39 results on '"Kawaoka, Yoshihiro"'
Search Results
2. Ebola Virus Infection Induces HCAR2 Expression Leading to Cell Death.
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Kuroda, Makoto, Halfmann, Peter J, and Kawaoka, Yoshihiro
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EBOLA virus disease ,GENE expression ,CELL death ,EBOLA virus ,VIRAL proteins - Abstract
Ebola virus (EBOV) induces cell death not only in infected permissive cells but also in nonpermissive, bystander cells by employing different mechanisms. Hydroxycarboxylic acid receptor 2 (HCAR2) has been reported to be involved in apoptotic cell death. We previously reported an increase in the expression of HCAR2 -specific mRNA in EBOV-infected individuals with fatal outcomes. Here, we report that infection with an EBOV lacking the VP30 gene (EBOVΔVP30) results in the upregulation of HCAR2 mRNA expression in human hepatocyte Huh7.0 cells stably expressing VP30. Transient overexpression of HCAR2 reduced the viability of Huh7.0 cells and human embryonic kidney cells. Phosphatidylserine externalization and cell membrane permeabilization by HCAR2 overexpression was also observed. Interestingly, coexpression of HCAR2 with EBOV VP40 further reduced cell viability in transfected cells compared to HCAR2 coexpression with other viral proteins. Our data suggest that HCAR2 may contribute to EBOV-induced cell death. [ABSTRACT FROM AUTHOR]
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- 2023
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3. An Antiviral Role for TRIM14 in Ebola Virus Infection.
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Kuroda, Makoto, Halfmann, Peter J, Thackray, Larissa B, Diamond, Michael S, Feldmann, Heinz, Marzi, Andrea, and Kawaoka, Yoshihiro
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EBOLA virus disease ,TYPE I interferons ,CYTOSKELETAL proteins ,EBOLA virus ,VIRAL proteins - Abstract
Ebola virus (EBOV) is a highly pathogenic virus that encodes 7 multifunctional structural proteins. Multiple host factors have been reported to interact with the EBOV proteins. Here, we found that tripartite motif-containing 14 (TRIM14), an interferon-stimulated gene that mediates cellular signaling pathways associated with type I interferon and inflammatory cytokine production, interacts with EBOV nucleoprotein to enhance interferon-β (IFN-β) and nuclear factor-κB (NF-κB) promotor activation. Moreover, TRIM14 overexpression reduced viral replication in an infectious but biologically contained EBOVΔVP30 system by approximately 10-fold without affecting viral protein expression. Furthermore, TRM14-deficient mice were more susceptible to mouse-adapted EBOV infection than wild-type mice. Our data suggest that TRIM14 is a host factor with anti-EBOV activity that limits EBOV pathogenesis. [ABSTRACT FROM AUTHOR]
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- 2023
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4. The Mucin-Like Domain of the Ebola Glycoprotein Does Not Impact Virulence or Pathogenicity in Ferrets.
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Halfmann, Peter J, Borisevich, Viktoriya, Levine, Corri B, Mire, Chad E, Fenton, Karla A, Geisbert, Thomas W, Kawaoka, Yoshihiro, and Cross, Robert W
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FERRET ,EBOLA virus ,VIRAL proteins ,DEATH rate ,ACUTE diseases - Abstract
Background Ebola virus (EBOV) is considered among the most dangerous viruses with case fatality rates approaching 90% depending on the outbreak. While several viral proteins (VPs) including VP24, VP35, and the soluble glycoprotein are understood to contribute to virulence, less is known of the contribution of the highly variable mucin-like domain (MLD) of EBOV. Early studies have defined a potential role in immune evasion of the MLD by providing a glycan shield to critical glycoprotein residues tied to viral entry. Nonetheless, little is known as to what direct role the MLD plays in acute EBOV disease (EVD). Methods We generated an infectious EBOV clone that lacks the MLD and assessed its virulence in ferrets compared with wild-type (WT) virus. Results No differences in growth kinetics were observed in vitro, nor were there any differences in time to death, viremia, or clinical picture in ferrets infected with recombinant EBOV (rEBOV)–WT or rEBOV-Δmucin. Conclusions The EBOV MLD does not play a critical role in acute pathogenesis of EVD in ferrets. [ABSTRACT FROM AUTHOR]
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- 2023
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5. Efficacy of favipiravir against influenza virus resistant to both baloxavir and neuraminidase inhibitors.
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Kiso, Maki, Yamayoshi, Seiya, and Kawaoka, Yoshihiro
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NEURAMINIDASE ,INFLUENZA viruses ,REVERSE genetics ,VIRUS diseases ,PUBLIC health ,VIRAL replication - Abstract
Objectives Widespread resistance of influenza viruses to neuraminidase (NA) inhibitor or polymerase inhibitor, baloxavir, is a major public health concern. The amino acid mutations R152K in NA and I38T in polymerase acidic (PA) are responsible for resistance to NA inhibitors and baloxavir, respectively. Methods We generated recombinant A(H1N1)pdm09 viruses possessing NA-R152K, PA-I38T or both mutations by using a plasmid-based reverse genetics system, characterized their virological properties in vitro and in vivo , and examined whether oseltamivir, baloxavir and favipiravir are effective against these mutant viruses. Results The three mutant viruses showed similar or superior growth kinetics and virulence to those of wild-type virus. Although oseltamivir and baloxavir blocked the replication of the wild-type virus in vitro , oseltamivir and baloxavir failed to suppress the replication of the NA-R152K and PA-I38T viruses in vitro , respectively. Mutant virus possessing both mutations grew in the presence of oseltamivir or baloxavir in vitro. Baloxavir treatment protected mice from lethal infection with wild-type or NA-R152K virus, but failed to protect mice from lethal infection with PA-I38T or PA-I38T/NA-R152K virus. Favipiravir treatment protected mice from lethal infection with all viruses tested, whereas oseltamivir treatment did not protect at all. Conclusions Our findings indicate that favipiravir should be used to treat patients with suspected baloxavir-resistant virus infection. [ABSTRACT FROM AUTHOR]
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- 2023
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6. Evolution of a globally unique SARS-CoV-2 Spike E484T monoclonal antibody escape mutation in a persistently infected, immunocompromised individual.
