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Book ; Online ; Thesis: Exploring innate immune induction and interference mechanisms of Hepatitis A and C Viruses in human hepatocytes: a comparative analysis

Colasanti, Ombretta [Verfasser] / Lohmann, Volker [Akademischer Betreuer]

2024

Author's details	Ombretta Colasanti ; Betreuer: Volker Lohmann
Keywords	Biowissenschaften, Biologie ; Life Science, Biology
Subject code	sg570
Language	English
Publisher	Universitätsbibliothek Heidelberg
Publishing place	Heidelberg
Document type	Book ; Online ; Thesis
Database	Digital theses on the web

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Article ; Online: Recruitment of both the ESCRT and autophagic machineries to ejecting Mycobacterium marinum.

Gerstenmaier, Lilli / Colasanti, Ombretta / Behrens, Hannah / Kolonko, Margot / Hammann, Christian / Hagedorn, Monica

Molecular microbiology

2023 Volume 121, Issue 3, Page(s) 385–393

Abstract: Cytosolic Mycobacterium marinum are ejected from host cells such as macrophages or the amoeba Dictyostelium discoideum in a non-lytic fashion. As described previously, the autophagic machinery is recruited to ejecting bacteria and supports host cell ... ...

Abstract	Cytosolic Mycobacterium marinum are ejected from host cells such as macrophages or the amoeba Dictyostelium discoideum in a non-lytic fashion. As described previously, the autophagic machinery is recruited to ejecting bacteria and supports host cell integrity during egress. Here, we show that the ESCRT machinery is also recruited to ejecting bacteria, partially dependent on an intact autophagic pathway. As such, the AAA-ATPase Vps4 shows a distinct localization at the ejectosome structure in comparison to fluorescently tagged Vps32, Tsg101 and Alix. Along the bacterium engaged in ejection, ESCRT and the autophagic component Atg8 show partial colocalization. We hypothesize that both, the ESCRT and autophagic machinery localize to the bacterium as part of a membrane damage response, as well as part of a "frustrated autophagosome" that is unable to engulf the ejecting bacterium.
MeSH term(s)	Mycobacterium marinum/genetics ; Mycobacterium marinum/metabolism ; Dictyostelium/metabolism ; Dictyostelium/microbiology ; Endosomal Sorting Complexes Required for Transport/metabolism
Chemical Substances	Endosomal Sorting Complexes Required for Transport
Language	English
Publishing date	2023-05-25
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	619315-8
ISSN	1365-2958 ; 0950-382X
ISSN (online)	1365-2958
ISSN	0950-382X
DOI	10.1111/mmi.15075
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Article ; Online: Biochemical and structural characterization of hepatitis A virus 2C reveals an unusual ribonuclease activity on single-stranded RNA.

Chen, Pu / Wojdyla, Justyna Aleksandra / Colasanti, Ombretta / Li, Zhijian / Qin, Bo / Wang, Meitian / Lohmann, Volker / Cui, Sheng

Nucleic acids research

2022 Volume 50, Issue 16, Page(s) 9470–9489

Abstract: The HAV nonstructural protein 2C is essential for virus replication; however, its precise function remains elusive. Although HAV 2C shares 24-27% sequence identity with other 2Cs, key motifs are conserved. Here, we demonstrate that HAV 2C is an ATPase ... ...

Abstract	The HAV nonstructural protein 2C is essential for virus replication; however, its precise function remains elusive. Although HAV 2C shares 24-27% sequence identity with other 2Cs, key motifs are conserved. Here, we demonstrate that HAV 2C is an ATPase but lacking helicase activity. We identified an ATPase-independent nuclease activity of HAV 2C with a preference for polyuridylic single-stranded RNAs. We determined the crystal structure of an HAV 2C fragment to 2.2 Å resolution, containing an ATPase domain, a region equivalent to enterovirus 2C zinc-finger (ZFER) and a C-terminal amphipathic helix (PBD). The PBD of HAV 2C occupies a hydrophobic pocket (Pocket) in the adjacent 2C, and we show the PBD-Pocket interaction is vital for 2C functions. We identified acidic residues that are essential for the ribonuclease activity and demonstrated mutations at these sites abrogate virus replication. We built a hexameric-ring model of HAV 2C, revealing the ribonuclease-essential residues clustering around the central pore of the ring, whereas the ATPase active sites line up at the gaps between adjacent 2Cs. Finally, we show the ribonuclease activity is shared by other picornavirus 2Cs. Our findings identified a previously unfound activity of picornavirus 2C, providing novel insights into the mechanisms of virus replication.
MeSH term(s)	Viral Nonstructural Proteins/metabolism ; Hepatitis A virus/genetics ; Hepatitis A virus/metabolism ; Virus Replication/genetics ; RNA ; Picornaviridae/genetics ; Adenosine Triphosphatases/genetics ; Ribonucleases ; RNA, Viral/genetics ; RNA, Viral/metabolism
Chemical Substances	Viral Nonstructural Proteins ; RNA (63231-63-0) ; Adenosine Triphosphatases (EC 3.6.1.-) ; Ribonucleases (EC 3.1.-) ; RNA, Viral
Language	English
Publishing date	2022-08-10
Publishing country	England
Document type	Journal Article
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkac671
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Article ; Online: A Hepatitis C virus genotype 1b post-transplant isolate with high replication efficiency in cell culture and its adaptation to infectious virus production in vitro and in vivo.

