The Human Liver-Expressed Lectin CD302 Restricts Hepatitis C Virus Infection

Reinecke, Birthe; Frericks, Nicola; Lauber, Chris; Dinkelborg, Katja; Matthaei, Alina; Vondran, Florian W. R.; Behrendt, Patrick; Haid, Sibylle; Brown, Richard J. P.; Pietschmann, Thomas

doi:10.1128/jvi.01995-21

Cited by 5 publications

(4 citation statements)

References 52 publications

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“…Q5VY30 (retinol-binding protein, RBP4) has been already proved to have close association with NAFLD risks, and the possible clinical implications of treating NAFLD by targeting RBP4 have been demonstrated . B2R582 is a protein highly similar to C-type lectin domain, and C-type lectin-like domain was demonstrated to be essential for HCV restriction . A0A5C2FWP9 is a kind of immunoglobulin G light chain, and it is reported that aberrant immunoglobulin production is a common feature of various chronic inflammatory liver diseases .…”

Section: Resultsmentioning

confidence: 99%

“…36 B2R582 is a protein highly similar to C-type lectin domain, and C-type lectin-like domain was demonstrated to be essential for HCV restriction. 37 A0A5C2FWP9 is a kind of immunoglobulin G light chain, and it is reported that aberrant immunoglobulin production is a common feature of various chronic inflammatory liver diseases. 38 Generally, all these five proteins that interacted with SOF had specific and high relevance with liver tissue and its corresponding diseases, contributing to the further discovery of unknown therapeutic targets.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Novel Strategy for Screening Target Proteins by the Common Drugs─Sofosbuvir-Specific Profiling of HCV Patient Serum

Pan,

Wang,

Yan

et al. 2024

Anal. Chem.

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It is the scientific basis of precision medicine to study all of the targets of drugs based on the interaction between drugs and proteins. It is worth paying attention to unknown proteins that interact with drugs to find new targets for the design of new drugs. Herein, we developed a protein profiling strategy based on drug−protein interactions and drug-modified magnetic nanoparticles and took hepatitis C virus (HCV) and its corresponding drug sofosbuvir (SOF) as an example. A SOFmodified magnetic separation medium (Fe 3 O 4 @POSS@SOF) was prepared, and a gradient elution strategy was employed and optimized to profile specific proteins interacted with SOF. A series of proteomic analyses were performed to profile proteins based on SOF−protein interactions (SPIs) in the serum of HCV patients to evaluate the specificity of the profiling strategy. As a result, five proteins were profiled with strong SPIs and exhibited high relevance with liver tissue, which were potentially new drug targets. Among them, HSP60 was used to confirm the highly specific interactions between the SOF and its binding proteins by Western blotting analysis. Besides, 124 and 29 differential proteins were profiled by SOF material from three HCV patient serum and pooled 20 HCV patient serum, respectively, by comparing with healthy human serum. In comparison with those profiled by the polyhedral oligomeric silsesquioxane (POSS) material, differential proteins profiled by the SOF material were highly associated with liver diseases through GO analysis and pathway analysis. Furthermore, four common differential proteins profiled by SOF material but not by POSS material were found to be identical and expressed consistently in both pooled serum samples and independent serum samples, which might potentially be biomarkers of HCV infection. Taken together, our study proposes a highly specific protein profiling strategy to display distinctive proteomic profiles, providing a novel idea for drug design and development.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Novel Strategy for Screening Target Proteins by the Common Drugs─Sofosbuvir-Specific Profiling of HCV Patient Serum

Pan,

Wang,

Yan

et al. 2024

Anal. Chem.

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“…However, other restriction mechanisms cannot be excluded. Recently, new IFN-independent mechanisms of viral restriction have been described in hepatocytes: Among them, the IRF1 constitutive immunity 43 and the lectin CD302 driven restriction 44 have been associated with a resistance to infection by other RNA hepatitis viruses.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis D virus infection of stem cell-derived hepatocytes triggers an IFN- and NFκB-based innate immune response unable to clear infection

Lange

Garn

Anagho

et al. 2022

Preprint

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Human pluripotent stem cell-derived hepatocyte-like cells (HLCs) are a valuable model to investigate host-pathogen interactions of hepatitis viruses in a mature and authentic environment. Here, we investigated the susceptibility of HLCs to the Hepatitis D Virus (HDV), a virus that in co-infection with HBV is responsible for the most severe form of viral hepatitis. Cells undergoing hepatic differentiation became susceptible to HDV infection after acquiring expression of the Na+-taurocholate cotransporting polypeptide (NTCP), the receptor mediating HBV and HDV entry. Inoculation of mature HLCs with HDV lead to increasing amounts of intracellular HDV RNA and accumulation of the HDV antigen in the cells. The infection was abrogated when using known entry inhibitors targeting NTCP or by disrupting genome replication using the nucleoside analogue Ribavirin. Upon infection, the HLCs mounted an innate immune response based on induction of the interferons IFNB and L, but not IFNA, and were associated with an upregulation of interferon-stimulated genes. The intensity of this immune response positively correlated with the level of viral replication and was dependant on both the JAK/STAT and NFκB pathway activation. Importantly, neither this innate immune response nor an exogenous treatment of IFNα2b inhibited HDV replication. However, pre-treatment of the HLCs with IFNα2b reduced viral infection, suggesting that ISGs may limit early stages of infection. This novel HDV in vitro infection model represents a valuable tool for studying HDV replication and investigating candidate antiviral drugs in cells displaying mature hepatic functions.