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Halfmann, Peter J, Minor, Nicholas R, III, Luis A Haddock, Maddox, Robert, Moreno, Gage K, Braun, Katarina M, Baker, David A, Riemersa, Kasen K, Prasad, Ankur, Alman, Kirsten J, Lambert, Matthew C, Florek, Kelsey, Bateman, Allen, Westergaard, Ryan, Safdar, Nasia, Andes, David R, Kawaoka, Yoshihiro, Fida, Madiha, Yao, Joseph D, and Friedrich, Thomas C
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SARS-CoV-2 ,IMMUNOCOMPROMISED patients ,MONOCLONAL antibodies ,SARS-CoV-2 Omicron variant - Abstract
Prolonged infections in immunocompromised individuals may be a source for novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants, particularly when both the immune system and antiviral therapy fail to clear the infection and enable within-host evolution. Here we describe a 486-day case of SARS-CoV-2 infection in an immunocompromised individual. Following monotherapy with the monoclonal antibody Bamlanivimab, the individual's virus acquired resistance, likely via the earliest known occurrence of Spike amino acid variant E484T. Recently, E484T has arisen again as a derivative of E484A in the Omicron Variant of Concern, supporting the hypothesis that prolonged infections can give rise to novel variants long before they become prevalent in the human population. [ABSTRACT FROM AUTHOR]
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- 2023
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7. Intranasal M2SR (M2-deficient Single Replication) H3N2 Influenza Vaccine Provides Enhanced Mucosal and Serum Antibodies In Adults.
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Eiden, Joseph, Fierro, Carlos, Schwartz, Howard, Adams, Mark, Ellis, Kimberly J, Aitchison, Roger, Herber, Renee, Hatta, Yasuko, Marshall, David, Moser, Michael J, Belshe, Robert, Greenberg, Harry, Coelingh, Kathleen, Kawaoka, Yoshihiro, Neumann, Gabriele, and Bilsel, Pamuk
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INFLUENZA vaccines ,CLINICAL trial registries ,IMMUNOGLOBULINS ,TISSUE culture ,ADULTS - Abstract
Background: We previously demonstrated that an intranasal dose of 108 TCID50 M2SR (M2-deficient single replication) influenza vaccine protected against highly drifted H3N2 influenza challenge in a subset of subjects who demonstrated ≥2-fold increase in microneutralization (MN) antibodies to Belgium2015 (the challenge strain) after vaccination. Here, we describe a phase 1b, observer-blinded, dose-escalation study demonstrating an increased proportion of responders with this signal of immune protection.Methods: Sero-susceptible subjects ages 18-49 years were randomized to receive two doses (108-109TCID50) of M2SR or placebo administered 28 days apart. Clinical specimens were collected before and after each dose. The primary objective was to demonstrate safety of M2SR vaccines (ClinicalTrials.gov number NCT03999554).Results: The vaccine was well-tolerated at all dose levels. Against Belgium2015, ≥ 2-fold increases in MN antibodies were noted among 40% (95% CI 24.9-56.7) of subjects following a single 108 TCID50 M2SR dose and among 80.6% (95% CI 61.4-92.3) after 109 dose (P < 0.001). A single 109 TCID50 dose of M2SR generated ≥4-fold HAI seroconversion against the vaccine strain in 71% (95% CI 52.0-85.8) of recipients. Mucosal and cellular immune responses were also induced.Conclusions: These results indicate that M2SR may provide substantial protection against infection with highly drifted strains of H3N2 influenza. [ABSTRACT FROM AUTHOR]- Published
- 2023
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8. Avian H7N9 influenza viruses are evolutionarily constrained by stochastic processes during replication and transmission in mammals.
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Braun, Katarina M, Haddock III, Luis A, Crooks, Chelsea M, Barry, Gabrielle L, Lalli, Joseph, Neumann, Gabriele, Watanabe, Tokiko, Imai, Masaki, Yamayoshi, Seiya, Ito, Mutsumi, Moncla, Louise H, Koelle, Katia, Kawaoka, Yoshihiro, and Friedrich, Thomas C
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AVIAN influenza A virus ,INFLUENZA A virus, H7N9 subtype ,MAMMAL evolution ,STOCHASTIC processes ,INFLUENZA A virus, H1N1 subtype ,MAMMALS - Abstract
H7N9 avian influenza viruses (AIVs) have caused over 1,500 documented human infections since emerging in 2013. Although wild-type H7N9 AIVs can be transmitted by respiratory droplets in ferrets, they have not yet caused widespread outbreaks in humans. Previous studies have revealed molecular determinants of H7N9 AIV host switching, but little is known about potential evolutionary constraints on this process. Here, we compare patterns of sequence evolution for H7N9 AIV and mammalian H1N1 viruses during replication and transmission in ferrets. We show that three main factors—purifying selection, stochasticity, and very narrow transmission bottlenecks—combine to severely constrain the ability of H7N9 AIV to effectively adapt to mammalian hosts in isolated, acute spillover events. We find rare evidence of natural selection favoring new, potentially mammal-adapting mutations within ferrets but no evidence of natural selection acting during transmission. We conclude that human-adapted H7N9 viruses are unlikely to emerge during typical spillover infections. Our findings are instead consistent with a model in which the emergence of a human-transmissible virus would be a rare and unpredictable, though highly consequential, 'jackpot' event. Strategies to control the total number of spillover infections will limit opportunities for the virus to win this evolutionary lottery. [ABSTRACT FROM AUTHOR]
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- 2023
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9. Immunological Correlates of Prevention of the Onset of Seasonal H3N2 Influenza.
