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1. Activation of PERK-Nrf2 oncogenic signaling promotes Mdm2-mediated Rb degradation in persistently infected HCV culture

   https://doi.org/10.1038/s41598-017-10087-6  

   Aydin, Yucel ; Chedid, Milad ; Chava, Srinivas ; Danielle Williams, Donkita ; Liu, Shuanghu ; Hagedorn, Curt H. ; Sumitran-Holgersson, Suchitra ; Reiss, Krzysztof ; Moroz, Krzysztof ; Lu, Hua ; et al ( December 2017 , Scientific Reports)

   null (Ed.)

   Abstract The mechanism of how chronic hepatitis C virus (HCV) infection leads to such a high rate of hepatocellular carcinoma (HCC) is unknown. We found that the PERK axis of endoplasmic reticulum (ER) stress elicited prominent nuclear translocation of Nrf2 in 100% of HCV infected hepatocytes. The sustained nuclear translocation of Nrf2 in chronically infected culture induces Mdm2-mediated retinoblastoma protein (Rb) degradation. Silencing PERK and Nrf2 restored Mdm2-mediated Rb degradation, suggesting that sustained activation of PERK/Nrf2 axis creates oncogenic stress in chronically infected HCV culture model. The activation of Nrf2 and its nuclear translocation were prevented by ER-stress and PERK inhibitors, suggesting that PERK axis is involved in the sustained activation of Nrf2 signaling during chronic HCV infection. Furthermore, we show that HCV clearance induced by interferon-α based antiviral normalized the ER-stress response and prevented nuclear translocation of Nrf2, whereas HCV clearance by DAAs combination does neither. In conclusion, we report here a novel mechanism for how sustained activation of PERK axis of ER-stress during chronic HCV infection activates oncogenic Nrf2 signaling that promotes hepatocyte survival and oncogenesis by inducing Mdm2-mediated Rb degradation. 

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2. Investigating Virus–Host Interactions in Cultured Primary Honey Bee Cells

   https://doi.org/10.3390/insects12070653  

   McMenamin, Alexander J. ; Parekh, Fenali ; Lawrence, Verena ; Flenniken, Michelle L. ( July 2021 , Insects)

   Honey bee (Apis mellifera) health is impacted by viral infections at the colony, individual bee, and cellular levels. To investigate honey bee antiviral defense mechanisms at the cellular level we further developed the use of cultured primary cells, derived from either larvae or pupae, and demonstrated that these cells could be infected with a panel of viruses, including common honey bee infecting viruses (i.e., sacbrood virus (SBV) and deformed wing virus (DWV)) and an insect model virus, Flock House virus (FHV). Virus abundances were quantified over the course of infection. The production of infectious virions in cultured honey bee pupal cells was demonstrated by determining that naïve cells became infected after the transfer of deformed wing virus or Flock House virus from infected cell cultures. Initial characterization of the honey bee antiviral immune responses at the cellular level indicated that there were virus-specific responses, which included increased expression of bee antiviral protein-1 (GenBank: MF116383) in SBV-infected pupal cells and increased expression of argonaute-2 and dicer-like in FHV-infected hemocytes and pupal cells. Additional studies are required to further elucidate virus-specific honey bee antiviral defense mechanisms. The continued use of cultured primary honey bee cells for studies that involve multiple viruses will address this knowledge gap. 

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3. The Heat Shock Response in the Western Honey Bee (Apis mellifera) is Antiviral

   https://doi.org/10.3390/v12020245  

   McMenamin, Alexander J. ; Daughenbaugh, Katie F. ; Flenniken, Michelle L. ( February 2020 , Viruses)

   Honey bees (Apis mellifera) are an agriculturally important pollinator species that live in easily managed social groups (i.e., colonies). Unfortunately, annual losses of honey bee colonies in many parts of the world have reached unsustainable levels. Multiple abiotic and biotic stressors, including viruses, are associated with individual honey bee and colony mortality. Honey bees have evolved several antiviral defense mechanisms including conserved immune pathways (e.g., Toll, Imd, JAK/STAT) and dsRNA-triggered responses including RNA interference and a non-sequence specific dsRNA-mediated response. In addition, transcriptome analyses of virus-infected honey bees implicate an antiviral role of stress response pathways, including the heat shock response. Herein, we demonstrate that the heat shock response is antiviral in honey bees. Specifically, heat-shocked honey bees (i.e., 42 °C for 4 h) had reduced levels of the model virus, Sindbis-GFP, compared with bees maintained at a constant temperature. Virus-infection and/or heat shock resulted in differential expression of six heat shock protein encoding genes and three immune genes, many of which are positively correlated. The heat shock protein encoding and immune gene transcriptional responses observed in virus-infected bees were not completely recapitulated by administration of double stranded RNA (dsRNA), a virus-associated molecular pattern, indicating that additional virus–host interactions are involved in triggering antiviral stress response pathways. 

