恒河猴H5N1禽流感病毒性肺炎模型建立及其发病机制

目的 探讨H5N1病毒(AF148678/ACGoose/Guangdong/11961H5N1)感染恒河猴诱发自初期至恢复期过程肺炎的机制。方法 以H5N1 病毒液经鼻滴入恒河猴，染毒后第0 h、12 h、1 d、2 d、3 d、4 d、6 d、10 d、12 d和14 d采血作血液学和流感特异抗体检测。染毒后第1、3、6、14 d分别剖杀1 只恒河猴，取气管支气管淋巴结、肺、心、肝、肾、大脑及小脑进行病毒分离、滴定、病理及免疫组化检测并观察感染后临床表现。结果 猴感染后出现发热、呼吸困难，食欲下降等。病毒仅在肺组织复制，主要侵犯下呼吸道的肺泡上皮细胞和肺巨噬细胞。感染后第1~3 d引起暂时性的严重肺炎，主要为中性粒细胞浸润；第6 d后逐渐恢复，以巨噬细胞浸润为主；第14 d后以T淋巴细胞浸润为主，肺组织呈恢复期状态。结论 下呼吸道是H5N1病毒感染主要攻击的对象，这可能是H5N1病毒在人与人之间传递的障碍之一，其发病可能经过病毒侵入、复制阶段及免疫损伤阶段。

Pathogenesis of influenza A (H5N1) virus-induced viral pneumonia in the rhesus macaque

At present,the mechanism of highly pathogenic avian influenza H5N1 virus causing human infection or death is still not fully clear. In order to better understand the pathogenesis of the disease,the rhesus macaques were infected with H5N1 virus (AF148678/ACGoose/Guangdong/11961H5N1). We analyzed the clinical symptoms,characteristics of the virus invades body,pathological changes,and immune response to discuss the pathogenesis of viral pneumonia induced by H5N1 virus infection from the early time to the recovery time. The rhesus macaques were infected with H5N1 virus through nasal. Clinical signs were assessed daily,and major organs and blood were collected for detection of blood routine analysis,viruses were isolated and titrated from organs,and pathologic and immunohistochemical were also conducted. As a result,the rhesus macaques infected with H5N1 virus experienced fever,dyspnea,and anorexia. The respiratory tract was the major target of the virus and the virus could not replicate in organs outside the respiratory tract. Positive staining cells by immunohistochemistry were bronchial epithelial cells and alveolar macrophages. Rhesus macaques experienced temporary severe pneumonia after 1-3 days,mainly because of neutrophils infiltration; gradual recovery 6 days later,mainly with macrophage infiltration; lung tissue presented recovery state after 14 days,mainly with T lymphocytes infiltration. Finally,we concluded that the predilection of the H5N1 virus to infect the lower airway suggests that it may be a limiting factor in human-to-human transmissibility of the H5N1 virus. The pathogenesis may include virus invasion,replication and immune injury.