低了PHV导向的IFN反应，表明NY-1V负向调节防御性细胞反应。这些发现表明致病性和非致病性汉坦病毒对先天细胞防御的调节存在差异，并提示致病性汉坦病毒改变内皮细胞反应的能力是汉坦病毒发病机制的基本决定因素。虽然没有关于汉坦病毒蛋白如何指导或调节IFN反应的信息，但我们最近

Hantaviruses cause two highly lethal human diseases, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), and have the potential to be used as bioterrorism agents. Hantaviruses replicate predominantly in endothelial cells but cause no apparent damage to the infected endothelium. Non-pathogenic hantaviruses also infect human endothelial cells, indicating that intracellular events determine the capacity for hantaviruses to cause disease. Using DNA arrays we have found that the non-pathogenic hantavirus Prospect Hill Virus (PHV) rapidly induces interferon (IFN) responses within endothelial cells that are not elicited by pathogenic Hantaan virus (HTNV) (HFRS) or New York-1 virus (NY-1V) (HPS). PHV replication is consequently inhibited while HTNV and NY-1V replicate within human endothelial cells. In addition, co-infection of PHV and NY-1V reduced PHV-directed IFN responses, suggesting that NY-1V negatively regulates defensive cellular responses. These findings indicate that pathogenic and non-pathogenic hantaviruses differentially regulate innate cellular defenses and suggest that the ability of pathogenic hantaviruses to alter endothelial cell responses is a fundamental determinant of hantavirus pathogenesis. Although there is no information about how hantavirus proteins might direct or regulate IFN responses, we recently identified hantavirus protein interactions that may influence IFN responses. Our preliminary results suggest that pathogenic hantavirus proteins play a role in blocking cellular defenses and thereby permit pathogenic hantaviruses to replicate within endothelial cells. Objective: We propose to investigate the differential regulation of endothelial cell responses by pathogenic and non-pathogenic hantaviruses. We will define hantavirus proteins that repress IFNb responses and determine the role of IRF-3 and NF-kB activation on hantavirus replication in order to define signaling pathways and proteins that are regulated by pathogenic hantaviruses. These experiments provide a fundamental understanding of hantavirus regulation of innate cellular defenses, define determinants of hantavirus pathogenesis and are anticipated to provide therapeutic targets for hantavirus disease interventions. Specific Aims: Aim 1) Define Hantavirus Proteins that Regulate Cellular IFN Responses. Aim 2) Evaluate Mechanisms of Signaling Pathway Regulation by Pathogenic Hantaviruses.