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Publications (10 of 54) Show all publications
Victoria, C., Schulz, G., Klöhn, M., Weber, S., Holicki, C. M., Brüggemann, Y., . . . Kirschning, A. (2024). Halogenated rocaglate derivatives: pan-antiviral agents against hepatitis E virus and emerging viruses. Journal of Medicinal Chemistry, 67(1), 289-321
Open this publication in new window or tab >>Halogenated rocaglate derivatives: pan-antiviral agents against hepatitis E virus and emerging viruses
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2024 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 67, no 1, p. 289-321Article in journal (Refereed) Published
Abstract [en]

The synthesis of a library of halogenated rocaglate derivatives belonging to the flavagline class of natural products, of which silvestrol is the most prominent example, is reported. Their antiviral activity and cytotoxicity profile against a wide range of pathogenic viruses, including hepatitis E, Chikungunya, Rift Valley Fever virus and SARS-CoV-2, were determined. The incorporation of halogen substituents at positions 4′, 6 and 8 was shown to have a significant effect on the antiviral activity of rocaglates, some of which even showed enhanced activity compared to CR-31-B and silvestrol.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2024
National Category
Medicinal Chemistry Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-220155 (URN)10.1021/acs.jmedchem.3c01357 (DOI)001141760200001 ()38127656 (PubMedID)2-s2.0-85181007683 (Scopus ID)
Available from: 2024-02-12 Created: 2024-02-12 Last updated: 2024-02-12Bibliographically approved
Passos, V., Henkel, L. M., Wang, J., Zapatero-Belinchón, F. J., Möller, R., Sun, G., . . . Viejo-Borbolla, A. (2024). Innate immune response to SARS-CoV-2 infection contributes to neuronal damage in human iPSC-derived peripheral neurons. Journal of Medical Virology, 96(2), Article ID e29455.
Open this publication in new window or tab >>Innate immune response to SARS-CoV-2 infection contributes to neuronal damage in human iPSC-derived peripheral neurons
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2024 (English)In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 96, no 2, article id e29455Article in journal (Refereed) Published
Abstract [en]

Severe acute respiratory coronavirus 2 (SARS-CoV-2) causes neurological disease in the peripheral and central nervous system (PNS and CNS, respectively) of some patients. It is not clear whether SARS-CoV-2 infection or the subsequent immune response are the key factors that cause neurological disease. Here, we addressed this question by infecting human induced pluripotent stem cell-derived CNS and PNS neurons with SARS-CoV-2. SARS-CoV-2 infected a low number of CNS neurons and did not elicit a robust innate immune response. On the contrary, SARS-CoV-2 infected a higher number of PNS neurons. This resulted in expression of interferon (IFN) λ1, several IFN-stimulated genes and proinflammatory cytokines. The PNS neurons also displayed alterations characteristic of neuronal damage, as increased levels of sterile alpha and Toll/interleukin receptor motif-containing protein 1, amyloid precursor protein and α-synuclein, and lower levels of cytoskeletal proteins. Interestingly, blockade of the Janus kinase and signal transducer and activator of transcription pathway by Ruxolitinib did not increase SARS-CoV-2 infection, but reduced neuronal damage, suggesting that an exacerbated neuronal innate immune response contributes to pathogenesis in the PNS. Our results provide a basis to study coronavirus disease 2019 (COVID-19) related neuronal pathology and to test future preventive or therapeutic strategies.

Place, publisher, year, edition, pages
John Wiley & Sons, 2024
Keywords
interferon, iPSC-derived peripheral neurons, JAK/STAT, neuronal damage, SARM1, SARS-CoV-2
National Category
Neurosciences Infectious Medicine Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-221106 (URN)10.1002/jmv.29455 (DOI)38323709 (PubMedID)2-s2.0-85184531658 (Scopus ID)
Funder
German Research Foundation (DFG), 458632757German Research Foundation (DFG), 390874280German Research Foundation (DFG), 158989968
Available from: 2024-02-27 Created: 2024-02-27 Last updated: 2024-02-27Bibliographically approved
Matthaei, A., Joecks, S., Frauenstein, A., Bruening, J., Bankwitz, D., Friesland, M., . . . Pietschmann, T. (2024). Landscape of protein-protein interactions during hepatitis C virus assembly and release. Microbiology Spectrum, 12(2), Article ID e0256222.
Open this publication in new window or tab >>Landscape of protein-protein interactions during hepatitis C virus assembly and release
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2024 (English)In: Microbiology Spectrum, E-ISSN 2165-0497, Vol. 12, no 2, article id e0256222Article in journal (Refereed) Published
Abstract [en]

