Contribution of PB1-F2 to transmission in the guinea pig model

PB1-F2 对豚鼠模型传播的贡献

• 批准号: 7484065
• 负责人: Gina Conenello
• 金额: $ 3.78万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7484065
• 关键词: Contribution; PB1; F2; transmission; guinea

DESCRIPTION (provided by applicant): The PB1-F2 protein is the most recently discovered influenza A virus protein. The protein is translated from the +1 reading frame of the PB1 gene of the influenza A virus genome. This small protein of 87 amino acids has been shown to cause apoptosis in infected cells. PB1-F2 interacts with the mitochondrial membrane proteins adenine nucleotide translocator 3 (ANT3) and voltage dependent anion channel (VDAC1) and this interaction induces apoptosis via the mitochondrial pathway as shown by Zamarin et al. It has also been shown in the mouse model that viruses knocked out for PB1-F2 expression have reduced pathogenicity. Previous studies show that PB1-F2 contributes to pathogenesis and that amino acid change N66S in the C-terminus can increase pathogenicity in the mouse model. In this study we will examine the effects of PB1-F2 on transmission in the guinea pig model. We hypothesize that increased virus replication and pathogenesis caused by PB1-F2 in animal models may lead to more efficient transmission. Our study will focus on the use of the recombinant A/Texas/91 virus. This virus model has been used in previous transmission experiments in ferrets to examine the contribution of H5N1 and 1918 pandemic virus genes to pathogenesis. A/Texas/91 is a good model to study transmission because preliminary experiments have shown that this virus has a 17% transmission rate without expressing a full-length PB1-F2. PB1-F2 can be expressed without changing any other proteins or genes of the virus, by fixing a stop codon to a tryptophan in the coding sequence of PB1-F2. This is ideal because we know that there is not an inherent block in transmission coming from other genes of the virus, but we will also be able to observe changes, either increases or decreases in transmission. The experiments outlined in this proposal are designed to examine the effects of PB1-F2 on transmission in the guinea pig model using the recombinant A/Texas/91 virus. Contribution of PB1-F2 to transmission in the guinea pig model.

描述（申请人提供）：PB1-F2蛋白是最近发现的甲型流感病毒蛋白。该蛋白由甲型流感病毒基因组PB1基因的+1阅读框翻译而来。这种由 87 个氨基酸组成的小蛋白质已被证明可导致受感染细胞凋亡。 PB1-F2 与线粒体膜蛋白腺嘌呤核苷酸转位子 3 (ANT3) 和电压依赖性阴离子通道 (VDAC1) 相互作用，并且这种相互作用通过线粒体途径诱导细胞凋亡，如 Zamarin 等人所示。小鼠模型也显示，敲除 PB1-F2 表达的病毒的致病性降低。先前的研究表明，PB1-F2 有助于发病，并且 C 末端的 N66S 氨基酸变化可以增加小鼠模型中的致病性。在本研究中，我们将研究 PB1-F2 对豚鼠模型传播的影响。我们假设动物模型中 PB1-F2 引起的病毒复制和发病机制的增加可能会导致更有效的传播。我们的研究将集中于重组 A/Texas/91 病毒的使用。该病毒模型已用于之前在雪貂身上进行的传播实验，以检查 H5N1 和 1918 年大流行病毒基因对发病机制的贡献。 A/Texas/91是研究传播的良好模型，因为初步实验表明，这种病毒在不表达全长PB1-F2的情况下，传播率高达17%。通过将终止密码子固定到PB1-F2编码序列中的色氨酸上，可以在不改变病毒的任何其他蛋白质或基因的情况下表达PB1-F2。这是理想的，因为我们知道病毒的其他基因不会固有地阻止传播，但我们也能够观察变化，即传播的增加或减少。本提案中概述的实验旨在使用重组 A/Texas/91 病毒检查 PB1-F2 对豚鼠模型中传播的影响。 PB1-F2 对豚鼠模型传播的贡献。