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Okuda, Moe, Sakai-Tagawa, Yuko, Koga, Michiko, Koibuchi, Tomohiko, Kikuchi, Tadashi, Adachi, Eisuke, Ahyoung Lim, Lay, Yamamoto, Shinya, Yotsuyanagi, Hiroshi, Negishi, Kyota, Jubishi, Daisuke, Yamayoshi, Seiya, and Kawaoka, Yoshihiro
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INFLUENZA ,SEASONAL influenza ,VIRAL shedding ,ANTIBODY-dependent cell cytotoxicity ,INFLUENZA A virus, H3N2 subtype ,VIRUS diseases ,ENZYME-linked immunosorbent assay ,INFLUENZA vaccines ,PROTEINS ,IMMUNOMODULATORS ,SEASONS ,GLYCOSIDASES ,VIRAL antibodies ,INFLUENZA A virus, H1N1 subtype - Abstract
On influenza virus infection or vaccination, immune responses occur, including the production of antibodies with various functions that contribute to protection from seasonal influenza virus infection. In the current study, we attempted to identify the antibody functions that play a central role in preventing the onset of seasonal influenza by comparing the levels of several antibody titers for different antibody functions between 5 subclinically infected individuals and 16 patients infected with seasonal H3N2 virus. For antibody titers before influenza virus exposure, we found that the nAb titers and enzyme-linked immunosorbent assay titers against hemagglutinin and neuraminidase (NA) proteins in the subclinically infected individuals were significantly higher than those in the patients, whereas the NA inhibition titers and antibody-dependent cellular cytotoxicity activities did not significantly differ between subclinically infected individuals and infected patients. These results suggest that nAb and enzyme-linked immunosorbent assay titers against hemagglutinin and NA serve as correlates of symptomatic influenza infection. [ABSTRACT FROM AUTHOR]
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- 2022
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10. M2-Deficient Single-Replication Influenza Vaccine-Induced Immune Responses Associated With Protection Against Human Challenge With Highly Drifted H3N2 Influenza Strain.
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Eiden, Joseph, Volckaert, Bram, Rudenko, Oleg, Aitchison, Roger, Herber, Renee, Belshe, Robert, Greenberg, Harry, Coelingh, Kathleen, Marshall, David, Kawaoka, Yoshihiro, Neumann, Gabriele, and Bilsel, Pamuk
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INFLUENZA vaccines ,IMMUNOGLOBULINS ,INFLUENZA ,IMMUNITY ,RESEARCH funding ,VIRAL antibodies ,INFLUENZA A virus, H1N1 subtype ,INFLUENZA A virus, H3N2 subtype - Abstract
Background: Current influenza vaccines are strain specific and demonstrate low vaccine efficacy against H3N2 influenza disease, especially when vaccine is mismatched to circulating virus. The novel influenza vaccine candidate, M2-deficient single replication (M2SR), induces a broad, multi-effector immune response.Methods: A phase 2 challenge study was conducted to assess the efficacy of an M2SR vaccine expressing hemagglutinin and neuraminidase from A/Brisbane/10/2007 (Bris2007 M2SR H3N2; clade 1). Four weeks after vaccination, recipients were challenged with antigenically distinct H3N2 virus (A/Belgium/4217/2015, clade 3C.3b) and assessed for infection and clinical symptoms.Results: Adverse events after vaccination were mild and similar in frequency for placebo and M2SR recipients. A single dose of Bris2007 M2SR induced neutralizing antibody to the vaccine (48% of recipients) and challenge strain (27% of recipients). Overall, 54% of M2SR recipients were infected after challenge, compared with 71% of placebo recipients. The subset of M2SR recipients with a vaccine-induced microneutralization response against the challenge virus had reduced rates of infection after challenge (38% vs 71% of placebo recipients; P = .050) and reduced illness.Conclusions: Study participants with vaccine-induced neutralizing antibodies were protected against infection and illness after challenge with an antigenically distinct virus. This is the first demonstration of vaccine-induced protection against a highly drifted H3N2 challenge virus. [ABSTRACT FROM AUTHOR]- Published
- 2022
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11. SARS-CoV-2 Interference of Influenza Virus Replication in Syrian Hamsters.
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Halfmann, Peter J, Nakajima, Noriko, Sato, Yuko, Takahashi, Kenta, Accola, Molly, Chiba, Shiho, Fan, Shufang, Neumann, Gabriele, Rehrauer, William, Suzuki, Tadaki, Kawaoka, Yoshihiro, Halfmann, Peter, and Chibo, Shiho
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INFLUENZA A virus ,GOLDEN hamster ,INFLUENZA viruses ,VIRAL replication ,VIRUS diseases - Abstract
In hamsters, SARS-CoV-2 infection at the same time as or before H3N2 influenza virus infection resulted in significantly reduced influenza virus titers in the lungs and nasal turbinates. This interference may be correlated with SARS-CoV-2-induced expression of MX1. [ABSTRACT FROM AUTHOR]
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- 2022
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12. Pathogenesis of Influenza A(H7N9) Virus in Aged Nonhuman Primates.
