Molecular Mechanisms of Pathogenesis of Acute and Chronic Liver Diseases

National Institute Of Allergy And Infectious Diseases

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Abstract

In FY 21, the Hepatic Pathogenesis Section has developed an extensive program involving basic and clinical research to study the pathogenesis of acute and chronic liver disease, with a major focus on viral hepatitis and its long-term sequelae, cirrhosis and hepatocellular carcinoma (HCC), which contribute to a huge burden of disease worldwide. 1. Molecular Mechanisms of Pathogenesis of Acute Liver Failure (ALF) A. Role of Humoral Immunity against Hepatitis B Virus Core Antigen in the Pathogenesis of HBV-associated ALF The pathogenesis of HBV ALF, also known as fulminant hepatitis B, is still largely unknown due to the lack of experimental systems and the difficulties in obtaining liver samples. We identified viral and host factors uniquely associated with ALF. HBV strains detected in ALF livers were highly divergent from wild-type HBV with core (HBcAg) being the most variable region with the G1896A precore stop codon mutation invariably present in all patients both in serum and in liver (Chen et al. 2018). The association of ALF with HBV variants containing precore or core promoter mutations, prompted us to investigate archived liver samples from chimpanzees experimentally infected with a precore HBV mutant implicated in human ALF. This study demonstrated that although chimpanzees did not develop ALF, infection with a precore HBV mutant caused the most severe acute hepatitis B ever seen in chimpanzees infected with HBV with closer resemblance to HBV ALF than to classic acute hepatitis B. Thus, our study suggests that precore HBV mutants carry an inherently higher pathogenicity that, in addition to specific host factors, may play a critical role in determining the severity of acute HBV disease (Chen et al. 2020). B.Role of hepatitis E virus (HEV) in Severe Acute Liver Injury The US Acute Liver Failure Study Group (ALFSG) studies the etiology and outcomes of adults with ALF, enrolling patients with severe acute liver injury (ALI) since 2008. We investigated the role of hepatitis E virus (HEV) infection in a large cohort of prospectively enrolled patients with severe ALI. Our study demonstrated that acute HEV infection is an infrequent cause of ALI in hospitalized North American adults. Anti-HEV IgG-positive patients were significantly older and more likely to be non-Caucasian (Fontana et al. 2020). These data are consistent with other population-based studies that indicate exposure to HEV in the general US population is declining over time and might reflect a cohort effect. 2. Pathogenesis of Acute Hepatitis B and D. Historical chimpanzee studies performed at the NIH demonstrated a significant difference in ALT levels during acute hepatitis caused by different hepatitis viruses, with a hierarchy in the extent of liver damage according to the infecting virus: highest in HDV superinfection, followed by infection with a precore HBV mutant, HBV/HDV coinfection, and lastly wild-type HBV infection. However, the basis for these differences and the role of viral and host factors in determining disease severity and outcome remain unknown. We demonstrated that both the virus and host are important in disease pathogenesis and offers new insights into their roles. We found that distinct cytokine profiles were associated with disease severity and clinical outcome. In particular, resolution of classic acute hepatitis B (AHB) correlated with a predominant Th1 response, whereas HBV/HDV coinfection showed a predominant proinflammatory response. Severe AHB and HDV superinfection showed a restricted cytokine profile and no evidence of Th1 response. The lack of cytokines associated with adaptive T-cell responses toward the precore HBV mutant and HDV superinfection argues in favor of a direct cytopathic effect of these viruses (Engle et al. mBio 2020) 3. Pathogenesis of liver fibrosis progression, cirrhosis, and hepatocellular carcinoma (HCC): role of viral and host factors HCC is the third leading cause of cancer-related death worldwide, and chronic infection with hepatitis viruses accounts for more than 70% of cases. Cirrhosis is the single most important risk factor for HCC being present in 80-90% of the cases. Although the major etiologic agents and risk factors for HCC are well-defined, the molecular mechanisms of hepatocarcinogenesis remain unclear. A) Role of Age in Liver Fibrosis Progression Liver fibrosis plays a critical role in the outcome of chronic viral hepatitis. Patients with cirrhosis, the latest stage of liver fibrosis, have the highest risk of developing HCC. Older age at the time of infection with hepatitis viruses is associated with an increased risk of fibrosis progression, but the mechanisms remain unclear. We hypothesized that the pace of fibrosis progression may reflect changes in gene expression within the aging liver. By comparing gene expression in liver specimens from 54 adult donors without evidence of fibrosis, including 36 over 40 y old and 18 between 18 and 40 y old, we demonstrated that aging is accompanied by significant changes in gene expression (Nishimura et al. 2021). We identified a gene, chitinase 3-like 1 (CHI3L1), as having the greatest age-dependent increase in expression and as being overexpressed in cirrhotic livers. In vitro studies showed that recombinant CHI3L1 promotes proliferation and activation of primary human hepatic stellate cells (HSCs), the major drivers of liver fibrosis. These findings collectively demonstrate that CHI3L1 promotes liver fibrogenesis through a direct effect on HSCs and support a role for CHI3L1 in the increased susceptibility of aging livers to fibrosis progression. B. Molecular Signature and Immune Landscape of Viral-Associated HCC Chronic infection with HBV and HCV, two important carcinogenic viruses, account for 71% of all HCC cases worldwide. Therapeutic options are limited and ineffective. The increasing use of immune-based therapies in solid tumors highlights the need to expand our knowledge on the immunologic microenvironment of HCC. Access to paired liver samples (tumor and non-tumor) from 20 well-characterized patients with HCC associated with HCV or HBV gave us the opportunity to study by RNA-seq the immunologic landscape. We found that both HCV- and HBV-HCC are associated with a predominance of downregulated genes (74% and 67%, respectively). Analysis of the immune landscape using a curated gene list showed 9% of immune genes in HCV-HCC and 6% in HBV-HCC. However, only 8 immune genes (4%) were upregulated in HCV-HCC and 27 (16.5%) in HBV-HCC. HCV-HCC was characterized by an enrichment of downregulated genes related to T-cell activation and oxidative stress. Conversely, HBV-HCC was characterized by upregulation of genes related to monocyte/macrophage activation and cell cycle control, and downregulation of genes involved in various cell metabolisms. This study demonstrates a distinctive molecular signature and immune landscape in HCC of different viral etiology, with could provide new insights into pathogenesis and lead to the development of novel immune-based therapies. C. Role of HDV in hepatocellular carcinoma Studies conducted over the past decade provided evidence that HDV is associated with a significantly higher risk of developing HCC compared to HBV monoinfection. However, the mechanisms whereby HDV promotes liver cancer remain elusive. We demonstrated that the molecular profile of HCC-HDV is unique and distinct from that of HBV-HCC, with an enrichment of upregulated genes involved in cell-cycle/DNA replication, and DNA damage and repair, which point to genome instability as an important mechanism of HDV hepatocarcinogenesis (Diaz et al. 2018). These data suggest that HBV and HDV promote carcinogenesis by distinct molecular mechanisms despite the obligatory dependence of HDV on HBV (Farci et al. 2021 Viruses).