Measles virus receptors in the cotton rat model

描述(申请人提供)：麻疹病毒(MV)感染每年导致90万人死亡，原因是引起严重的免疫抑制，其特点是对继发性(通常是细菌)感染的敏感性很高。我们的长期目标是阐明控制麻疹病毒诱导免疫抑制的调控机制，作为设计治疗干预方案的必要必要条件。在人类中，疫苗和野生型病毒使用两种不同的受体分子。疫苗病毒可同时使用人CD46和CD150，感染淋巴系和成纤维细胞系，体内复制受到限制。野生型病毒只使用人类CD150，在淋巴细胞系中复制，并在患者中广泛传播。人们认为受体使用的不同是疫苗和野生型病毒在传播和免疫抑制方面存在差异的原因。我们使用棉鼠模型来研究麻疹病毒的致病机制。在棉鼠身上，人类细胞上的双重受体的使用反映在棉鼠细胞系的感染上。疫苗病毒可以感染成纤维细胞和淋巴细胞系；野生型病毒只感染淋巴细胞系。鼻内感染野生型病毒后，可以看到广泛的传播和免疫抑制。相比之下，疫苗病毒感染仅限于肺组织。基于这一数据，我们假设在棉花大鼠中，类似于人CD150和人CD46的类似物具有麻疹病毒受体的功能。我们建议使用已成功用于克隆和测序人类受体分子的技术来表征这些受体分子。我们将利用新生成的cdna文库，依靠我们在使用逆转录病毒载体和生产单抗方面的经验。通过克隆的受体分子和针对它们的抗体，我们将能够分析MV受体在体内的分布如何决定病毒的传播，确定MV血凝素(受体结合蛋白)作为毒力因子的作用，并解决MV受体在免疫抑制中的作用。

DESCRIPTION (provided by applicant): Measles virus (MV) infection causes 900,000 deaths per year due to the induction of severe immune suppression which is characterized by high susceptibility towards secondary (often bacterial) infections. Our long term goal is to elucidate the regulatory mechanisms controlling induction of immune suppression by measles virus as a necessary requisite to devise protocols for therapeutic intervention. In humans, 2 different receptor molecules are used by vaccine and wildtype virus. Vaccine virus can use both human CD46 and CD 150, infect lymphoid and fibroblast cell lines and is restricted in its in vivo replication. Wildtype virus uses human CD 150, only, replicates in lymphoid cell lines and is widely disseminated in patients. It is thought that the difference in receptor usage accounts for the difference in dissemination and immune suppression between vaccine and wildtype virus. We use the cotton rat model to study measles virus pathogenesis. In cotton rats, the dual receptor usage seen on human cells is reflected in infection of cotton rat cell lines. Vaccine virus can infect both fibroblast and lymphoid cell lines; wildtype virus infects lymphoid cell lines, only. After intranasal infection with wildtype virus widespread dissemination and immune suppression is seen. In contrast, vaccine virus infection is restricted to lung tissue. Based on this data, we hypothesize that in cotton rats analogs to human CD 150 and human CD46 function as measles virus receptors. We propose to characterize these receptor molecules by using techniques which have successfully been employed in the cloning and sequencing of the human receptor molecules. We will make use of a newly generated cDNA library and rely on our experience in using retroviral vectors and the production of monoclonal antibodies. With cloned receptor molecules and antibodies specific for them we will be able to analyze how the MV receptor distribution in vivo determines dissemination of virus, define the role of the MV hemagglutinin (the receptor-binding protein) as a virulence factor and address the role of MV receptors in immune suppression.