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      Prion protein protects mice from lethal infection with influenza A viruses

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          Abstract

          The cellular prion protein, designated PrP C, is a membrane glycoprotein expressed abundantly in brains and to a lesser extent in other tissues. Conformational conversion of PrP C into the amyloidogenic isoform is a key pathogenic event in prion diseases. However, the physiological functions of PrP C remain largely unknown, particularly in non-neuronal tissues. Here, we show that PrP C is expressed in lung epithelial cells, including alveolar type 1 and 2 cells and bronchiolar Clara cells. Compared with wild-type (WT) mice, PrP C-null mice ( Prnp 0/0 ) were highly susceptible to influenza A viruses (IAVs), with higher mortality. Infected Prnp 0/0 lungs were severely injured, with higher inflammation and higher apoptosis of epithelial cells, and contained higher reactive oxygen species (ROS) than control WT lungs. Treatment with a ROS scavenger or an inhibitor of xanthine oxidase (XO), a major ROS-generating enzyme in IAV-infected lungs, rescued Prnp 0/0 mice from the lethal infection with IAV. Moreover, Prnp 0/0 mice transgenic for PrP with a deletion of the Cu-binding octapeptide repeat (OR) region, Tg(PrPΔOR)/ Prnp 0/0 mice, were also highly susceptible to IAV infection. These results indicate that PrP C has a protective role against lethal infection with IAVs through the Cu-binding OR region by reducing ROS in infected lungs. Cu content and the activity of anti-oxidant enzyme Cu/Zn-dependent superoxide dismutase, SOD1, were lower in Prnp 0/0 and Tg(PrPΔOR)/ Prnp 0/0 lungs than in WT lungs. It is thus conceivable that PrP C functions to maintain Cu content and regulate SOD1 through the OR region in lungs, thereby reducing ROS in IAV-infected lungs and eventually protecting them from lethal infection with IAVs. Our current results highlight the role of PrP C in protection against IAV infection, and suggest that PrP C might be a novel target molecule for anti-influenza therapeutics.

          Author summary

          Influenza A virus (IAV) is an enveloped, negative sense, single-stranded RNA virus, causing seasonal epidemic outbreaks of influenza. Anti-influenza agents targeting viral molecules, such as neuraminidase inhibitors, are currently available. However, these agents have accelerated emergence of mutant IAVs that are resistant to these agents among human populations. Development of new types of anti-influenza agents is awaited. We show that the cellular prion protein PrP C has a protective role against lethal infection with IAVs through the octapeptide repeat (OR) region by abrogating lung epithelial cell apoptosis induced by reactive oxygen species (ROS) in infected lungs. We also show that PrP C could reduce ROS in IAV-infected lungs through the OR region by maintaining Cu ion homeostasis and thereby activating Cu/Zn-dependent superoxide dismutase, SOD1. These results highlight the protective role of PrP C in IAV infection. Elucidation of the exact mechanism underlying the PrP C-mediated protection against IAV infection would be important for further understanding the pathogenesis of IAV infection and could be useful for development of new types of anti-influenza therapeutics.

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          Most cited references55

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          Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein.

          PrPC is a host protein anchored to the outer surface of neurons and to a lesser extent of lymphocytes and other cells. The transmissible agent (prion) responsible for scrapie is believed to be a modified form of PrPC. Mice homozygous for disrupted PrP genes have been generated. Surprisingly, they develop and behave normally for at least seven months, and no immunological defects are apparent. It is now feasible to determine whether mice devoid of PrPC can propagate prions and are susceptible to scrapie pathogenesis.
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            Caspase 3 activation is essential for efficient influenza virus propagation.

            Apoptosis is a hallmark event observed upon infection with many viral pathogens, including influenza A virus. The apoptotic process is executed by a proteolytic system consisting of a family of cysteinyl proteases, termed caspases. Since the consequences of apoptosis induction and caspase activation for the outcome of an influenza virus infection are not clear, we have addressed this issue by interfering with expression or function of a major virus-induced apoptosis effector, caspase 3. Surprisingly, influenza virus propagation was strongly impaired in the presence of an inhibitor that blocks caspase 3 and in cells where caspase 3 was partially knocked down by small interfering RNAs. Consistent with these findings, poor replication efficiencies of influenza A viruses in cells deficient for caspase 3 could be boosted 30-fold by ectopic expression of the protein. Mechanistically, the block in virus propagation appeared to be due to retention of the viral RNP complexes in the nucleus, preventing formation of progeny virus particles. Our findings indicate that caspase 3 activation during the onset of apoptosis is a crucial event for efficient influenza virus propagation.
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              Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2008.

