研究背景和目的：呼吸道合胞病毒（Respiratory Syncytial Virus, RSV）是引起婴幼儿和老年人急性下呼吸道感染的主要病原体。尽管近年来RSV疫苗研发取得进展，但其临床应用仍面临疫苗增强型呼吸道疾病（Enhanced Respiratory Disease, ERD）的风险。叙利亚仓鼠用于RSV模型研制的报道较少，但是在多种传染病动物模型构建方面具有优势，曾被广泛用于SARS-CoV、SARS-CoV-2、尼帕病毒、流感病毒等感染模型研制。本研究旨在构建叙利亚仓鼠感染RSV模型，在此基础上利用热灭活RSV诱发ERD，并结合转录组学分析探讨ERD的发生机制。

材料与方法：对不同年龄叙利亚仓鼠滴鼻接种高、低剂量RSV，通过观察临床症状，检测病毒载量、病毒分布及病理损伤，确定不同年龄仓鼠感染RSV的疾病表征。选取70-80周龄老年叙利亚仓鼠，分别免疫热灭活RSV或免疫对照品，初次免疫21天后进行加强免疫，加强免疫后14天滴鼻接种10⁶ TCID₅₀ RSV，对比分析疾病表型，并对感染后5天肺组织与外周血进行转录组学分析。此外，在孕前期及孕期对母鼠免疫HI-RSV或免疫对照品，两次免疫间隔21天，免疫完成后对新生乳鼠滴鼻接种10⁶ TCID₅₀ RSV，分析母传抗体对ERD的影响。

结果：RSV可感染不同年龄叙利亚仓鼠，其中新生仓鼠对RSV的敏感性最高，肺组织病毒载量显著高于成年及老年仓鼠，病理表现与人类及棉鼠RSV感染相似，以细支气管炎为主要病理特征。热灭活RSV可诱导仓鼠产生中低水平中和抗体，降低感染后组织病毒载量，但会导致感染后肺部病理损伤显著加重，以肺部嗜酸性粒细胞浸润增多及组织实变为特征。转录组学分析显示，发生ERD的仓鼠肺组织中Th1/Th2免疫平衡失调，il-4、il-5和il-13等Th2型细胞因子mRNA表达水平显著上调，同时伴随嗜酸性粒细胞特异性标志物（如EPX、MBP）的高表达。HI-RSV在母鼠中诱导产生的中和抗体可通过胎盘屏障传递给乳鼠，降低乳鼠感染后肺病毒载量。然而，被动免疫的乳鼠在感染RSV后并未表现出ERD特征，提示ERD的发生机制主要与细胞免疫应答异常相关，而非单纯由抗体介导。

结论：构建了叙利亚仓鼠感染RSV动物模型，不同年龄仓鼠可感染RSV，感染后肺、气管、鼻甲内均能检测到病毒RNA分布，肺部病理表现为病毒性细支气管炎，与棉鼠及人类相似。其中3日龄新生仓鼠对病毒的敏感性最高，感染后肺部病毒载量显著高于成年及老年仓鼠。HI-RSV能够在老年仓鼠中诱导增强型呼吸道疾病，肺部病变明显加重，并表现出Th2型免疫反应偏移，符合ERD的常见特征。

Background and Objective: Respiratory syncytial virus (RSV) is a major pathogen responsible for acute lower respiratory tract infections in infants and the elderly. Although significant progress has been made in RSV vaccine development in recent years, clinical application remains challenged by the risk of vaccine-associated enhanced respiratory disease (ERD). While Syrian hamsters are not commonly used in RSV modeling, they offer clear advantages in infectious disease research and have been widely employed in models of SARS-CoV, SARS-CoV-2, Nipah virus, and influenza virus infections. This study aims to establish an RSV infection model in Syrian hamsters, induce ERD through heat-inactivated RSV (HI-RSV), and investigate the underlying mechanisms of ERD using transcriptomic analysis. Methods: Syrian hamsters of different ages were intranasally inoculated with high or low doses of RSV. Clinical symptoms, viral load, viral distribution, and pathological damage were monitored to characterize disease manifestations across age groups. Aged hamsters (70–80 weeks) were immunized with HI-RSV or a control preparation. A booster immunization was administered 21 days after the primary immunization, followed by an intranasal challenge with 10⁶ TCID₅₀ of RSV 14 days post-boost. Disease phenotypes were compared, and transcriptomic analyses were conducted on lung tissue and peripheral blood collected five days post-infection. Additionally, female hamsters were immunized with HI-RSV or a control agent before and during pregnancy, with a 21-day interval between doses. Following delivery, neonatal pups were intranasally challenged with 10⁶ TCID₅₀ RSV to assess the effect of maternal antibodies on ERD development. Results: RSV successfully infected Syrian hamsters across all age groups, with neonates exhibiting the highest susceptibility. Neonatal lung viral loads were significantly higher than those in adult and aged hamsters, and their pathological features resembled those seen in RSV-infected humans and cotton rats, characterized predominantly by bronchiolitis. HI-RSV immunization induced moderate neutralizing antibody titers and reduced tissue viral loads upon challenge, but markedly exacerbated pulmonary pathology, evidenced by increased eosinophilic infiltration and pulmonary consolidation. Transcriptomic analysis revealed disrupted Th1/Th2 immune balance in ERD-affected lungs, with significantly elevated mRNA expression of Th2 cytokines (e.g., il-4, il-5, il-13), and increased expression of eosinophil-specific markers such as EPX and MBP. Neutralizing antibodies induced by maternal HI-RSV immunization were transmitted to offspring via the placenta and reduced post-infection lung viral loads in neonates. However, passively immunized neonates did not display ERD symptoms following RSV infection, suggesting that ERD is primarily driven by aberrant cellular immune responses rather than antibody-mediated mechanisms alone. Conclusion: An RSV infection model was successfully established in Syrian hamsters. Hamsters of all ages were susceptible to RSV, with viral RNA detectable in the lungs, trachea, and nasal turbinates. Lung pathology was consistent with viral bronchiolitis, similar to that observed in cotton rats and humans. Neonates (3 days old) exhibited the highest viral loads post-infection. In aged hamsters, HI-RSV immunization induced ERD characterized by worsened lung pathology and a Th2-skewed immune response, consistent with classical features of ERD.