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4. Estimates of Hepatitis C Seroprevalence and Viremia in State Prison Populations in the United States

   https://doi.org/10.1093/infdis/jiad227  

   Spaulding, Anne C ; Kennedy, Shanika S ; Osei, Jeffery ; Sidibeh, Ebrima ; Batina, Isabella V ; Chhatwal, Jagpreet ; Akiyama, Matthew J ; Strick, Lara B ( September 2023 , The Journal of Infectious Diseases)

   Prior studies demonstrate that eliminating hepatitis C virus (HCV) in the United States (US) heavily depends on treating incarcerated persons. Knowing the scope of the carceral HCV epidemic by state will help guide national elimination efforts.

   Between 2019 and 2023, all state prison systems received surveys requesting data on hepatitis C antibody and viremic prevalence. We supplemented survey information with publicly available HCV data to corroborate responses and fill in data gaps.

   Weighting HCV prevalence by state prison population size, we estimate that 15.2% of the US prison population is HCV seropositive and 8.7% is viremic; 54.9% of seropositive persons have detectable RNA. Applying prevalence estimates to the total prison population at year-end 2021, 91 090 persons with HCV infection resided in a state prison.

   With updated and more complete HCV data from all 50 states, HCV prevalence in state prisons is nearly 9-fold higher than the US general population. The heterogeneity in HCV prevalence by state prison system may reflect variable exposure before arrest and/or differences in treatment availability during incarceration. Elimination of HCV in the country depends on addressing the carceral epidemic, and one of the first steps is understanding the size of the problem.

    

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5. Role of Viral Hemorrhagic Septicemia Virus Matrix (M) Protein in Suppressing Host Transcription

   https://doi.org/10.1128/JVI.00279-17  

   Ke, Qi ; Weaver, Wade ; Pore, Adam ; Gorgoglione, Bartolomeo ; Wildschutte, Julia Halo ; Xiao, Peng ; Shepherd, Brian S. ; Spear, Allyn ; Malathi, Krishnamurthy ; Stepien, Carol A. ; et al ( July 2017 , Journal of Virology)

   Viral Hemorrhagic Septicemia virus (VHSV) is a pathogenic fish rhabdovirus found in discrete locales throughout the northern hemisphere. VHSV infection of fish cells leads to upregulation of the host's virus detection response, but the virus quickly suppresses interferon (IFN) production and antiviral genes expression. By systematically screening each of the six VHSV structural and nonstructural genes, we have identified matrix protein (M) as its most potent anti-host protein. VHSV-IVb M alone suppressed mitochondrial antiviral signaling protein (MAVS) and type I IFN-induced gene expression in a dose-dependent manner. M also suppressed the constitutively active SV40 promoter and globally decreased cellular RNA levels. Chromatin immunoprecipitation (ChIP) studies illustrated that M inhibited RNA polymerase II (RNAP II) recruitment to gene promoters, and decreased RNAP II CTD Ser2 phosphorylation during VHSV infection. However, transcription directed by RNAP I-III was suppressed by M. To identify regions of functional importance, M proteins from a variety of VHSV strains were tested in cell-based transcriptional inhibition assays. M protein of a particular VHSV-Ia strain, F1, was significantly less potent than -IVb M at inhibiting SV40/luc expression, yet differed by just four amino acids. Mutation of D62 to alanine alone, or in combination with an E181 to alanine mutation (D62A/E181A), dramatically reduced the ability of -IVb M to suppress host transcription. Introducing either M D62A or D62A/E181A mutations into VHSV-IVb via reverse genetics resulted in viruses that replicated efficiently but exhibited less cytotoxicity and reduced anti-transcriptional activities, implicating M as a primary regulator of cytopathicity and host transcriptional suppression. Importance: Viruses must suppress host antiviral responses to replicate and spread between hosts. In these studies, we identified the matrix protein of the deadly fish Novirhabdovirus, VHSV, as a critical mediator of host suppression during infection. Our studies indicated that M alone could block cellular gene expression at very low expression levels. We identified several subtle mutations in M that were less potent at suppressing host transcription. When these mutations were engineered back into recombinant viruses, the resulting viruses replicated well but elicited less toxicity in infected cells and activated host innate immune responses more robustly. These data demonstrated that VHSV M plays an important role in mediating both virus-induced cell toxicity and viral replication. Our data suggest that its roles in these two processes can be separated to design effective attenuated viruses for vaccine candidates. 

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