Entry and exit of extracellular vesicles to and from the blood circulation.

Extracellular vesicles and lipoproteins are lipid-based biological nanoparticles that play important roles in (patho)physiology. Recent evidence suggests that extracellular vesicles and lipoproteins can interact to form functional complexes. Such complexes have been observed in biofluids from healthy human donors and in various in vitro disease models such as breast cancer and hepatitis C infection. Lipoprotein components can also form part of the biomolecular corona that surrounds extracellular vesicles and contributes to biological identity. Potential mechanisms and the functional relevance of extracellular vesicle-lipoprotein complexes remain poorly understood. This Review addresses the current knowledge of the extracellular vesicle-lipoprotein interface while drawing on pre-existing knowledge of liposome interactions with biological nanoparticles. There is an urgent need for further research on the lipoprotein-extracellular vesicle interface, which could return important mechanistic, therapeutic, and diagnostic findings.

Extracellular Vesicle and Lipoprotein Interactions.

A single hepatitis B virus (HBV) particle is sufficient to establish chronic infection of the liver after intravenous injection, suggesting that the virus targets hepatocytes via a highly efficient transport pathway. We therefore investigated whether HBV uses a physiological liver-directed pathway that supports specific host-cell targeting in vivo.We established the ex vivo perfusion of intact human liver tissue that recapitulates the liver physiology to investigate HBV liver targeting. This model allowed us to investigate virus-host cell interactions in a cellular microenvironment mimicking the in vivo situation.HBV was rapidly sequestered by liver macrophages within 1 hour after a virus pulse perfusion but was detected in hepatocytes only after 16 hours. We found that HBV associates with lipoproteins in serum and within machrophages. Electron and immunofluorescence microscopy corroborated a co-localization in recycling endosomes within peripheral and liver macrophages. Recycling endosomes accumulated HBV and cholesterol, followed by transport of HBV back to the cell surface along the cholesterol efflux pathway. To reach hepatocytes as final target cells, HBV was able to utilize the hepatocyte-directed cholesterol transport machinery of macrophages.Our results propose that by binding to liver targeted lipoproteins and using the reverse cholesterol transport pathway of macrophages, HBV hijacks the physiological lipid transport pathways to the liver to most efficiently reach its target organ. This may involve transinfection of liver macrophages and result in deposition of HBV in the perisinusoidal space from where HBV can bind its receptor on hepatocytes. 

Hepatitis B virus targets lipid transport pathways to infect hepatocytes.

Liver disease represents a significant global burden, placing individuals at a heightened risk of developing cirrhosis and liver cancer. Viral infections act as a primary cause of liver diseases on a worldwide scale. Infections involving hepatitis viruses, notably hepatitis B, C, and E viruses, stand out as the most prevalent contributors to acute and chronic intrahepatic adverse outcome, although the hepatitis C virus (HCV) can be effectively cured with antiviral drugs, but no preventative vaccination developed. Hepatitis B virus (HBV) and HCV can lead to both acute and chronic liver diseases, including liver cirrhosis and hepatocellular carcinoma (HCC), which are principal causes of worldwide morbidity and mortality. Other viruses, such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV), are capable of causing liver damage. Therefore, it is essential to recognize that virus infections and liver diseases are intricate and interconnected processes. A profound understanding of the underlying relationship between virus infections and liver diseases proves pivotal in the effective prevention, diagnosis, and treatment of these conditions. In this review, we delve into the mechanisms by which virus infections induce liver diseases, as well as explore the pathogenesis, diagnosis, and treatment of liver diseases. This article is categorized under: Infectious Diseases > Biomedical Engineering.

The intersection of virus infection and liver disease: A comprehensive review of pathogenesis, diagnosis, and treatment.

RNA binding motif protein 39 (RBM39) is an RNA-binding protein involved in tumorigenesis, cell metabolism and development. Here, we performed a genome-wide CRISPR/Cas9 screen in two liver-derived cell lines and identified RBM39 as a regulator of cell intrinsic innate immune responses, affecting transcription and/or splicing of key pathway components, in particular interferon regulatory factor 3 (IRF3). Knockdown of RBM39 or treatment with Indisulam, an aryl sulfonamide drug targeting RBM39 for proteasomal degradation, strongly reduced the induction of interferon-stimulated genes (ISGs) in response to double-stranded RNA (dsRNA), lipopolysaccharide (LPS) and viral infections mediated by IRF3. RBM39 knockdown further restrained the type III interferon (IFN) pathway, by reducing expression of the receptor subunit Interleukin 10 Receptor Subunit Beta (IL-10RB). RNAseq and mass spectrometry revealed altered expression of additional signaling factors, highlighting the importance of RBM39 in orchestrating innate immunity. One Sentence Summary RBM39 acts as a novel innate immune factor by regulating transcription and/or alternative splicing of IRF3 and several other key proteins involved in innate immune responses.

RBM39 shapes innate immunity through transcriptional and splicing control of IRF3 and other key factors