Assembly of infectious hepatitis C virus (HCV) particles requires multiple cellular proteins including for instance apolipoprotein E (ApoE). To describe these protein-protein interactions, we performed an affinity purification mass spectrometry screen of HCV-infected cells. We used functional viral constructs with epitope-tagged envelope protein 2 (E2), protein (p) 7, or nonstructural protein 4B (NS4B) as well as cells expressing a tagged variant of ApoE. We also evaluated assembly stage-dependent remodeling of protein complexes by using viral mutants carrying point mutations abrogating particle production at distinct steps of the HCV particle production cascade. Five ApoE binding proteins, 12 p7 binders, 7 primary E2 interactors, and 24 proteins interacting with NS4B were detected. Cell-derived PREB, STT3B, and SPCS2 as well as viral NS2 interacted with both p7 and E2. Only GTF3C3 interacted with E2 and NS4B, highlighting that HCV assembly and replication complexes exhibit largely distinct interactomes. An HCV core protein mutation, preventing core protein decoration of lipid droplets, profoundly altered the E2 interactome. In cells replicating this mutant, E2 interactions with HSPA5, STT3A/B, RAD23A/B, and ZNF860 were significantly enhanced, suggesting that E2 protein interactions partly depend on core protein functions. Bioinformatic and functional studies including STRING network analyses, RNA interference, and ectopic expression support a role of Rad23A and Rad23B in facilitating HCV infectious virus production. Both Rad23A and Rad23B are involved in the endoplasmic reticulum (ER)-associated protein degradation (ERAD). Collectively, our results provide a map of host proteins interacting with HCV assembly proteins, and they give evidence for the involvement of ER protein folding machineries and the ERAD pathway in the late stages of the HCV replication cycle.IMPORTANCEHepatitis C virus (HCV) establishes chronic infections in the majority of exposed individuals. This capacity likely depends on viral immune evasion strategies. One feature likely contributing to persistence is the formation of so-called lipo-viro particles. These peculiar virions consist of viral structural proteins and cellular lipids and lipoproteins, the latter of which aid in viral attachment and cell entry and likely antibody escape. To learn about how lipo-viro particles are coined, here, we provide a comprehensive overview of protein-protein interactions in virus-producing cells. We identify numerous novel and specific HCV E2, p7, and cellular apolipoprotein E-interacting proteins. Pathway analyses of these interactors show that proteins participating in processes such as endoplasmic reticulum (ER) protein folding, ER-associated protein degradation, and glycosylation are heavily engaged in virus production. Moreover, we find that the proteome of HCV replication sites is distinct from the assembly proteome, suggesting that transport process likely shuttles viral RNA to assembly sites.

Place, publisher, year, edition, pages
American Society for Microbiology, 2024
Keywords
affinity purification, endoplasmic reticulum, ERAD, hepatitis C virus, host-pathogen interactions, HSPA5, lipoproteins, proteomics, Rad23B, viral assembly and release, virus-host interactions
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-221113 (URN)10.1128/spectrum.02562-22 (DOI)001143555400001 ()38230952 (PubMedID)2-s2.0-85184516987 (Scopus ID)
Funder
German Research Foundation (DFG), 158989968German Research Foundation (DFG), GE 2145/3-2Knut and Alice Wallenberg FoundationGerman Research Foundation (DFG), 390874280
Available from: 2024-02-19 Created: 2024-02-19 Last updated: 2024-02-19Bibliographically approved
Haid, S., Matthaei, A., Winkler, M., Sake, S. M., Gunesch, A. P., Milke, V., . . . Pietschmann, T. (2024). Repurposing screen identifies novel candidates for broad-spectrum coronavirus antivirals and druggable host targets. Antimicrobial Agents and Chemotherapy, 68(3), Article ID e01210-23.
Open this publication in new window or tab >>Repurposing screen identifies novel candidates for broad-spectrum coronavirus antivirals and druggable host targets
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2024 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 68, no 3, article id e01210-23Article in journal (Refereed) Published
Abstract [en]

