Grant: Fellowship - Priority Announcement - HIV/AIDS and/or STBBI

Chronic liver disease accounts for 1 in every 25 deaths worldwide, with males representing two-thirds of these cases. The reasons for this biological sex disparity likely involve hormones, lifestyle factors, and genetics, though the exact causes remain unclear. Liver disease progresses from fibrosis (scarring) to cirrhosis (irreversible scarring), and ultimately to liver failure or cancer. Fatty liver disease affects 1 in 4 Canadians and is a leading cause of cirrhosis, while chronic viral hepatitis impacts 354 million people globally and is the main cause of liver cancer. This study aims to: (1) assess how diet, gut microbiome diversity/composition, and biological sex influence liver fibrosis and cancer development during chronic viral hepatitis infection and (2) characterize the immune responses during acute and chronic infection. To conduct this study, we will use the "wildling" mouse model developed by Dr. Rehermann's team at the NIH. These mice combine the genetics of lab mice with the natural microbiome of wild mice, offering a more accurate preclinical model for studying human immune responses. These mice will be infected with Norway rat hepacivirus (NrHV), close relative of hepatitis C, which causes chronic liver infection and male-dominant fibrosis development. We hypothesize that male mice infected with NrHV on a high-fat diet will develop liver fibrosis and cancer more rapidly than females, and that a more natural microbiome will slow disease progression.We will study age- and sex-matched mice under various conditions, focusing on viral infection status, diet, and microbiome composition. Blood and liver samples will be collected regularly to analyze immune responses and fecal samples to assess microbiome changes. Disease progression will be tracked using biochemical tests and imaging techniques, including MRI and ultrasound. Understanding how these factors contribute to liver disease progression can help identify strategies to improve patient care.