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Fukuyama, Satoshi, Iwatsuki-Horimoto, Kiyoko, Kiso, Maki, Nakajima, Noriko, Gregg, Robert W, Katsura, Hiroaki, Tomita, Yuriko, Maemura, Tadashi, Lopes, Tiago Jose da Silva, Watanabe, Tokiko, Shoemaker, Jason E, Hasegawa, Hideki, Yamayoshi, Seiya, Kawaoka, Yoshihiro, and da Silva Lopes, Tiago Jose
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PATHOLOGY ,OLDER patients ,AVIAN influenza ,INFLUENZA ,VIRUS diseases ,H7N9 Influenza ,ORTHOMYXOVIRUS infections ,BIOLOGICAL models ,CYTOKINES ,RESEARCH ,INFLUENZA A virus ,LUNGS ,ANIMAL experimentation ,RESEARCH methodology ,MEDICAL cooperation ,EVALUATION research ,PRIMATES ,COMPARATIVE studies ,AGING - Abstract
The avian influenza A(H7N9) virus has caused high mortality rates in humans, especially in the elderly; however, little is known about the mechanistic basis for this. In the current study, we used nonhuman primates to evaluate the effect of aging on the pathogenicity of A(H7N9) virus. We observed that A(H7N9) virus infection of aged animals (defined as age 20-26 years) caused more severe symptoms than infection of young animals (defined as age 2-3 years). In aged animals, lung inflammation was weak and virus infection was sustained. Although cytokine and chemokine expression in the lungs of most aged animals was lower than that in the lungs of young animals, 1 aged animal showed severe symptoms and dysregulated proinflammatory cytokine and chemokine production. These results suggest that attenuated or dysregulated immune responses in aged animals are responsible for the severe symptoms observed among elderly patients infected with A(H7N9) virus. [ABSTRACT FROM AUTHOR]
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- 2020
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13. Baloxavir Marboxil Treatment of Nude Mice Infected With Influenza A Virus.
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Kiso, Maki, Yamayoshi, Seiya, Murakami, Jurika, and Kawaoka, Yoshihiro
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INFLUENZA A virus ,RESPIRATORY organs ,WEIGHT loss ,MICE ,NUDITY ,ANIMAL experimentation ,ANTIVIRAL agents ,COMPARATIVE studies ,DOSE-effect relationship in pharmacology ,HETEROCYCLIC compounds ,RESEARCH methodology ,MEDICAL cooperation ,PYRIDINE ,RESEARCH ,EVALUATION research ,ORTHOMYXOVIRUS infections - Abstract
Background: Immunocompromised patients infected with influenza virus require prolonged treatment with neuraminidase inhibitors, because these patients are not able to eradicate the virus from the respiratory tract, leading to the emergence of drug-resistant mutant viruses.Methods: In this study, we examined the efficacy of baloxavir marboxil in nude mice that were immunologically deficient.Results: Daily treatment with a suboptimal dose of baloxavir marboxil increased the survival time of the virus-infected nude mice but did not clear the virus from their respiratory organs, resulting in gradual body weight loss after termination of treatment.Conclusions: Despite the prolonged baloxavir marboxil treatment, few resistant mutants were detected. [ABSTRACT FROM AUTHOR]- Published
- 2020
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14. Predicting the Next Influenza Pandemics.
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Neumann, Gabriele and Kawaoka, Yoshihiro
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PANDEMICS , *INFLUENZA , *INFLUENZA A virus , *KNOWLEDGE gap theory , *IMMUNE response , *PREVENTION of epidemics , *INFLUENZA transmission , *INFLUENZA epidemiology , *ANIMALS , *AVIAN influenza , *BIOLOGICAL models , *EPIDEMIOLOGY , *GENOMES , *GLYCOSIDASES , *OLIGOSACCHARIDES , *POULTRY , *PROTEINS , *RISK assessment , *RNA , *SWINE , *INFLUENZA A virus, H1N1 subtype , *INFECTIOUS disease transmission - Abstract
Worldwide outbreaks of influenza (pandemics) are caused by influenza A viruses to which persons lack protective immune responses. Currently, we are unable to predict which influenza virus strains may cause a pandemic. In this article, we summarize some of the information that will be needed to better assess the pandemic potential of influenza viruses, and we discuss our current gaps in knowledge. [ABSTRACT FROM AUTHOR]
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- 2019
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15. The Induction of IL-1β Secretion Through the NLRP3 Inflammasome During Ebola Virus Infection.
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Halfmann, Peter, Hill-Batorski, Lindsay, and Kawaoka, Yoshihiro
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INFLAMMASOMES ,EBOLA virus disease ,INTERLEUKIN-18 ,INTERLEUKIN-1 ,CYTOKINES - Abstract
The inflammasome is part of the innate immune system that regulates the secretion of proinflammatory cytokines such as interleukin-1β (IL-1β). Ebola virus (EBOV) infection of monocytes and macrophages (primary target cells early during infection) leads to the production of proinflammatory cytokines; however, the mechanism behind the activation and release of these cytokines is not fully understood. Here, we demonstrate that EBOV infection leads to the activation of the NLRP3 inflammasome and the subsequent secretion of IL-1β and IL-18. This process is dependent on protease caspase-1, a component of the NLRP3 inflammasome complex, but is independent of virus replication. These findings may lead to the development of novel drugs that impede the pathogenesis of EBOV infection. [ABSTRACT FROM AUTHOR]
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- 2018
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16. Lung-Derived Exosomal miR-483-3p Regulates the Innate Immune Response to Influenza Virus Infection.