Heuss, Christian / Rothhaar, Paul / Burm, Rani / Lee, Ji-Young / Ralfs, Philipp / Haselmann, Uta / Ströh, Luisa J / Colasanti, Ombretta / Tran, Cong Si / Schäfer, Noemi / Schnitzler, Paul / Merle, Uta / Bartenschlager, Ralf / Patel, Arvind H / Graw, Frederik / Krey, Thomas / Laketa, Vibor / Meuleman, Philip / Lohmann, Volker

PLoS pathogens

2022 Volume 18, Issue 6, Page(s) e1010472

Abstract: Hepatitis C virus (HCV) is highly diverse and grouped into eight genotypes (gts). Infectious cell culture models are limited to a few subtypes and isolates, hampering the development of prophylactic vaccines. A consensus gt1b genome (termed GLT1) was ... ...

Abstract	Hepatitis C virus (HCV) is highly diverse and grouped into eight genotypes (gts). Infectious cell culture models are limited to a few subtypes and isolates, hampering the development of prophylactic vaccines. A consensus gt1b genome (termed GLT1) was generated from an HCV infected liver-transplanted patient. GLT1 replicated to an outstanding efficiency in Huh7 cells upon SEC14L2 expression, by use of replication enhancing mutations or with a previously developed inhibitor-based regimen. RNA replication levels almost reached JFH-1, but full-length genomes failed to produce detectable amounts of infectious virus. Long-term passaging led to the adaptation of a genome carrying 21 mutations and concomitant production of high levels of transmissible infectivity (GLT1cc). During the adaptation, GLT1 spread in the culture even in absence of detectable amounts of free virus, likely due to cell-to-cell transmission, which appeared to substantially contribute to spreading of other isolates as well. Mechanistically, genome replication and particle production efficiency were enhanced by adaptation, while cell entry competence of HCV pseudoparticles was not affected. Furthermore, GLT1cc retained the ability to replicate in human liver chimeric mice, which was critically dependent on a mutation in domain 3 of nonstructural protein NS5A. Over the course of infection, only one mutation in the surface glycoprotein E2 consistently reverted to wildtype, facilitating assembly in cell culture but potentially affecting CD81 interaction in vivo. Overall, GLT1cc is an efficient gt1b infectious cell culture model, paving the road to a rationale-based establishment of new infectious HCV isolates and represents an important novel tool for the development of prophylactic HCV vaccines.
MeSH term(s)	Animals ; Cell Culture Techniques ; Genotype ; Hepacivirus ; Hepatitis C ; Humans ; Mice ; Mutation ; Viral Nonstructural Proteins/metabolism ; Virus Replication
Chemical Substances	Viral Nonstructural Proteins
Language	English
Publishing date	2022-06-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1010472
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Article ; Online: Phosphatidylinositol 4-Kinase III Alpha Governs Cytoskeletal Organization for Invasiveness of Liver Cancer Cells.

Tran, Cong Si / Kersten, Julia / Yan, Jingyi / Breinig, Marco / Huth, Thorben / Poth, Tanja / Colasanti, Ombretta / Riedl, Tobias / Faure-Dupuy, Suzanne / Diehl, Stefan / Verhoye, Lieven / Li, Teng-Feng / Lingemann, Marit / Schult, Philipp / Ahlén, Gustaf / Frelin, Lars / Kühnel, Florian / Vondran, Florian W R / Breuhahn, Kai /

Meuleman, Philip / Heikenwälder, Mathias / Schirmacher, Peter / Bartenschlager, Ralf / Laketa, Vibor / Roessler, Stephanie / Tschaharganeh, Darjus Felix / Sällberg, Matti / Lohmann, Volker

Gastroenterology

2024

Abstract: Background & aims: High expression of phosphatidylinositol 4-kinase III alpha (PI4KIIIα) correlates with poor survival rates in patients with hepatocellular carcinoma. In addition, hepatitis C virus (HCV) infections activate PI4KIIIα and contribute to ... ...

