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Innate immune responses to human hepatotropic viral infections

Periodic Reporting for period 3 - HBV1 (Innate immune responses to human hepatotropic viral infections)

Reporting period: 2018-06-01 to 2019-11-30

Viral hepatitis including hepatitis B and C virus (HBV, HCV) are a major public health concern. Even though novel direct-acting antiviral drugs are currently facilitating the cure of HCV, HBV remains incurable. With over 257 million chronically infected patients living with chronic HBV, novel therapeutic interventions and curative approaches are urgently needed. Among the main reasons complicating the development of novel drugs is the very narrow species tropism of these viruses, which currently restrict work with hepatitis B virus in vitro and in vivo. Since both, HBV and HCV infect human hepatocytes, the main cell population within the liver, the study of these pathogens is furthermore complicated by the fragile nature of these cells. Cultures of human liver cells cannot be maintained for more than a few days and small-animal models for either virus are currently unavailable.
During the project we, and others, have described that innate immunity, predominantly through cell-intrinsic innate immune responses and interferon-stimulated effector genes are able to epigenetically suppress a number of human-tropic pathogens, including Epstein-Barr virus, hepatitis B virus and HIV. Interferons, which are the main molecular effector molecules for the induction of a potent innate immune response, resulting in the expression of several hundred interferon-stimulated genes (ISG), of which only a few have been characterized in detail.
The aim of this project was the development of novel pre-clinical platforms to study human-tropic hepatitis viruses which was achieved. The project also aimed to analyze host responses to hepatitis B and C virus on a single cell level on which progress was being made and a special emphasis of this research programme was the identification of novel targets for therapy to treat and eventually cure HBV infection. The Principal Investigator sadly passed away during the planned project period and the work curtailed so these aims were not completed.
"We described the first pre-clinical model system enabling the study of both, HBV and HCV in its natural target cell for prolonged durations (Ortega-Prieto et al. 2018 Nature Communications). This was the first description of the utility of artificial organ-on-a-chip technology being used to evaluate novel treatments for pathogens as well as for the identification of novel biomarkers. Building on a microfluidic recirculation platform seeded with either primary human hepatocytes (PHH) or PHH and Kupffer cells, the liver-resident macrophages, we were able to demonstrate that, in contrast to previous theories, HBV infection interferes with early innate immune responses within infected hepatocytes. We demonstrate that HBV, which by itself is less immunogenic than other viral pathogens, fine-tunes the hepatic microenvironment in order to prevent innate immune recognition. We used this platform to test novel potentially curative HBV treatments and analyze the single cell host response to HBV and HCV infection. We also used this model to further our understanding of the contribution of ISG to durable suppression of HBV or HCV infection.
This was supplemented by the use of human liver-chimeric mice, in which the normal mouse liver is repopulated with human hepatocytes, which renders the resulting ""humanized mouse"" highly susceptible to HBV, HCV as well as other highly human-tropic infectious diseases (e.g. Plasmodium spp., hepatitis E virus, hepatitis D virus). We were one of the few laboratories worldwide which integrated the use of human liver-chimeric and human immune system-containing mice in order to evaluate the role of the human interferon regulatory network in disease progression and viral control."
We developed and published a novel 3D spheroid-based primary human hepatocyte model for HBV infection, which allows high throughput screening approaches. We engaged with stakeholders with the aim of commercialising this platform.