@article{Sequential:6524,
      recid = {6524},
      author = {So, Chui Wa},
      title = {Sequential Entry of Hepatitis C Virus into Polarized  Hepatoma Organoids},
      publisher = {University of Chicago},
      school = {Ph.D.},
      address = {2023-06},
      abstract = {Hepatitis C virus (HCV) is a hepatotropic RNA virus. An  estimated 58 million people are chronically infected with  HCV, while HCV-associated hepatocellular carcinoma and  cirrhosis accounted for 290, 000 deaths in 2019. HCV entry  into hepatocytes is highly complex with distinct stages and  multiple host cofactors. However, the precise functions of  most of the host factors in HCV entry are not fully  appreciated. Moreover, studies of entry using polarized  cell culture that physiologically resembles hepatocytes in  vivo are limited. Using single particle imaging of HCV  infection of polarized hepatoma organoids, we observed that  epidermal growth factor receptor (EGFR) performs multiple  functions in HCV entry, both phosphorylation-dependent and  -independent. EGFR is required for the recruitment of  clathrin endocytic proteins to HCV in a  phosphorylation-independent manner. EGFR phosphorylation is  required for virion internalization. HCV entry activates  the RAF-MEK-ERK signaling pathway downstream of EGFR  phosphorylation. This signaling pathway regulates the  sorting and maturation of internalized HCV into early  endosomes, which form the site of virion uncoating.  The  tight junction proteins, claudin-1 (CLDN1) and occludin  (OCLN), function at two distinct stages of HCV entry. CLDN1  is required for efficient HCV virion accumulation at the  tight junction. OCLN is required for the internalization of  virions. Our findings provide insights into the mechanism  of HCV entry and highlight potential interventional  strategies.},
      url = {http://knowledge.uchicago.edu/record/6524},
      doi = {https://doi.org/10.6082/uchicago.6524},
}