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Tadashi Maemura, Satoshi Fukuyama, Yukihiko Sugita, Lopes, Tiago J. S., Tomomi Nakao, Takeshi Noda, Yoshihiro Kawaoka, Maemura, Tadashi, Fukuyama, Satoshi, Sugita, Yukihiko, Nakao, Tomomi, Noda, Takeshi, and Kawaoka, Yoshihiro
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MICRORNA ,INFLUENZA viruses ,BRONCHOALVEOLAR lavage ,CYTOKINES ,INTERFERONS - Abstract
Exosomes regulate cell-cell communication by transferring functional proteins and RNAs between cells. Here, to clarify the function of exosomes during influenza virus infection, we characterized lung-derived exosomal microRNAs (miRNAs). Among the detected miRNAs, miR-483-3p was present at high levels in bronchoalveolar lavage fluid (BALF) exosomes during infection of mice with various strains of influenza virus, and miR-483-3p transfection potentiated gene expression of type I interferon and proinflammatory cytokine upon viral infection of MLE-12 cells. RNF5, a regulator of the RIG-I signaling pathway, was identified as a target gene of miR-483-3p. Moreover, we found that CD81, another miR-483-3p target, functions as a negative regulator of RIG-I signaling in MLE-12 cells. Taken together, this study indicates that BALF exosomal miRNAs may mediate the antiviral and inflammatory response to influenza virus infection. [ABSTRACT FROM AUTHOR]
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- 2018
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17. Combination Therapy With Neuraminidase and Polymerase Inhibitors in Nude Mice Infected With Influenza Virus.
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Maki Kiso, Lopes, Tiago J. S., Seiya Yamayoshi, Mutsumi Ito, Makoto Yamashita, Noriko Nakajima, Hideki Hasegawa, Neumann, Gabriele, Yoshihiro Kawaoka, Kiso, Maki, Yamayoshi, Seiya, Ito, Mutsumi, Yamashita, Makoto, Nakajima, Noriko, Hasegawa, Hideki, and Kawaoka, Yoshihiro
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INFLUENZA treatment ,INFLUENZA transmission ,DRUG resistance ,COMMUNICABLE diseases ,GENETIC mutation ,LABORATORY mice ,PREVENTION - Abstract
Background: Treatment of immunocompromised, influenza virus-infected patients with the viral neuraminidase inhibitor oseltamivir often leads to the emergence of drug-resistant variants. Combination therapy with compounds that target different steps in the viral life cycle may improve treatment outcomes and reduce the emergence of drug-resistant variants.Methods: Here, we infected immunocompromised nude mice with an influenza A virus and treated them with neuraminidase (oseltamivir, laninamivir) or viral polymerase (favipiravir) inhibitors, or combinations thereof.Results: Combination therapy for 28 days increased survival times compared with monotherapy, but the animals died after treatment was terminated. Mono- and combination therapies did not consistently reduce lung virus titers. Prolonged viral replication led to the emergence of neuraminidase inhibitor-resistant variants, although viruses remained sensitive to favipiravir. Overall, favipiravir provided greater benefit than neuraminidase inhibitors.Conclusions: Collectively, our data demonstrate that combination therapy in immunocompromised hosts increases survival times, but does not suppress the emergence of neuraminidase inhibitor-resistant variants. [ABSTRACT FROM AUTHOR]- Published
- 2018
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18. A Bivalent Vaccine Based on a PB2-Knockout Influenza Virus Protects Mice From Secondary Pneumococcal Pneumonia.
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Ryuta Uraki, Zhenyu Piao, Yukihiro Akeda, Kiyoko Iwatsuki-Horimoto, Maki Kiso, Makoto Ozawa, Kazunori Oishi, Yoshihiro Kawaoka, Uraki, Ryuta, Piao, Zhenyu, Akeda, Yukihiro, Iwatsuki-Horimoto, Kiyoko, Kiso, Maki, Ozawa, Makoto, Oishi, Kazunori, and Kawaoka, Yoshihiro
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GENE knockout ,INFLUENZA viruses ,PNEUMOCOCCAL pneumonia ,LABORATORY mice ,INFLUENZA vaccines ,INTRANASAL medication ,STREPTOCOCCUS pneumoniae ,RECOMBINANT viruses ,PNEUMONIA prevention ,MIXED infections ,ANIMAL experimentation ,BACTERIAL proteins ,BIOLOGICAL models ,GENETIC techniques ,MICE ,ORTHOMYXOVIRUSES ,PNEUMOCOCCAL vaccines ,PROTEINS ,DISEASE complications ,ORTHOMYXOVIRUS infections ,PREVENTION - Abstract
Background: Secondary bacterial infections after influenza can be a serious problem, especially in young children and the elderly, yet the efficacy of current vaccines is limited. Earlier work demonstrated that a replication-incompetent PB2-knockout (PB2-KO) influenza virus possessing a foreign gene in the coding region of its PB2 segment can serve as a platform for a bivalent vaccine.Methods: In the current study, we generated the PB2-KO virus expressing pneumococcal surface protein A (PspA), PB2-KO-PspA virus, the replication of which is restricted to PB2-expressing cells. We then examined the protective efficacy of intranasal immunization with this virus as a bivalent vaccine in a mouse model.Results: High levels of influenza virus-specific and PspA-specific antibodies were induced in the serum and airways of immunized mice. The intranasally immunized mice were protected from lethal doses of influenza virus or Streptococcus pneumoniae. These mice were also completely protected from secondary pneumococcal pneumonia after influenza virus infection.Conclusions: These findings indicate that our recombinant influenza virus serves as a novel and powerful bivalent vaccine against primary and secondary pneumococcal pneumonia as well as influenza. [ABSTRACT FROM AUTHOR]- Published
- 2015
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19. A Syrian Golden Hamster Model Recapitulating Ebola Hemorrhagic Fever.
