Updates in Hepatitis E virus (HEV) field; lessons learned from human liver chimeric mice

Sayed, Ibrahim M.; Meuleman, Philip

doi:10.1002/rmv.2086

Cited by 23 publications

(30 citation statements)

References 119 publications

(313 reference statements)

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“…In this study, we assessed the replication of HEV in murine and human myeloid cells. Although mice are considered a query model for HEV [ 40 , 41 ], we tested the susceptibility of MMOs, MMACs, and murine BMDMs to HEV. We previously reported that non-transplanted immunocompromised mice (uPA +/+ /SCID and FRG) were not susceptible to HEV-1 and HEV-3 infection [ 32 , 33 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

“…In this study, we did not record a significant difference in the replication of HEV-1 and HEV-3 in HMOs, HMACs, and BMDMs. Although HEV-1 is more virulent than HEV-3 in infected patients and in vivo animal model [ 3 , 41 , 49 ], HEV-3 replicates more efficiently in the hepatoma-derived cell line, neuron-derived cell line, and placenta-derived cell line in vitro [ 18 , 29 , 31 ]. Some HEV-3 strains were adapted to grow in cell culture due to a recombination event resulting in an insertion of 174 ribonucleotides (58 amino acids) of the human ribosomal protein S17 gene into the viral genome [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

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Replication of Hepatitis E Virus (HEV) in Primary Human-Derived Monocytes and Macrophages In Vitro

et al. 2020

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HEV is the most causative agent of acute viral hepatitis globally. HEV causes acute, chronic, and extrahepatic manifestations. Chronic HEV infection develops in immunocompromised patients such as organ transplant patients, HIV-infected patients, and leukemic patients. The source of chronic HEV infection is not known. Also, the source of extrahepatic manifestations associated with HEV infection is still unclear. Hepatotropic viruses such as HCV and HBV replicate in peripheral blood mononuclear cells (PBMCs) and these cells become a source of chronic reactivation of the infections in allograft organ transplant patients. Herein, we reported that PBMCs and bone marrow-derived macrophages (BMDMs), isolated from healthy donors (n = 3), are susceptible to HEV in vitro. Human monocytes (HMOs), human macrophages (HMACs), and human BMDMs were challenged with HEV-1 and HEV-3 viruses. HEV RNA was measured by qPCR, the marker of the intermediate replicative form (ds-RNA) was assessed by immunofluorescence, and HEV capsid protein was assessed by flow cytometry and ELISA. HEV infection was successfully established in primary HMOs, HMACs, and human BMDMs, but not in the corresponding cells of murine origin. Intermediate replicative form (ds RNA) was detected in HMOs and HMACs challenged with HEV. The HEV load was increased over time, and the HEV capsid protein was detected intracellularly in the HEV-infected cells and accumulated extracellularly over time, confirming that HEV completes the life cycle inside these cells. The HEV particles produced from the infected BMDMs were infectious to naive HMOs in vitro. The HEV viral load was comparable in HEV-1- and HEV-3-infected cells, but HEV-1 induced more inflammatory responses. In conclusion, HMOs, HMACs, and human BMDMs are permissive to HEV infection and these cells could be the source of chronic and recurrent infection, especially in immunocompromised patients. Replication of HEV in human BMDMs could be related to hematological disorders associated with extrahepatic manifestations.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Replication of Hepatitis E Virus (HEV) in Primary Human-Derived Monocytes and Macrophages In Vitro

et al. 2020

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“…HEV-1 and HEV-2 are transmitted by the fecal–oral route, and they are mainly associated with waterborne HEV outbreaks in developing countries [ 4 , 5 ]. HEV-3 and HEV-4 infect humans and animals such as pigs, wild boars, deer, rabbits, cows, and goats [ 6 , 7 ]. They are zoonotic, infection is mainly transmitted to humans either by contact with these animals or the ingestion of undercooked meat, sausages, liver, or other products from them [ 8 , 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Enhancement of the Molecular and Serological Assessment of Hepatitis E Virus in Milk Samples

