Zhiqiang Zheng1, Ching Wooen Sze2, Choong Tat Keng1, Muthafar Al-Haddawi1, Min Liu1, Sue Yee Tan1, Hwee Ling Kwek1, Zhisheng Her1, Xue Ying Chan1, Bhaskar Barnwal1, Eva Loh3, Kenneth Tou En Chang3,5, Thiam Chye Tan4,5, Yee-Joo Tan1,2,*, , Qingfeng Chen1,2,6,*.
1 Institute of Molecular and Cell Biology, 138673, Singapore
2 Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, 117597, Singapore
3 Department of Pathology and Laboratory Medicine, KK Women's and Children's Hospital, 229899, Singapore
4 Department of Obstetrics & Gynaecology, KK Women's and Children's Hospital, 229899, Singapore
5 Duke-NUS Graduate Medical School, 169857, Singapore
6 Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China.
* Corresponding authors: firstname.lastname@example.org (Y-JT), email@example.com (QC)
Published in Plos One, 2017, 8 September.
Hepatitis C is a liver disease caused by infection of the Hepatitis C virus (HCV). Many individuals infected by the virus are unable to resolve the viral infection and develop chronic hepatitis, which can lead to formation of liver cirrhosis and cancer. To understand better how initial HCV infections progress to chronic liver diseases, we characterised the long term pathogenic effects of HCV infections with the use of a humanised mouse model (HIL mice) we have previously established. Although HCV RNA could be detected in infected mice up to 9 weeks post infection, HCV infected mice developed increased incidences of liver fibrosis, granulomatous inflammation and tumour formation in the form of hepatocellular adenomas or hepatocellular carcinomas by 28 weeks post infection compared to uninfected mice. We also demonstrated that chronic liver inflammation in HCV infected mice was mediated by the human immune system, particularly by monocytes/macrophages and T cells which exhibited exhaustion phenotypes. In conclusion, HIL mice can recapitulate some of the clinical symptoms such as chronic inflammation, immune cell exhaustion and tumorigenesis seen in HCV patients. Our findings also suggest that persistence of HCV-associated liver disease appear to require initial infections of HCV and immune responses but not long term HCV viraemia.
Figure legend: Majority of dividing cells in liver tumours in HCV infected humanized mice are of human origin (A-C) H&E stain of a hepatocellular adenoma containing liver section. (B&C) Nodular growth, loss of normal architecture with irregular growth pattern and compression of the surrounding parenchyma. (D-F) Serial section stained using an antibody specific against HSA showing 80-90% human albumin positivity within the liver tumours. (G) HSA expressing hepatocytes of mock (n=3), non-tumour (n=2) and tumour (n=2) regions within liver sections were counted and expressed as a percentage of total hepatocytes. Percentages represent averaged counts of HSA expressing hepatocytes against total hepatocytes from five randomly selected 500 x 250 µm regions per sample. Error bars represent standard error of the means. (H-I) Representative images of mitotically active hepatocytes that (H) express HSA or (I) do not express HSA.
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