戊型肝炎病毒兔分离株跨种系传播及致病性研究

由戊型肝炎病毒(HEV)引起的戊型肝炎(HE)近年来在我国发病呈迅速上升趋势。目前已从猪、野猪、鹿等动物中分离到HEV，但猪是HEV主要宿主。最近我国学者及本研究组首先从兔群分离到HEV，与已知4个型别HEV同源性高达73%-79%，但与3型最接近。3型HEV具有人畜共患特征，因此兔HEV也有可能跨种系传播。鉴于人与兔接触密切，兔HEV跨种系传播问题亟待明确。此外近年HE出现了慢性化、神经症状等新问题，亟待深入研究HEV致病性。.本课题组前期研究发现25个氨基酸位点与HEV宿主范围和致病性相关。本课题将围绕兔HEV跨种系传播及致病性深入研究并阐明其分子机制。拟采用与兔密切接触人群的流行病学调查、兔HEV实验感染兔、猴和猪，构建兔HEV感染性克隆并定点突变与宿主特异性相关位点等方法，揭示兔HEV跨种系传播的可能性并验证其宿主特异性和致病性的分子机制。本研究成果对我国HE防控有重要意义。

The morbidity of Hepatitis E (HE), caused by hepatitis E virus (HEV), has increased dramatically in China over the last decade. HEV has been isolated from a variety of domestic and wild mammals, including pigs, boar and deer, and swine is the main reservoir of HEV. Recently HEV has been first isolated from rabbits in China by researchers including our group. The newly identified rabbit HEVs shared high nucleotide sequence identity (73%-79%) with HEV genotypes 1-4 and was most closely related to HEV genotype 3. Because of the zoonosis specificity of HEV genotype 3, the possibility of cross-species transmission of rabbit HEV is supposed. Rabbits are mainly domestic animals which has frequent contacts with humans, therefore, it is urgent to determine the possibility of cross-species transmission of rabbit HEV. Besides, new problems associated with HEV infection, such as chronicity and neurological symptoms, are emerging in recent years, so that further study for the pathogenicity of HEV is urgently needed..Our previous study supposed that 25 amino acid positions were involved in specifying the host range of HEV and/or determining the severity of hepatitis E disease. The present study will focus on the mechanism of host specificity and pathogenicity of rabbit HEV. To find out direct evidences of zoonotic transmission of rabbit HEV, the investigation of HEV antibody prevalence among persons who work with rabbits and patients with acute viral hepatitis will be carried out. Experimental infection of rabbits, cynomolgus monkeys and pigs with rabbit HEV will be also done to demonstrate the possibility of cross-species transmission of rabbit HEV. Meanwhile, infectious full-length cDNA clones of rabbit HEV will be constructed and the mechanisms of cross-species infection will be clarified using site-directed mutagenesis to mutate the 25 specific amino acid positions mentioned above. The results of this study will greatly contribute to the prevention of hepatitis E in our country.