Pietschmann Lab
Virology

Mechanisms of HCV tissue and species tropism: A guide for development of animal models

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About this project

Due to its narrow species tropism, natural infection of HCV only occurs in humans. The factors that determine this limited tropism are not yet fully understood. As a consequence, it is difficult to study HCV infection in animal models. This impedes the development of an HCV vaccine because it is impossible to directly evaluate whether a vaccine candidate can protect against an HCV infection in the absence of an immunological competent small animal model. The inability of HCV to replicate in non-human cells could be due to the absence or incompatibility of essential co-factors for viral replication and/or antiviral restriction mechanisms in non-human cells that effectively prevent viral replication. Under these assumptions, we apply various genetic screening systems to generate a comprehensive profile of all relevant factors for the species barrier to HCV infection in mouse cells. Using this information, we aim to develop in vivo models for HCV vaccine research. This project was funded by an ERC Starting Grant (VIRAFRONT, 2012-2017) and is now being pursued with support from the German Center for Infection Research (DZIF) and a grant from the National Institutes of Health (NIH, USA).Using a genome-wide cDNA screening, we identified two novel murine restriction factors that suppress HCV infection of murine liver cells. The lectin CD302 and the complement receptor CR1L cooperate, interfering with HCV cell entry and triggering transcriptional changes that block HCV infection (Brown et al. 2020). Knockout of CD302 increases the susceptibility to HCV infection of transgenic animals expressing the HCV receptor. These results reveal a new facet of liver-intrinsic immunity and point to new avenues for the development of animal models to further qualify HCV vaccines. 

Interestingly, human CD302 is also expressed in human liver cells and partially restricts HCV and HEV infection (Reinecke et al. J. Virol. 2022).

Image for visualization of the topicUsing a cDNA library for genes expressed in the mouse liver, n4mBid cells were transduced and infected with HCV. n4mBid cells contain a modified Bid protein that is cleaved when the cell is productively infected with HCV, thereby forcing infected cells to die. Cells that contained protective genes survived and were thereby selected. Subsequent comparative gene expression analysis identified these protective genes. In this way, the lectin CD302 and the complement receptor CR1L were identified as restriction factors that individually and cooperatively impede HCV infection in liver cells. Adapted from Brown et al. 2020.