Libraries composed of licensed drugs represent a vast repertoire of molecules modulating physiological processes in humans, providing unique opportunities for the discovery of host-targeting antivirals. We screened the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) repurposing library with approximately 12,000 molecules for broad-spectrum coronavirus antivirals and discovered 134 compounds inhibiting an alphacoronavirus and mapping to 58 molecular target categories. Dominant targets included the 5-hydroxytryptamine receptor, the dopamine receptor, and cyclin-dependent kinases. Gene knock-out of the drugs’ host targets including cathepsin B and L (CTSB/L; VBY-825), the aryl hydrocarbon receptor (AHR; Phortress), the farnesyl-diphosphate farnesyltransferase 1 (FDFT1; P-3622), and the kelch-like ECH-associated protein 1 (KEAP1; Omaveloxolone), significantly modulated HCoV-229E infection, providing evidence that these compounds inhibited the virus through acting on their respective host targets. Counter-screening of all 134 primary compound candidates with SARS-CoV-2 and validation in primary cells identified Phortress, an AHR activating ligand, P-3622-targeting FDFT1, and Omaveloxolone, which activates the NFE2-like bZIP transcription factor 2 (NFE2L2) by liberating it from its endogenous inhibitor KEAP1, as antiviral candidates for both an Alpha- and a Betacoronavirus. This study provides an overview of HCoV-229E repurposing candidates and reveals novel potentially druggable viral host dependency factors hijacked by diverse coronaviruses.

Place, publisher, year, edition, pages
American Society for Microbiology, 2024
Keywords
antivirals, coronavirus, CRISPR/Cas9, HCoV-229E, host-targeting antiviral therapy, repurposing, SARS-CoV-2
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-222422 (URN)10.1128/aac.01210-23 (DOI)001158282200001 ()38319076 (PubMedID)2-s2.0-85187004901 (Scopus ID)
Funder
German Research Foundation (DFG), 158989968German Research Foundation (DFG), 417852234Knut and Alice Wallenberg Foundation
Available from: 2024-03-28 Created: 2024-03-28 Last updated: 2024-03-28Bibliographically approved
Li, D., Bühler, M., Runft, S., Gerold, G., Marek, K., Baumgärtner, W., . . . Gerhauser, I. (2023). ASC- and caspase-1-deficient C57BL/6 mice do not develop demyelinating disease after infection with Theiler's murine encephalomyelitis virus. Scientific Reports, 13(1), Article ID 10960.
Open this publication in new window or tab >>ASC- and caspase-1-deficient C57BL/6 mice do not develop demyelinating disease after infection with Theiler's murine encephalomyelitis virus
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2023 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 13, no 1, article id 10960Article in journal (Refereed) Published
Abstract [en]

Theiler's murine encephalomyelitis virus (TMEV) induces an acute polioencephalomyelitis and a chronic demyelinating leukomyelitis in SJL mice. C57BL/6 (B6) mice generally do not develop TMEV-induced demyelinating disease (TMEV-IDD) due to virus elimination. However, TMEV can persist in specific immunodeficient B6 mice such as IFNβ-/- mice and induce a demyelinating process. The proinflammatory cytokines IL-1β and IL-18 are activated by the inflammasome pathway, which consists of a pattern recognition receptor molecule sensing microbial pathogens, the adaptor molecule Apoptosis-associated speck-like protein containing a CARD (ASC), and the executioner caspase-1. To analyze the contribution of the inflammasome pathway to the resistance of B6 mice to TMEV-IDD, ASC- and caspase-1-deficient mice and wild type littermates were infected with TMEV and investigated using histology, immunohistochemistry, RT-qPCR, and Western Blot. Despite the antiviral activity of the inflammasome pathway, ASC- and caspase-1-deficient mice eliminated the virus and did not develop TMEV-IDD. Moreover, a similar IFNβ and cytokine gene expression was found in the brain of immunodeficient mice and their wild type littermates. Most importantly, Western Blot showed cleavage of IL-1β and IL-18 in all investigated mice. Consequently, inflammasome-dependent activation of IL-1β and IL-18 does not play a major role in the resistance of B6 mice to TMEV-IDD.

