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

摘要 沙粒病毒如拉沙热病毒（LASV）可在人类中引起出血热，并且可潜在地用作生物制剂。高水平的遏制限制的必要性与这种病毒的工作（在BLS-4实验室）和使用非人灵长类动物LASV研究的昂贵费用显着阻碍了了解疾病的发病机制的进展。由相关沙粒病毒Pichinde（PICV）感染的豚鼠代表了一种安全、方便和经济的拉沙热小动物模型。脾脏传代的PICV引起仅限于豚鼠的拉沙热样症状。与人类LASV感染一样，PICV病毒血症水平与疾病结局密切相关，并可准确预测豚鼠的致死率。此外，PICV感染的豚鼠表现出血管渗漏综合征和病毒分布与LASV感染的个体相似。我们首次开发了PIVC强毒（P18）和无毒（P2）毒株的分子克隆，并鉴定了可能导致感染动物中病毒致命致病性的毒株之间的遗传变化。为了确定病毒的毒力因子，我们建议使用我们最近开发的反向遗传学系统产生重组病毒，并评估其对豚鼠致病性的影响。 这些研究将为病毒诱导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，以对抗严重的甚至是致命的出血病毒感染。

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.