iPSCs for modeling hepatotropic pathogen infections

Bove, G.; Mehnert, Ann-Kathrin; Thi, Viet Loan Dao

doi:10.1016/b978-0-12-823808-0.00013-4

Cited by 4 publications

(4 citation statements)

References 497 publications

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“…Moreover, patient‐derived iPSC allows to produce HLCs with genetic backgrounds of interest. HLCs are permissive for hepatitis virus infection both in vitro (HAV, 11 HBV, 12 HCV, 13 HEV 14 ) and in vivo 15 and are being used to investigate host‐pathogen interactions (reviewed in 16 ), with applications ranging from reproducing polarized secretory pathways 11 to studying single nucleotide polymorphisms‐related permissivity 17 . To our knowledge, no study has yet examined the susceptibility of HLCs to HDV.…”

Section: Introductionmentioning

confidence: 99%

Hepatitis D virus infection, innate immune response and antiviral treatments in stem cell‐derived hepatocytes

Lange

Garn

Anagho

et al. 2023

Liver International

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BackgroundHuman pluripotent stem cell (hPSC)‐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 investigate the susceptibility of HLCs to the hepatitis delta virus (HDV).MethodsWe differentiated hPSC into HLCs, and inoculated them with infectious HDV produced in Huh7NTCP. HDV infection and cellular response was monitored by RTqPCR and immunostaining.ResultsCells undergoing hepatic differentiation become susceptible to HDV after acquiring expression of the viral receptor Na+‐taurocholate co‐transporting polypeptide (NTCP) during hepatic specification. Inoculation of HLCs with HDV leads to detection of intracellular HDV RNA and accumulation of the HDV antigen in the cells. Upon infection, the HLCs mounted an innate immune response based on induction of the interferons IFNB and L, and 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, this innate immune response did not inhibit HDV replication. However, pre‐treatment of the HLCs with IFNα2b reduced viral infection, suggesting that ISGs may limit early stages of infection. Myrcludex efficiently abrogated infection and blocked innate immune activation. Lonafarnib treatment of HDV mono infected HLCs on the other hand led to exacerbated viral replication and innate immune response.ConclusionThe HDV in vitro mono‐infection model represents a new tool to study HDV replication, its host‐pathogen interactions and evaluate new antiviral drugs in cells displaying mature hepatic functions.

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Section: Introductionmentioning

confidence: 99%

Hepatitis D virus infection, innate immune response and antiviral treatments in stem cell‐derived hepatocytes

Lange

Garn

Anagho

et al. 2023

Liver International

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“…Previous studies have demonstrated the utility of stem cell-derived HLCs for hepatotropic virus infection, including HBV (reviewed in 27 ). Here, we analyzed whether HLCs are likewise permissive to HDV infection.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, numerous protocols have been developed to differentiate human induced or embryonic pluripotent stem cells (hiPSC/ESC) into hepatocyte-like cells (HLCs) (reviewed in 27 ). HLCs resemble PHHs and better recapitulate physiological features, such as drug metabolism or innate immune response, than hepatoma cells 28 .…”

Section: Introductionmentioning

confidence: 99%

Human pluripotent stem cell-derived hepatocyte-like cells for hepatitis D virus studies

Chi,

Qu,

Prawira

et al. 2023

Preprint

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Current culture systems available for studying hepatitis D virus (HDV) are suboptimal. In this study, we demonstrate that hepatocyte-like cells (HLCs) derived from human pluripotent stem cells (hPSCs) are fully permissive to HDV infection across various tested genotypes. When co- infected with the helper hepatitis B virus (HBV) or transduced to express the HBV envelope protein HBsAg, HLCs effectively secrete infectious progeny virions. We also show that HLCs expressing HBsAg support extracellular spread of HDV, thus providing a valuable platform for testing available anti-HDV regimens. By challenging the cells along the differentiation with HDV infection, we have identified CD63 as a potential HDV/HBV co-entry factor, which was rate-limiting HDV infection in immature hepatocytes. Given their renewable source and the potential to derive hPSCs from individual patients, we propose HLCs as a promising model for investigating HDV biology. Our findings offer new insights into HDV infection and expand the repertoire of research tools available for the development of therapeutic interventions.TeaserA human stem cell-derived hepatocyte culture model for hepatitis D virus studies

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“…1 Human pluripotent stem cells (hPSC)-derived hepatocyte like cells (HLCs) have shown to be a valuable alternative, reproducing key metabolic features of PHHs without the aforementioned limitations. 2 HLCs are permissive for hepatitis virus infection both in vitro (HAV, 3 HBV, 4 HCV, 5 HEV 6 ) and in vivo 7 and are being used to investigate host pathogens interactions (reviewed in 8 ), with applications ranging from reproducing polarized secretory pathways 3 to studying single nucleotide polymorphisms-related permissivity. 9 One aspect of viral infection that is difficult to study in a transformed cell line is the interplay between the virus and the innate immune response.…”

Section: Introductionmentioning

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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iPSCs for modeling hepatotropic pathogen infections

Cited by 4 publications

References 497 publications

Hepatitis D virus infection, innate immune response and antiviral treatments in stem cell‐derived hepatocytes

Hepatitis D virus infection, innate immune response and antiviral treatments in stem cell‐derived hepatocytes

Human pluripotent stem cell-derived hepatocyte-like cells for hepatitis D virus studies

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

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