Place, publisher, year, edition, pages
Springer Nature, 2023
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-212230 (URN)10.1038/s41598-023-38152-3 (DOI)37414913 (PubMedID)2-s2.0-85164254632 (Scopus ID)
Available from: 2023-07-21 Created: 2023-07-21 Last updated: 2023-11-28Bibliographically approved
Becker, M., Conca, D. V., Dorma, N., Mistry, N., Hahlin, E., Frängsmyr, L., . . . Gerold, G. (2023). Efficient clathrin-mediated entry of enteric adenoviruses in human duodenal cells. Journal of Virology, 97(10)
Open this publication in new window or tab >>Efficient clathrin-mediated entry of enteric adenoviruses in human duodenal cells
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2023 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 97, no 10Article in journal (Refereed) Published
Abstract [en]

Enteric adenovirus types F40 and 41 (EAdVs) are a leading cause of diarrhea and diarrhea-associated death in young children and have recently been proposed to cause acute hepatitis in children. EAdVs have a unique capsid architecture and exhibit — unlike other human adenoviruses — a relatively strict tropism for gastrointestinal tissues with, to date, understudied infection mechanism and unknown target cells. In this study, we turn to potentially limiting host factors by comparing EAdV entry in cell lines with respiratory and intestinal origin by cellular perturbation, virus particle tracking, and transmission electron microscopy. Our analyses highlight kinetic advantages for EAdVs in duodenal HuTu80 cell infection and reveal a larger fraction of mobile particles, faster virus uptake, and infectious particle entry in intestinal cells. Moreover, EAdVs display a dependence on clathrin- and dynamin-dependent pathways in intestinal cells. Detailed knowledge of virus entry routes and host factor requirements is essential to understanding pathogenesis and developing new countermeasures. Hence, this study provides novel insights into the entry mechanisms of a medically important virus with emerging tropism in a cell line originating from a relevant tissue. IMPORTANCE Enteric adenoviruses have historically been difficult to grow in cell culture, which has resulted in lack of knowledge of host factors and pathways required for infection of these medically relevant viruses. Previous studies in non-intestinal cell lines showed slow infection kinetics and generated comparatively low virus yields compared to other adenovirus types. We suggest duodenum-derived HuTu80 cells as a superior cell line for studies to complement efforts using complex intestinal tissue models. We show that viral host cell factors required for virus entry differ between cell lines from distinct origins and demonstrate the importance of clathrin-mediated endocytosis.

Keywords
clathrin-mediated endocytosis, electron microscopy, enteric adenovirus, single particle tracking, virus entry
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-216662 (URN)10.1128/jvi.00770-23 (DOI)37823645 (PubMedID)2-s2.0-85175844402 (Scopus ID)
Funder
Swedish Research Council, 2020-06242Swedish Research Council, 2019-01472Knut and Alice Wallenberg FoundationKnut and Alice Wallenberg Foundation
Available from: 2023-11-27 Created: 2023-11-27 Last updated: 2023-11-28Bibliographically approved
Marek, K., Armando, F., Asawapattanakul, T., Nippold, V. M., Plattet, P., Gerold, G., . . . Puff, C. (2023). Functional Granulocyte–Macrophage Colony-Stimulating Factor (GM-CSF) Delivered by Canine Histiocytic Sarcoma Cells Persistently Infected with Engineered Attenuated Canine Distemper Virus. Pathogens, 12(7), Article ID 877.
Open this publication in new window or tab >>Functional Granulocyte–Macrophage Colony-Stimulating Factor (GM-CSF) Delivered by Canine Histiocytic Sarcoma Cells Persistently Infected with Engineered Attenuated Canine Distemper Virus
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2023 (English)In: Pathogens, E-ISSN 2076-0817, Vol. 12, no 7, article id 877Article in journal (Refereed) Published
Abstract [en]