et al. 2020

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Hepatitis E virus (HEV) infection is endemic in developing and developed countries. HEV was reported to be excreted in the milk of ruminants, raising the possibility of transmission of HEV infection through the ingestion of contaminated milk. Therefore, the detection of HEV markers in milk samples becomes pivotal. However, milk includes inhibitory components that affect HEV detection assays. Previously it was reported that dilution of milk matrix improves the performance of HEV molecular assay, however, the dilution of milk samples is not the best strategy especially when the contaminated milk sample has a low HEV load. Therefore, the objective of this study is to compare the effect of extraction procedures on the efficiency of HEV RNA detection in undiluted milk samples. In addition, we assessed the effect of the removal of milk components such as fats and casein on the performance of the molecular and serological assays of HEV. Phosphate buffered saline (PBS) and different milk matrices (such as whole milk, skim milk, and milk serum) were inoculated with different HEV inoculums and subjected to two different extraction procedures. Method A includes manual extraction using spin column-based extraction, while method B includes silica-based automated extraction. Method A was more sensitive than method B in the whole milk and skim milk matrices with a LoD95% of 300 IU/mL, and virus recovery yield of 47%. While the sensitivity and performance of method B were significantly improved using the milk serum matrix, with LoD95% of 96 IU/mL. Interestingly, retesting HEV positive milk samples using the high sensitivity assay based on method B extraction and milk serum matrix increased the HEV RNA detection rate to 2-fold. Additionally, the performance of HEV serological assays such as anti-HEV IgG and HEV Ag in the milk samples was improved after the removal of the fat globules from the milk matrix. In conclusion, HEV RNA assay is affected by the components of milk and the extraction procedure. Removal of inhibitory substances, such as fat and casein from the milk sample increased the performance of HEV molecular and serological assays which will be suitable for the low load HEV milk with no further dilutions.

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“…On the other hand, the replication of HEV-1 was inhibited in vitro in a swine kidney cell line, probably HEV-1 produced insufficient capsid protein for optimal assembly in swine cells [ 49 ]. Additionally, HEV was not replicating in the kidney of human liver chimeric mice, which was murine in its origin [ 36 , 50 ]…”

Section: Discussionmentioning

confidence: 99%

Hepatitis E Virus Mediates Renal Injury via the Interaction between the Immune Cells and Renal Epithelium

et al. 2020

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Renal disorders are associated with Hepatitis E virus (HEV) infection. Progression to end-stage renal disease and acute kidney injury are complications associated with HEV infection. The mechanisms by which HEV mediates the glomerular diseases remain unclear. CD10+/CD13+ primary proximal tubular (PT) epithelial cells, isolated from healthy donors, were infected with HEV. Inflammatory markers and kidney injury markers were assessed in the presence or absence of peripheral blood mononuclear cells (PBMCs) isolated from the same donors. HEV replicated efficiently in the PT cells as shown by the increase in HEV load over time and the expression of capsid Ag. In the absence of PBMCs, HEV was not nephrotoxic, with no direct effect on the transcription of chemokines (Cxcl-9, Cxcl-10, and Cxcl-11) nor the kidney injury markers (kidney injury molecule 1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and interleukin 18 (lL-18)). While higher inflammatory responses, upregulation of chemokines and kidney injury markers expression, and signs of nephrotoxicity were recorded in HEV-infected PT cells cocultured with PBMCs. Interestingly, a significantly higher level of IFN-γ was released in the PBMCs-PT coculture compared to PT alone during HEV infection. In conclusion: The crosstalk between immune cells and renal epithelium and the signal axes IFN-γ/chemokines and IL-18 could be the immune-mediated mechanisms of HEV-induced renal disorder.

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Updates in Hepatitis E virus (HEV) field; lessons learned from human liver chimeric mice

Cited by 23 publications

References 119 publications

Replication of Hepatitis E Virus (HEV) in Primary Human-Derived Monocytes and Macrophages In Vitro

Replication of Hepatitis E Virus (HEV) in Primary Human-Derived Monocytes and Macrophages In Vitro

Enhancement of the Molecular and Serological Assessment of Hepatitis E Virus in Milk Samples

Hepatitis E Virus Mediates Renal Injury via the Interaction between the Immune Cells and Renal Epithelium

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