              This report updates the 2007 recommendations by CDC's Advisory Committee on Immunization Practices (ACIP) regarding the use of influenza vaccine and antiviral agents (CDC. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2007;56[No. RR-6]). The 2008 recommendations include new and updated information. Principal updates and changes include 1) a new recommendation that annual vaccination be administered to all children aged 5--18 years, beginning in the 2008--09 influenza season, if feasible, but no later than the 2009--10 influenza season; 2) a recommendation that annual vaccination of all children aged 6 months through 4 years (59 months) continue to be a primary focus of vaccination efforts because these children are at higher risk for influenza complications compared with older children; 3) a new recommendation that either trivalent inactivated influenza vaccine or live, attenuated influenza vaccine (LAIV) be used when vaccinating healthy persons aged 2 through 49 years (the previous recommendation was to administer LAIV to person aged 5--49 years); 4) a recommendation that vaccines containing the 2008--09 trivalent vaccine virus strains A/Brisbane/59/2007 (H1N1)-like, A/Brisbane/10/2007 (H3N2)-like, and B/Florida/4/2006-like antigens be used; and, 5) new information on antiviral resistance among influenza viruses in the United States. Persons for whom vaccination is recommended are listed in boxes 1 and 2. These recommendations also include a summary of safety data for U.S. licensed influenza vaccines. This report and other information are available at CDC's influenza website (http://www.cdc.gov/flu), including any updates or supplements to these recommendations that might be required during the 2008--09 influenza season. Vaccination and health-care providers should be alert to announcements of recommendation updates and should check the CDC influenza website periodically for additional information.
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                Author and article information

                Contributors
                Role: Funding acquisitionRole: InvestigationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Resources
                Role: Resources
                Role: Investigation
                Role: Investigation
                Role: Resources
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: ResourcesRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, CA USA )
                1553-7366
                1553-7374
                3 May 2018
                May 2018
                : 14
                : 5
                : e1007049
                Affiliations
                [1 ] Division of Molecular Neurobiology, Institute for Enzyme Research (KOSOKEN), Tokushima University, Tokushima, Japan
                [2 ] Division of Enzyme Chemistry, Institute for Enzyme Research, Tokushima University, Tokushima, Japan
                [3 ] Animal Research Center, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
                [4 ] Avian Zoonosis Research Center, Faculty of Agriculture, Tottori University, Koyama-cho, Tottori, Japan
                University of Georgia, UNITED STATES
                Author notes

                The authors declare no competing financial interests.

                Author information
                http://orcid.org/0000-0002-5667-3509
                http://orcid.org/0000-0002-8824-3124
                Article
                PPATHOGENS-D-17-01127
                10.1371/journal.ppat.1007049
                5953499
                29723291
                906189e3-2c73-4893-8229-74d69de95a70
                © 2018 Chida et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 26 May 2017
                : 23 April 2018
                Page count
                Figures: 8, Tables: 0, Pages: 28
                Funding
                Funded by: Research Committee of Molecular Pathogenesis and Therapies for Prion Disease and Slow Virus Infection, Research on Rare and Intractable Diseases, Health and Labour Sciences Research Commissions, The Ministry of Health, Labour and Welfare, Japan
                Award Recipient :
                Funded by: JSPS KAKENHI
                Award ID: 26293212
                Award Recipient :
                Funded by: JSPS KAKENHI
                Award ID: 15K15380
                Award Recipient :
                Funded by: Grant-in-Aid for Scientific Research on Innovative Areas (Brain Protein Aging and Dementia Control) from MEXT
                Award ID: 15H01560, 17H05701
                Award Recipient :
                Funded by: JSPS KAKENHI
                Award ID: 16K10029
                Award Recipient :
                Funded by: Cooperative Research Grant of the Institute for Enzyme Research, the University of Tokushima
                Award Recipient :
                This work was partly supported to SS by the Research Committee of Molecular Pathogenesis and Therapies for Prion Disease and Slow Virus Infection, Research on Rare and Intractable Diseases, Health and Labour Sciences Research Commissions, The Ministry of Health, Labour and Welfare, Japan ( http://www.mhlw.go.jp/english/), JSPS KAKENHI Grant Number 26293212 ( https://www.jsps.go.jp/english/e-grants/) and 15K15380 and 17K19661 ( https://www.jsps.go.jp/english/e-grants/), and Grant-in-Aid for Scientific Research on Innovative Areas (Brain Protein Aging and Dementia Control) Grant Number 15H01560, 17H05701 from MEXT ( http://www.mext.go.jp/), to JC by JSPS KAKENHI Grant Number 16K10029 ( https://www.jsps.go.jp/english/e-grants/), and to HM by a Cooperative Research Grant of the Institute for Enzyme Research, the University of Tokushima. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
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                Custom metadata
                vor-update-to-uncorrected-proof
                2018-05-15
                All relevant data are within the paper and its Supporting Information files.

                Infectious disease & Microbiology
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