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“…CD63, CD68, CD9, and CD5l (hepatic macrophage markers) were increased in ASH mice livers, while CD59a/b, CD79a/b, CD177, and CD302 were downregulated. Importantly, CD59 and CD302 have been shown to be expressed not only on immune cells, but also on hepatocytes [38][39][40]. CD79a/b is a marker of B cells [41,42], while CD177 is expressed in neutrophils [43].…”

Section: Ash/ah Pathogenesis Is Associated With Significant Changes I...mentioning

confidence: 99%

Dysregulated Cyclic Nucleotide Metabolism in Alcohol-Associated Steatohepatitis: Implications for Novel Targeted Therapies

Montoya-Durango,

Walter,

Rodriguez

et al. 2023

Biology

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Background: Cyclic nucleotides are second messengers, which play significant roles in numerous biological processes. Previous work has shown that cAMP and cGMP signaling regulates various pathways in liver cells, including Kupffer cells, hepatocytes, hepatic stellate cells, and cellular components of hepatic sinusoids. Importantly, it has been shown that cAMP levels and enzymes involved in cAMP homeostasis are affected by alcohol. Although the role of cyclic nucleotide signaling is strongly implicated in several pathological pathways in liver diseases, studies describing the changes in genes regulating cyclic nucleotide metabolism in ALD are lacking. Methods: Male C57B/6 mice were used in an intragastric model of alcohol-associated steatohepatitis (ASH). Liver injury, inflammation, and fibrogenesis were evaluated by measuring plasma levels of injury markers, liver tissue cytokines, and gene expression analyses. Liver transcriptome analysis was performed to examine the effects of alcohol on regulators of cyclic AMP and GMP levels and signaling. cAMP and cGMP levels were measured in mouse livers as well as in livers from healthy human donors and patients with alcohol-associated hepatitis (AH). Results: Our results show significant changes in several phosphodiesterases (PDEs) with specificity to degrade cAMP (Pde4a, Pde4d, and Pde8a) and cGMP (Pde5a, Pde6d, and Pde9a), as well as dual-specificity PDEs (Pde1a and Pde10a) in ASH mouse livers. Adenylyl cyclases (ACs) 7 and 9, which are responsible for cAMP generation, were also affected by alcohol. Importantly, adenosine receptor 1, which has been implicated in the pathogenesis of liver diseases, was significantly increased by alcohol. Adrenoceptors 1 and 3 (Adrb), which couple with stimulatory G protein to regulate cAMP and cGMP signaling, were significantly decreased. Additionally, beta arrestin 2, which interacts with cAMP-specific PDE4D to desensitize G-protein-coupled receptor to generate cAMP, was significantly increased by alcohol. Notably, we observed that cAMP levels are much higher than cGMP levels in the livers of humans and mice; however, alcohol affected them differently. Specifically, cGMP levels were higher in patients with AH and ASH mice livers compared with controls. As expected, these changes in liver cyclic nucleotide signaling were associated with increased inflammation, steatosis, apoptosis, and fibrogenesis. Conclusions: These data strongly implicate dysregulated cAMP and cGMP signaling in the pathogenesis of ASH. Future studies to identify changes in these regulators in a cell-specific manner could lead to the development of novel targeted therapies for ASH.

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The Human Liver-Expressed Lectin CD302 Restricts Hepatitis C Virus Infection

Abstract: The liver represents an immunoprivileged organ characterized by enhanced resistance to immune responses. However, the importance of liver cell-endogenous, noncytolytic innate immune responses in pathogen control is not well defined.

Cited by 5 publications

References 52 publications

Novel Strategy for Screening Target Proteins by the Common Drugs─Sofosbuvir-Specific Profiling of HCV Patient Serum

Novel Strategy for Screening Target Proteins by the Common Drugs─Sofosbuvir-Specific Profiling of HCV Patient Serum

Hepatitis D virus infection of stem cell-derived hepatocytes triggers an IFN- and NFκB-based innate immune response unable to clear infection

Dysregulated Cyclic Nucleotide Metabolism in Alcohol-Associated Steatohepatitis: Implications for Novel Targeted Therapies

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