Abstract	Background & aims: High expression of phosphatidylinositol 4-kinase III alpha (PI4KIIIα) correlates with poor survival rates in patients with hepatocellular carcinoma. In addition, hepatitis C virus (HCV) infections activate PI4KIIIα and contribute to hepatocellular carcinoma progression. We aimed at mechanistically understanding the impact of PI4KIIIα on the progression of liver cancer and the potential contribution of HCV in this process. Methods: Several hepatic cell culture and mouse models were used to study the functional importance of PI4KIIIα on liver pathogenesis. Antibody arrays, gene silencing, and PI4KIIIα-specific inhibitor were applied to identify the involved signaling pathways. The contribution of HCV was examined by using HCV infection or overexpression of its nonstructural protein. Results: High PI4KIIIα expression and/or activity induced cytoskeletal rearrangements via increased phosphorylation of paxillin and cofilin. This led to morphologic alterations and higher migratory and invasive properties of liver cancer cells. We further identified the liver-specific lipid kinase phosphatidylinositol 3-kinase C2 domain-containing subunit gamma (PIK3C2γ) working downstream of PI4KIIIα in regulation of the cytoskeleton. PIK3C2γ generates plasma membrane phosphatidylinositol 3,4-bisphosphate-enriched, invadopodia-like structures that regulate cytoskeletal reorganization by promoting Akt2 phosphorylation. Conclusions: PI4KIIIα regulates cytoskeleton organization via PIK3C2γ/Akt2/paxillin-cofilin to favor migration and invasion of liver cancer cells. These findings provide mechanistic insight into the contribution of PI4KIIIα and HCV to the progression of liver cancer and identify promising targets for therapeutic intervention.
Language	English
Publishing date	2024-04-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	80112-4
ISSN	1528-0012 ; 0016-5085
ISSN (online)	1528-0012
ISSN	0016-5085
DOI	10.1053/j.gastro.2024.04.009
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Article ; Online: Comparison of HAV and HCV infections in vivo and in vitro reveals distinct patterns of innate immune evasion and activation.

Journal of hepatology

2023 Volume 79, Issue 3, Page(s) 645–656

Abstract: Background & aims: Hepatitis 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 ... ...

Abstract	Background & aims: Hepatitis 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. Methods: Albumin-urokinase-type plasminogen activator/severe combined immunodeficiency (Alb/uPA-SCID) mice with humanised livers were infected with HAV and HCV. Hepatic cell culture models were used to assess HAV and HCV sensing by Toll-like receptor 3 and retinoic acid-inducible gene I/melanoma differentiation-associated protein 5 (RIG-I/MDA5), respectively. Cleavage of the adaptor proteins TIR-domain-containing adapter-inducing interferon-β (TRIF) and mitochondrial antiviral-signalling protein (MAVS) was analysed by transient and stable expression of HAV and HCV proteases and virus infection. Results: We detected similar levels of interferon-stimulated gene induction in hepatocytes of HAV- and HCV-infected mice with humanised liver. In cell culture, HAV induced interferon-stimulated genes exclusively upon MDA5 sensing and depended on LGP2 (laboratory of genetics and physiology 2). 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 cleavage was not detected. Conclusions: HAV induces an innate immune response in hepatocytes via MDA5/LGP2, with limited control of both pathways by proteolytic cleavage. HCV activates Toll-like receptor 3 and lacks TRIF cleavage, suggesting that this pathway mainly contributes to HCV-induced antiviral responses in hepatocytes. Our results shed new light on the induction of innate immunity and counteraction by HAV and HCV. Impact and implications: Understanding the mechanisms that determine the differential outcomes of HAV and HCV infections is crucial for the development of effective therapies. Our study provides insights into the interplay between these viruses and the host innate immune response in vitro and in vivo, shedding light on previously controversial or only partially investigated aspects. This knowledge could tailor the development of new strategies to combat HCV persistence, as well as improve our understanding of the factors underlying successful HAV clearance.
MeSH term(s)	Hepatitis A virus ; Hepatitis A ; Hepacivirus ; Hepatitis C ; Animals ; Mice ; Immune Evasion ; Immunity, Innate ; Mice, SCID
Language	English
Publishing date	2023-04-29
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	605953-3
ISSN	1600-0641 ; 0168-8278
ISSN (online)	1600-0641
ISSN	0168-8278
DOI	10.1016/j.jhep.2023.04.023
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Article ; Online: 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].