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Ebihara, Hideki, Zivcec, Marko, Gardner, Donald, Falzarano, Darryl, LaCasse, Rachel, Rosenke, Rebecca, Long, Dan, Haddock, Elaine, Fischer, Elizabeth, Kawaoka, Yoshihiro, and Feldmann, Heinz
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VIRAL disease treatment ,GOLDEN hamster ,EBOLA virus disease ,VIRAL vaccines ,DRUG efficacy ,LABORATORY rodents - Abstract
Ebola hemorrhagic fever (EHF) is a severe viral infection for which no effective treatment or vaccine is currently available. While the nonhuman primate (NHP) model is used for final evaluation of experimental vaccines and therapeutic efficacy, rodent models have been widely used in ebolavirus research because of their convenience. However, the validity of rodent models has been questioned given their low predictive value for efficacy testing of vaccines and therapeutics, a result of the inconsistent manifestation of coagulopathy seen in EHF. Here, we describe a lethal Syrian hamster model of EHF using mouse-adapted Ebola virus. Infected hamsters displayed most clinical hallmarks of EHF, including severe coagulopathy and uncontrolled host immune responses. Thus, the hamster seems to be superior to the existing rodent models, offering a better tool for understanding the critical processes in pathogenesis and providing a new model for evaluating prophylactic and postexposure interventions prior to testing in NHPs. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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20. Differences in Cytokine Production in Human Macrophages and in Virulence in Mice Are Attributable to the Acidic Polymerase Protein of Highly Pathogenic Influenza A Virus Subtype H5N1.
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Sakabe, Saori, Takano, Ryo, Nagamura-Inoue, Tokiko, Yamashita, Naohide, Nidom, Chairul A., Quynh Le, Mai thi, Iwatsuki-Horimoto, Kiyoko, and Kawaoka, Yoshihiro
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CYTOKINES ,MACROPHAGES ,POLYMERASES ,INFLUENZA A virus, H1N1 subtype ,GENE expression ,CELL growth ,LABORATORY mice - Abstract
Background. The pathogenesis of influenza A virus subtype H5N1 (hereafter, “H5N1”) infection in humans is not completely understood, although hypercytokinemia is thought to play a role. We previously reported that most H5N1 viruses induce high cytokine responses in human macrophages, whereas some H5N1 viruses induce only a low level of cytokine production similar to that induced by seasonal viruses.Methods. To identify the viral molecular determinants for cytokine induction of H5N1 viruses in human macrophages, we generated a series of reassortant viruses between the high cytokine inducer A/Vietnam/UT3028II/03 clone 2 (VN3028IIcl2) and the low inducer A/Indonesia/UT3006/05 (IDN3006) and evaluated cytokine expression in human macrophages.Results. Viruses possessing the acidic polymerase (PA) gene of VN3028IIcl2 exhibited high levels of hypercytokinemia-related cytokine expression in human macrophages, compared with IDN3006, but showed no substantial differences in viral growth in these cells. Further, the PA gene of VN3028IIcl2 conferred enhanced virulence in mice.Conclusions. These results demonstrate that the PA gene of VN3028IIcl2 affects cytokine production in human macrophages and virulence in mice. These findings provide new insights into the cytokine-mediated pathogenesis of H5N1 infection in humans. [ABSTRACT FROM AUTHOR]
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- 2013
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21. Molecular Mechanisms Underlying Oseltamivir Resistance Mediated by an I117V Substitution in the Neuraminidase of Subtype H5N1 Avian Influenza A Viruses.
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Takano, Ryo, Kiso, Maki, Igarashi, Manabu, Le, Quynh Mai, Sekijima, Masakazu, Ito, Kimihito, Takada, Ayato, and Kawaoka, Yoshihiro
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MOLECULAR biology ,OSELTAMIVIR ,DRUG resistance in microorganisms ,NEURAMINIDASE ,VIRAL disease treatment ,H5N1 Influenza ,INFLUENZA viruses ,CHEMICAL inhibitors - Abstract
Background. The neuraminidase (NA) inhibitor oseltamivir is widely used to treat patients infected with influenza viruses. An Ile-to-Val change at position 117 in influenza A virus subtype H5N1 NA (NA-I117V) confers a reduction in susceptibility to oseltamivir carboxylate. However, the in vivo relevance and molecular basis of the decreased sensitivity mediated by this mutation are poorly understood.Methods. We created single-point-mutant viruses with 3 genetically different backgrounds (ie, 1 belonging to clade 1 and 2 belonging to clade 2.3.4) and evaluated the effects of the I117V mutation on oseltamivir susceptibility in vitro, in vivo, and in silico.Results. The NA-I117V mutation conferred a slight reduction in susceptibility to oseltamivir in vitro (1.3- to 6.3-fold changes), although it did not substantially compromise NA enzymatic activity. Mice infected with I117V virus exhibited reduced susceptibility to oseltamivir and decreased survival in 2 of 3 virus pairs tested. Molecular dynamics simulations revealed that I117V caused the loss of hydrogen bonds between an arginine at position 118 and the carboxyl group of oseltamivir, leading to a lower binding affinity for oseltamivir.Conclusions. Our findings provide new insight into the mechanism of NA-I117V–mediated oseltamivir resistance in highly pathogenic H5N1 avian influenza viruses. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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22. Tissue-specific subnetworks and characteristics of publicly available human protein interaction databases.