The immune response plays a key role in the treatment of malignant tumors. One important molecule promoting humoral and cellular immunity is granulocyte–macrophage colony-stimulating factor (GM-CSF). Numerous successful trials have led to the approval of this immune-stimulating molecule for cancer therapy. However, besides immune stimulation, GM-CSF may also accelerate tumor cell proliferation, rendering this molecule a double-edged sword in cancer treatment. Therefore, detailed knowledge about the in vitro function of GM-CSF produced by infected tumor cells is urgently needed prior to investigations in an in vivo model. The aim of the present study was to functionally characterize a persistent infection of canine histiocytic sarcoma cells (DH82 cells) with the canine distemper virus strain Onderstepoort genetically engineered to express canine GM-CSF (CDV-Ondneon-GM-CSF). The investigations aimed (1) to prove the overall functionality of the virally induced production of GM-CSF and (2) to determine the effect of GM-CSF on the proliferation and motility of canine HS cells. Infected cells consistently produced high amounts of active, pH-stable GM-CSF, as demonstrated by increased proliferation of HeLa cells. By contrast, DH82 cells lacked increased proliferation and motility. The significantly increased secretion of GM-CSF by persistently CDV-Ondneon-GM-CSF-infected DH82 cells, the pH stability of this protein, and the lack of detrimental effects on DH82 cells renders this virus strain an interesting candidate for future studies aiming to enhance the oncolytic properties of CDV for the treatment of canine histiocytic sarcomas.

Place, publisher, year, edition, pages
MDPI, 2023
Keywords
canine distemper virus, DH82 cells, genetically engineered viruses, GM-CSF, histiocytic sarcoma, viral oncolysis
National Category
Immunology
Identifiers
urn:nbn:se:umu:diva-212750 (URN)10.3390/pathogens12070877 (DOI)001036641600001 ()37513724 (PubMedID)2-s2.0-85166220649 (Scopus ID)
Available from: 2023-08-14 Created: 2023-08-14 Last updated: 2023-11-28Bibliographically approved
Carriquí-Madroñal, B., Lasswitz, L., von Hahn, T. & Gerold, G. (2023). Genetic and pharmacological perturbation of hepatitis-C virus entry. Current Opinion in Virology, 62, Article ID 101362.
Open this publication in new window or tab >>Genetic and pharmacological perturbation of hepatitis-C virus entry
2023 (English)In: Current Opinion in Virology, ISSN 1879-6257, E-ISSN 1879-6265, Vol. 62, article id 101362Article, review/survey (Refereed) Published
Abstract [en]

Hepatitis-C virus (HCV) chronically infects 58 million individuals worldwide with variable disease outcome. While a subfraction of individuals exposed to the virus clear the infection, the majority develop chronic infection if untreated. Another subfraction of chronically ill proceeds to severe liver disease. The underlying causes of this interindividual variability include genetic polymorphisms in interferon genes. Here, we review available data on the influence of genetic or pharmacological perturbation of HCV host dependency factors on the clinically observed interindividual differences in disease outcome. We focus on host factors mediating virus entry into human liver cells. We assess available data on genetic variants of the major entry factors scavenger receptor class-B type I, CD81, claudin-1, and occludin as well as pharmacological perturbation of these entry factors. We review cell culture experimental and clinical cohort study data and conclude that entry factor perturbation may contribute to disease outcome of hepatitis C.

Place, publisher, year, edition, pages
Elsevier, 2023
National Category
Infectious Medicine Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-214535 (URN)10.1016/j.coviro.2023.101362 (DOI)37678113 (PubMedID)2-s2.0-85170438180 (Scopus ID)
Available from: 2023-09-26 Created: 2023-09-26 Last updated: 2023-11-28Bibliographically approved
Löw, K., Möller, R., Stegmann, C., Becker, M., Rehburg, L., Obernolte, H., . . . Gerold, G. (2023). Luminescent reporter cells enable the identification of broad-spectrum antivirals against emerging viruses. Journal of Medical Virology, 95(11), Article ID e29211.
Open this publication in new window or tab >>Luminescent reporter cells enable the identification of broad-spectrum antivirals against emerging viruses
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2023 (English)In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 95, no 11, article id e29211Article in journal (Refereed) Published
Abstract [en]

The emerging viruses SARS-CoV-2 and arenaviruses cause severe respiratory and hemorrhagic diseases, respectively. The production of infectious particles of both viruses and virus spread in tissues requires cleavage of surface glycoproteins (GPs) by host proprotein convertases (PCs). SARS-CoV-2 and arenaviruses rely on GP cleavage by PCs furin and subtilisin kexin isozyme-1/site-1 protease (SKI-1/S1P), respectively. We report improved luciferase-based reporter cell lines, named luminescent inducible proprotein convertase reporter cells that we employ to monitor PC activity in its authentic subcellular compartment. Using these sensor lines we screened a small compound library in high-throughput manner. We identified 23 FDA-approved small molecules, among them monensin which displayed broad activity against furin and SKI-1/S1P. Monensin inhibited arenaviruses and SARS-CoV-2 in a dose-dependent manner. We observed a strong reduction in infectious particle release upon monensin treatment with little effect on released genome copies. This was reflected by inhibition of SARS-CoV-2 spike processing suggesting the release of immature particles. In a proof of concept experiment using human precision cut lung slices, monensin potently inhibited SARS-CoV-2 infection, evidenced by reduced infectious particle release. We propose that our PC sensor pipeline is a suitable tool to identify broad-spectrum antivirals with therapeutic potential to combat current and future emerging viruses.

