Wednesday, April 2, 2025
4/2/2025
Host Response to Hepatitis Delta Virus Infection - Abstract Hepatitis delta virus (HDV) is a satellite virus of hepatitis B virus (HBV); thus, infection occurs only in individuals with concurrent HBV infection. Currently, more than 35 million people worldwide are persistently coinfected with HBV-HDV. Coinfection with HDV substantially exacerbates liver inflammation, accelerating the progression to end-stage liver disease (ESLD) within 5-10 years, whereas HBV mono-infection typically requires 40 years to develop ESLD. Currently, no effective therapy is available, presenting a significant public health threat. To mitigate the disease burden, elucidating the mechanisms underlying HDV pathogenesis is imperative. Melanoma Differentiation-Associated Gene 5 (MDA5), a pattern recognition receptor (PRR), is thought to play a central role in recognizing HDV infection. Our genetic, biochemical, and signaling studies reveal that HDV infection of human hepatocytes produces viral RNA species that act as pathogen-associated molecular patterns (PAMPs), resulting in a potent activation of MDA5 signaling. This event promotes a robust and constitutive induction of over 300 antiviral genes, namely interferon-stimulated genes (ISGs). Despite the strong activation of the hepatic IFN system, which is expected to repress the viral lifecycle, our study found that HDV displays significant resistance to the antiviral properties of ISGs. Furthermore, one of the ISGs, adenosine deaminase acting on RNA 1 (ADAR1), is indispensable for the HDV lifecycle as it introduces a site-specific viral genome mutation necessary for producing two viral protein isoforms—small- and large- hepatitis delta antigen—that regulate genome replication and virion assembly, respectively. These findings suggest that MDA5 signaling functions as a proviral, rather than an antiviral, host factor in HDV infection, challenging the existing paradigm. Moreover, our transcriptome analysis and polysome profiling suggest that the constitutive and potent ISGs induction by HDV leads to the activation of programmed cell death through their protein translation inhibition properties. These observations form the basis of our central hypothesis: “HDV exploits the ISGs induction pathway to sustain its viral lifecycle, while simultaneously mediating pathogenesis through the activation of programmed cell death”. Accordingly, this exploratory proposal is designed to elucidate the mechanism and significance of the viral innate immune evasion program as the critical pathophysiology of HDV infection through the following specific aims: Aim 1: Determine the proviral role of MDA5 signaling in HDV infection and Aim 2: Define the mechanism of HDV infection-induced hepatocyte-intrinsic programmed cell death. Both aims are centered around the host response to HDV infection, in particular the robust and persistent induction of ISGs. The successful completion of the proposed studies will provide novel insights that aid knowledge gaps in our understanding of HDV pathogenesis and provide the framework for future investigations with in vivo models as well as clinical specimens, ultimately leading to the development of novel therapeutic strategies.
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