- Author
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Lopes, Tiago J. S., Schaefer, Martin, Shoemaker, Jason, Matsuoka, Yukiko, Fontaine, Jean−Fred, Neumann, Gabriele, Andrade-Navarro, Miguel A., Kawaoka, Yoshihiro, and Kitano, Hiroaki
- Subjects
PROTEIN-protein interactions ,GENE expression ,TISSUE engineering ,BIOINFORMATICS ,CYTOLOGY ,DATABASES ,PREDICTION models - Abstract
Motivation: Protein-protein interaction (PPI) databases are widely used tools to study cellular pathways and networks; however, there are several databases available that still do not account for cell type-specific differences. Here, we evaluated the characteristics of six interaction databases, incorporated tissue-specific gene expression information and finally, investigated if the most popular proteins of scientific literature are involved in good quality interactions.Results: We found that the evaluated databases are comparable in terms of node connectivity (i.e. proteins with few interaction partners also have few interaction partners in other databases), but may differ in the identity of interaction partners. We also observed that the incorporation of tissue-specific expression information significantly altered the interaction landscape and finally, we demonstrated that many of the most intensively studied proteins are engaged in interactions associated with low confidence scores. In summary, interaction databases are valuable research tools but may lead to different predictions on interactions or pathways. The accuracy of predictions can be improved by incorporating datasets on organ- and cell type-specific gene expression, and by obtaining additional interaction evidence for the most ‘popular’ proteins.Contact: kitano@sbi.jpSupplementary information: Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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23. Contribution of Sec61&agr; to the Life Cycle of Ebola Virus.
- Author
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Iwasa, Ayaka, Halfmann, Peter, Noda, Takeshi, Oyama, Masaaki, Kozuka-Hata, Hiroko, Watanabe, Shinji, Shimojima, Masayuki, Watanabe, Tokiko, and Kawaoka, Yoshihiro
- Subjects
VIRAL proteins ,EBOLA virus ,VIRAL replication ,CYTOSKELETAL proteins ,VIRAL genomes ,GENE expression ,PLASMID genetics ,INTERFERONS - Abstract
Background. Similar to other viruses, the viral proteins of Ebola virus (EBOV) interact with a variety of host proteins for its replication. Of the 7 structural proteins encoded in the EBOV genome, VP24 is the smallest and is multifunctional. Methods. To identify host factors that interact with VP24 and are required for EBOV replication, we transfected 293 cells with plasmid expressing FLAG- and HA-tagged VP24, immunoprecipitated the host proteins that bound to VP24, and analyzed the immunoprecipitants with use of mass spectrometry. Results. Of the 68 candidate host proteins identified, we selected Sec61&agr; because of its similar intracellular localization to that of VP24 (ie, perinuclear region), its involvement in various biological functions, and its roles in pathogenesis, such as type 2 diabetes and hepatosteatosis, and investigated its possible role in the EBOV life cycle. Our results suggest that Sec61&agr; is not involved in EBOV entry, interferon antagonism by VP24, nucleocapsid formation, or budding. However, Sec61&agr; colocalized with VP24 contributed to the ability of VP24 to inhibit EBOV genome transcription and reduced the polymerase activity of EBOV. Conclusions. The present study indicates that Sec61&agr; is a host protein involved in EBOV replication, specifically in EBOV genome transcription and replication. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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- View/download PDF
24. The Ebolavirus VP24 Protein Blocks Phosphorylation of p38 Mitogen-Activated Protein Kinase.
- Author
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Halfmann, Peter, Neumann, Gabriele, and Kawaoka, Yoshihiro
- Subjects
VIRAL proteins ,EBOLA virus ,PHOSPHORYLATION ,MITOGEN-activated protein kinases ,INTERFERONS ,CELLULAR signal transduction ,HELA cells - Abstract
Type I interferon (IFN) signaling is mediated through several signaling pathways, including the Janus kinase and signal transducer and activator (JAK-STAT) and p38 mitogen-activated protein (MAP) kinase pathways. The VP24 protein of Ebolavirus is an IFN antagonist, blocking type I IFN signaling through the JAK-STAT pathway. Here, we show that, in 293 cells, VP24 also interferes with the p38 MAP kinase pathway by blocking IFN-&bgr;-stimulated phosphorylation of p38-&agr;. Similar inhibition was not observed in HeLa cells, suggesting cell type-specific differences in signal transduction. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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25. sGP Serves as a Structural Protein in Ebola Virus Infection.
- Author
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Iwasa, Ayaka, Shimojima, Masayuki, and Kawaoka, Yoshihiro
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CYTOSKELETAL proteins ,EBOLA virus disease ,GLYCOPROTEINS ,AMINO acids ,EBOLA virus ,VIRAL proteins ,GENE expression - Abstract
Background sGP, which is perceived as nonstructural, secretory glycoprotein, shares 295 amino acids at its N-terminal with GP
1,2 , which include the specific residue necessary to interact with GP2 . In the present study, we tested whether the sGP protein of Zaire ebolavirus (ZEBOV) could substitute for GP1 and form a complex with GP2 , thus serving as a structural protein. Methods. We expressed ZEBOV GP1,2 , VP40, and NP proteins, together with sGP protein, from expression plasmids and examined the resultant virus-like particles by using Western blot. Cells expressing GP2 in combination with either GP2 or sGP were analyzed by using flow cytometry with the KZ52 antibody, which recognizes a GP1,2 conformational epitope. A VSV pseudotype, VSVDG*, which expresses a GFP reporter gene instead of the G protein, was used to produce pseudotyped viruses encoding sGP and variants of GP to test the contribution of sGP to infectivity. Results. Western blot and flow cytometric analyses suggested the existence of a covalently linked sGP-GP2 molecule. VSVDG*(sGP + GP2 ) and VSVDG*(GP1,2 ) infected Vero E6 cells and were neutralized by the KZ52 antibody. Overexpression of sGP reduced the titer of VSVDG*(GP1,2 ). Conclusions. ZEBOV sGP can substitute for GP1 , forming a sGP-GP2 complex and conferring infectivity. Our studies suggest a novel role for sGP as a structural protein. [ABSTRACT FROM AUTHOR]- Published
- 2011
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26. Identification of Amino Acids in Marburg Virus VP40 That Are Important for Virus-Like Particle Budding.