Journal of hepatology

2023 Volume 80, Issue 1, Page(s) 171–172

Language	English
Publishing date	2023-11-30
Publishing country	Netherlands
Document type	Published Erratum
ZDB-ID	605953-3
ISSN	1600-0641 ; 0168-8278
ISSN (online)	1600-0641
ISSN	0168-8278
DOI	10.1016/j.jhep.2023.11.007
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Article ; Conference proceedings: Contribution of the Cellular Lipid Kinase PI4KA to HCV-induced Liver Pathogenesis

Tran, CongSi / Kersten, Julia / Diehl, Stefan / Breinig, Marco / Colasanti, Ombretta / Fleischmann-Mundt, Bettina / Peter, Malin / Heuss, Christian / Faure-Dupuy, Suzanne / Riedl, Tobias / Mutz, Pascal / Poth, Tanja / Schirmacher, Peter / Bartenschlager, Ralf / Kühnel, Florian / Heikenwälder, Mathias / Tschaharganeh, Darjus / Lohmann, Volker

Zeitschrift für Gastroenterologie

2022 Volume 60, Issue 01

Event/congress	38. Jahrestagung der Deutsche Arbeitsgemeinschaft zum Studium der Leber, Mannheim, 2022-01-28
Language	English
Publishing date	2022-01-01
Publisher	Georg Thieme Verlag
Publishing place	Stuttgart ; New York
Document type	Article ; Conference proceedings
ZDB-ID	201387-3
ISSN	1439-7803 ; 0044-2771 ; 0172-8504
ISSN (online)	1439-7803
ISSN	0044-2771 ; 0172-8504
DOI	10.1055/s-0041-1740787
Database	Thieme publisher's database

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Zs.A 111: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.A 111/X: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Secretion of Hepatitis C Virus Replication Intermediates Reduces Activation of Toll-Like Receptor 3 in Hepatocytes.

Gastroenterology

2018 Volume 154, Issue 8, Page(s) 2237–2251.e16

Abstract: Background & aims: Hepatitis C virus (HCV) infections most often result in chronic outcomes, although the virus constantly produces replication intermediates, in particular double-stranded RNA (dsRNA), representing potent inducers of innate immunity. We ...

Abstract	Background & aims: Hepatitis C virus (HCV) infections most often result in chronic outcomes, although the virus constantly produces replication intermediates, in particular double-stranded RNA (dsRNA), representing potent inducers of innate immunity. We aimed to characterize the fate of HCV dsRNA in hepatocyte cultures to identify mechanisms contributing to viral persistence in presence of an active innate immune response. Methods: We analyzed hepatocyte-based culture models for HCV for induction of innate immunity, secretion of virus positive- or negative-strand RNA, and viral replication using different quantification methods and microscopy techniques. Expression of pattern recognition receptors was reconstituted in hepatoma cells by lentiviral transduction. Results: HCV-infected cells secrete substantial amounts of virus positive- and negative-strand RNAs in extracellular vesicles (EVs), toward the apical and basolateral domain of hepatocytes. Secretion of negative-strand RNA was independent from virus production, and viral RNA secreted in EVs contained higher relative amounts of negative-strands, indicating that mostly virus dsRNA is released. A substantial part of viral replication complexes and dsRNA was found in the endosomal compartment and multivesicular bodies, indicating that secretion of HCV replication intermediates is mediated by the exosomal pathway. Block of vesicle release in HCV-positive cells increased intracellular dsRNA levels and increased activation of toll-like receptor 3, inhibiting HCV replication. Conclusions: Using hepatocyte-based culture models for HCV, we found a portion of HCV dsRNA intermediates to be released from infected cells in EVs, which reduces activation of toll-like receptor 3. This represents a novel mechanism how HCV evades host immune responses, potentially contributing to viral persistence.
MeSH term(s)	Cell Line ; Extracellular Vesicles/immunology ; Extracellular Vesicles/metabolism ; Hepacivirus/physiology ; Hepatitis C, Chronic/blood ; Hepatitis C, Chronic/immunology ; Hepatitis C, Chronic/virology ; Hepatocytes/immunology ; Hepatocytes/metabolism ; Host-Pathogen Interactions/immunology ; Humans ; Immunity, Innate ; Interferons/immunology ; Interferons/metabolism ; Primary Cell Culture ; RNA, Double-Stranded/immunology ; RNA, Double-Stranded/isolation & purification ; RNA, Double-Stranded/secretion ; RNA, Viral/immunology ; RNA, Viral/isolation & purification ; RNA, Viral/secretion ; Signal Transduction/immunology ; Toll-Like Receptor 3/immunology ; Toll-Like Receptor 3/metabolism ; Virus Replication/immunology
Chemical Substances	RNA, Double-Stranded ; RNA, Viral ; TLR3 protein, human ; Toll-Like Receptor 3 ; Interferons (9008-11-1)
Language	English
Publishing date	2018
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80112-4
ISSN	1528-0012 ; 0016-5085
ISSN (online)	1528-0012
ISSN	0016-5085
DOI	10.1053/j.gastro.2018.03.020
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