Pichinde virus-infected guinea pigs as animal model for human hemorrhagic fever

摘要 像拉沙热病毒(LASV)这样的阿拉伯病毒可以引起人类的出血热，并可能被用作生物制剂。(在BLS-4实验室)对这种病毒进行高水平遏制限制的必要性，以及使用非人类灵长类动物进行LASV研究的昂贵费用，大大阻碍了对疾病发病机制的了解。豚鼠感染相关冠状病毒Pichinde(PICV)是一种安全、方便、经济的拉沙热小动物模型。经脾途径的猪传染性非典型肺炎病毒引起的拉沙热样症状仅限于豚鼠。与人类LASV感染一样，PICV病毒血症水平与疾病结局密切相关，可以准确预测豚鼠的致死率。此外，PICV感染的豚鼠表现出与LASV感染者相似的血管渗漏综合征和病毒分布。我们首次开发了PIVC强毒(P18)和无毒(P2)毒株的分子克隆，并确定了毒株之间的基因变化，这些变化可能导致该病毒在受感染动物中的致命致病性质。为了确定病毒毒力因子(S)，我们建议使用我们最近开发的反向遗传学系统来产生重组病毒，并评估它们对豚鼠致病性的影响。 这些研究将对病毒引起的出血热的分子机制提供重要的见解，这可能导致开发有效的治疗方式和疫苗来预防严重的、有时甚至是致命的出血热病毒感染。

Abstract Arenaviruses such as Lassa Fever Virus (LASV) can cause hemorrhagic fevers in humans and can potentially be employed as biological agents. The necessity of high-level containment restriction to work with this virus (in BLS-4 Laboratory) and the costly expenses of using non-human primates for LASV studies significantly hinder progress in understanding the disease pathogenesis. Guinea pig infected by a related arenavirus Pichinde (PICV) represents a safe, convenient, and economical small animal model for Lassa fever. A spleen-passaged PICV causes Lassa fever-like symptoms that are limited to guinea pigs. As with human LASV infection, PICV viremia levels are closely associated with disease outcome and can accurately predict lethality in guinea pigs. Additionally, PICV-infected guinea pigs exhibit vascular leakage syndrome and viral distribution similar to individuals infected by LASV. We have developed for the first time molecular clones for both virulent (P18) and avirulent (P2) strains of PIVC and have identified genetic changes between the strains that may be responsible for the deadly pathogenic nature of the virus in infected animals. To determine the viral virulence factor(s), we propose to generate recombinant viruses using our recently developed reverse genetics system and to assess their effects on pathogenicity in guinea pigs. These studies will provide important insights into the molecular mechanisms of virally induced hemorrhagic fevers, which may lead to the development of effective treatment modalities and vaccines against serious and sometime fatal hermorrhagic virus infections.