Objective Hepatitis A virus (HAV) infections are considered not to trigger an innate immune response in vivo, in contrast to hepatitis C virus (HCV). This lack of immune induction has been imputed to strong immune counteraction by HAV proteases 3CD and 3ABC. We aimed at elucidating the mechanisms of innate immune induction and counteraction by HAV and HCV in vivo and in vitro. Design uPA-SCID mice with humanized liver were infected with HAV and HCV. Hepatic cell culture models were used to assess HAV and HCV sensing by TLR3 and RIG-I/MDA5, respectively. Cleavage of the adaptor proteins TRIF and MAVS was analyzed by transient and stable expression of HAV and HCV proteases and virus infection. Results We detected similar levels of Interferon stimulated genes (ISGs) induction in hepatocytes of HAV and HCV infected human liver chimeric mice. In cell culture, HAV induced ISGs exclusively upon sensing by MDA5 and dependent on LGP2. TRIF and MAVS were only partially cleaved by HAV 3ABC and 3CD, not sufficiently to abrogate signalling. In contrast, HCV NS3-4A efficiently degraded MAVS, as previously reported, whereas TRIF was not cleaved. Conclusions HAV induces an innate immune response in hepatocytes via MDA5/LGP2, with limited control of both pathways by proteolytic cleavage. HCV activates TLR3 and lacks TRIF cleavage, suggesting that this pathway mainly contributes to HCV induced antiviral response in hepatocytes. Our results shed new light on induction and counteraction of innate immunity by HAV and HCV and their potential contribution to clearance and persistence. SIGNIFICANCE OF THIS STUDY What is already known on this topic? — Despite sharing biological and molecular similarities, HAV infections are always cleared while HCV infections persist in most cases. — In infected chimpanzees HAV does not trigger a strong innate immune response, as opposed to HCV. This has been imputed to the action of HAV proteases abrogating the signalling pathways. — Physiological in vitro and in vivo models, based on human hepatocytes, to assess HAV and HCV mechanisms of induction and interference of innate immunity are still missing. What this study adds — HAV induces an innate immune response in vitro and in vivo, in systems with intact signalling pathways and devoid of adaptive immunity. — HAV 3ABC and 3CD proteases do not abolish the host innate immune response. — HCV NS3-4A protease disrupts the RLRs pathways, but cannot cleave TRIF and has no impact on TLR3 response. How this study might affect research, practice or policy — This study offers a comprehensive, side-by-side investigation on HAV and HCV infections in physiological models which recapitulate a cytokine response in the human liver, and allows a precise assessment of the viral interference related to the function of the respective signalling pathways. — Our results elucidate mechanisms, so far controversial or poorly investigated, thus contributing to our understanding of HAV clearance and HCV persistence.

Comparison of HAV and HCV infections in vivo and in vitro reveals distinct patterns of innate immune evasion and activation

Liver-generated plasma Apolipoprotein E (ApoE)-containing lipoproteins (LPs) (ApoE-LPs) play central roles in lipid transport and metabolism. Perturbations of ApoE can result in several metabolic disorders and ApoE genotypes have been associated with multiple diseases. ApoE is synthesized at the endoplasmic reticulum and transported to the Golgi apparatus for LP assembly; however, ApoE-LPs transport from there to the plasma membrane is largely unknown. Here, we established an integrative imaging approach based on a fully functional fluorescently tagged ApoE. We found that ApoE-LPs accumulate in CD63-positive endosomes of hepatocytes. In addition, we observed the co-egress of ApoE-LPs and extracellular vesicles (EVs) along the late endosomal trafficking route. Moreover, complexes of ApoE-LPs and CD63-positive EVs were found to be transmitted from cell to cell. Given the important role of ApoE in viral infections, we studied the hepatitis C virus (HCV) and found that the viral replicase protein NS5A is enriched in ApoE-containing intraluminal vesicles. Interaction between NS5A and ApoE is required for the efficient release of EVs containing viral RNA. These vesicles are transported along the endosomal ApoE egress pathway. Taken together, our data argue for endosomal egress and transmission of hepatic ApoE-LPs, a pathway that is hijacked by HCV. Given the more general role of EV-mediated cell-to-cell communication, these insights provide new starting points for research into the pathophysiology of ApoE-related metabolic and infection-related disorders. Author Summary The post-Golgi egress pathway of hepatocyte-derived ApoE-containing lipoproteins (ApoE-LPs) is largely unknown. By using integrative imaging analyses, we show that ApoE-LPs are enriched in CD63-positive endosomes suggesting that these endosomes might be a central hub for the storage of ApoE-LPs from which they are released into the circulation. In addition, we provide evidence for the co-egress of ApoE-LPs with extracellular vesicles (EVs) along the late endosomal route and their transfer from cell to cell. This pathway is hijacked by the hepatitis C virus that induces the production of ApoE-associated EVs containing viral RNA. Given the important role of ApoE in multiple metabolic, degenerative and infectious diseases, and the role of EVs in cell-to-cell communication, these results provide important information how perturbations of ApoE might contribute to various pathophysiologies.

Endosomal egress and intercellular transmission of hepatic ApoE-containing lipoproteins and its exploitation by the hepatitis C virus

Comparison of HAV and HCV infections in vivo and in vitro reveals distinct patterns of innate immune evasion and activationJournal of HepatologyVol. 79Issue 3PreviewHepatitis A virus (HAV) infections are considered not to trigger innate immunity in vivo, in contrast to hepatitis C virus (HCV). This lack of induction has been imputed to strong interference by HAV proteases 3CD and 3ABC. We aimed to elucidate the mechanisms of immune activation and counteraction by HAV and HCV in vivo and in vitro. Full-Text PDF Open Access It has come to our attention that there was an error in Fig. 4G (left panel) of our manuscript. The size of the protein Flag-3ABC was incorrectly labelled as ‘75 kDa’ instead of its correct size ‘38 kDa’. This is corrected in the updated figure below. We apologise for any inconvenience caused. 

Corrigendum to "Comparison of HAV and HCV infections in vivo and in vitro reveals distinct patterns of innate immune evasion and activation" [J Hepatol (2023) 645-656].

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Comparison of HAV and HCV infections in vivo and in vitro reveals distinct patterns of innate immune evasion and activation

Endosomal egress and intercellular transmission of hepatic ApoE-containing lipoproteins and its exploitation by the hepatitis C virus

Corrigendum to "Comparison of HAV and HCV infections in vivo and in vitro reveals distinct patterns of innate immune evasion and activation" [J Hepatol (2023) 645-656].