Place, publisher, year, edition, pages
John Wiley & Sons, 2023
Keywords
antiviral, arenavirus, broad-spectrum, emerging virus, furin, high-throughput screening, inducible sensor cell lines, inhibition, pandemic preparedness, proprotein convertase, SARS-CoV-2, SKI-1/S1P, viral GP cleavage
National Category
Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-217400 (URN)10.1002/jmv.29211 (DOI)37975336 (PubMedID)2-s2.0-85177040918 (Scopus ID)
Funder
Knut and Alice Wallenberg Foundation
Available from: 2023-12-04 Created: 2023-12-04 Last updated: 2023-12-04Bibliographically approved
Mhlekude, B., Postmus, D., Stenzel, S., Weiner, J., Jansen, J., Zapatero-Belinchón, F. J., . . . Goffinet, C. (2023). Pharmacological inhibition of bromodomain and extra-terminal proteins induces an NRF-2-mediated antiviral state that is subverted by SARS-CoV-2 infection. PLoS Pathogens, 19(9), Article ID e1011657.
Open this publication in new window or tab >>Pharmacological inhibition of bromodomain and extra-terminal proteins induces an NRF-2-mediated antiviral state that is subverted by SARS-CoV-2 infection
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2023 (English)In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 19, no 9, article id e1011657Article in journal (Refereed) Published
Abstract [en]

Inhibitors of bromodomain and extra-terminal proteins (iBETs), including JQ-1, have been suggested as potential prophylactics against SARS-CoV-2 infection. However, molecular mechanisms underlying JQ-1-mediated antiviral activity and its susceptibility to viral subversion remain incompletely understood. Pretreatment of cells with iBETs inhibited infection by SARS-CoV-2 variants and SARS-CoV, but not MERS-CoV. The antiviral activity manifested itself by reduced reporter expression of recombinant viruses, and reduced viral RNA quantities and infectious titers in the culture supernatant. While we confirmed JQ-1-mediated downregulation of expression of angiotensin-converting enzyme 2 (ACE2) and interferon-stimulated genes (ISGs), multi-omics analysis addressing the chromatin accessibility, transcriptome and proteome uncovered induction of an antiviral nuclear factor erythroid 2-related factor 2 (NRF-2)-mediated cytoprotective response as an additional mechanism through which JQ-1 inhibits SARS-CoV-2 replication. Pharmacological inhibition of NRF-2, and knockdown of NRF-2 and its target genes reduced JQ-1-mediated inhibition of SARS-CoV-2 replication. Serial passaging of SARS-CoV-2 in the presence of JQ-1 resulted in predominance of ORF6-deficient variant, which exhibited resistance to JQ-1 and increased sensitivity to exogenously administered type I interferon (IFN-I), suggesting a minimised need for SARS-CoV-2 ORF6-mediated repression of IFN signalling in the presence of JQ-1. Importantly, JQ-1 exhibited a transient antiviral activity when administered prophylactically in human airway bronchial epithelial cells (hBAECs), which was gradually subverted by SARS-CoV-2, and no antiviral activity when administered therapeutically following an established infection. We propose that JQ-1 exerts pleiotropic effects that collectively induce an antiviral state in the host, which is ultimately nullified by SARS-CoV-2 infection, raising questions about the clinical suitability of the iBETs in the context of COVID-19.

Place, publisher, year, edition, pages
Public Library of Science (PLoS), 2023
National Category
Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-215392 (URN)10.1371/journal.ppat.1011657 (DOI)001079681800001 ()37747932 (PubMedID)2-s2.0-85173471701 (Scopus ID)
Available from: 2023-10-27 Created: 2023-10-27 Last updated: 2023-12-12Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-1326-5038

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