- Author
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Makino, Akiko, Yamayoshi, Seiya, Shinya, Kyoko, Noda, Takeshi, and Kawaoka, Yoshihiro
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MARBURG virus ,AMINO acids ,EXTRACELLULAR matrix proteins ,PROMOTERS (Genetics) ,GENETIC mutation ,BIOACCUMULATION ,ALANINE - Abstract
The matrix protein VP40 of Marburg virus promotes the formation and release of virus-like particles (VLPs). Marburg virus VP40 interacts with cellular Tsg101 via its L domain motif; however, mutation of this motif does not affect VLP budding or the accumulation of VP40 in multivesicular bodies (MVBs), which are platforms for virus particle formation. To identify regions of Marburg virus VP40 that are important for VLP budding, we examined deletion mutants and alanine-scanning mutants at the N- and C-terminus of VP40 for their involvement in VLP budding. VLPs were not detected in the presence of alanine-replacementmutants at Ile39 and Thr40, and the level of VLP budding for the alanine mutant at Asn297 was decreased. Moreover, these mutants did not accumulate in MVBs. Our results suggest the involvement of a novel host factor(s) in VLP budding and VP40 transport to MVBs. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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27. The Importance of the NP: VP35 Ratio in Ebola Virus Nucleocapsid Formation.
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Noda, Takeshi, Kolesnikova, Larissa, Becker, Stephan, and Kawaoka, Yoshihiro
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VIRAL proteins ,EBOLA virus disease ,RNA polymerases ,NUCLEOCAPSIDS ,GENE expression ,ULTRACENTRIFUGATION ,VIRAL replication - Abstract
Ebola virus VP35 is a cofactor of the viral RNA polymerase complex and, together with NP and VP24, is an essential component for nucleocapsid formation. In the present study, we examined the interactions between VP35 and NP and found that VP35 interacts with helical NP-RNA complexes through the C-terminus of NP. We also found that coexpression of excess VP35 with NP reduced the yields of NP-RNA complexes purified by CsCl gradient ultracentrifugation and inhibited the formation of the NP-induced inclusion bodies that typically form in Ebola virus-infected cells. These findings suggest that the NP to VP35 ratio is important in the Ebola virus replication cycle and advance our knowledge of nucleocapsid morphogenesis. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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- View/download PDF
28. Frequency of Drug-resistant Viruses and Virus Shedding in Pediatric Influenza Patients Treated With Neuraminidase Inhibitors.
- Author
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Tamura, Daisuke, Sugaya, Norio, Ozawa, Makoto, Takano, Ryo, Ichikawa, Masataka, Yamazaki, Masahiko, Kawakami, Chiharu, Shimizu, Hideaki, Uehara, Ritei, Kiso, Maki, Kawakami, Eiryo, Mitamura, Keiko, and Kawaoka, Yoshihiro
- Subjects
INFLUENZA treatment ,JUVENILE diseases ,NEURAMINIDASE ,RESPIRATORY infections ,HEMAGGLUTININ - Abstract
Background. Although influenza virus resistance to the neuraminidase inhibitor zanamivir is reported less frequently than is resistance to the neuraminidase inhibitor oseltamivir in clinical settings, it is unknown whether this difference is due to the limited use of zanamivir or to an inherent property of the drug. We therefore compared the prevalence of drug-resistant viruses and virus shedding in seasonal influenza virus-infected children treated with either oseltamivir or zanamivir. Methods. Clinical specimens (throat or nasal swab) were collected from a total of 144 pediatric influenza patients during the 2005-2006, 2006-2007, 2007-2008, and 2008-2009 influenza seasons. Neuraminidase inhibitor-resistant mutants were detected among the isolated viruses by sequencing the viral hemagglutinin and neuraminidase genes. Sensitivity of the viruses to neuraminidase inhibitors was tested by neuraminidase inhibition assay. Results. In oseltamivir- or zanamivir-treated influenza patients who were statistically comparable in their age distribution, vaccination history, and type or subtype of virus isolates, the virus-shedding period in zanamivirtreated patients was significantly shorter than that in oseltamivir-treated patients. Furthermore, the frequency of zanamivir-resistant viruses was significantly lower than that of oseltamivir-resistant viruses. Conclusion. In comparison with treatment with oseltamivir, treatment of pediatric patients with zanamivir resulted in the emergence of fewer drug-resistant influenza viruses and a shorter virus-shedding period. We conclude that zanamivir shows promise as a better therapy for pediatric influenza patients. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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29. Comparison of the Clinical Effectiveness of Oseltamivir and Zanamivir against Influenza Virus Infection in Children.
- Author
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Sugaya, Norio, Tamura, Daisuke, Yamazaki, Masahiko, Ichikawa, Masataka, Kawakami, Chiharu, Kawaoka, Yoshihiro, and Mitamura, Keiko
- Subjects
ANTIVIRAL agents ,DRUG efficacy ,INFLUENZA viruses ,INFLUENZA A virus ,VIRAL diseases in children ,COMMUNICABLE diseases ,RESPIRATORY infections ,INFECTION in children ,JUVENILE diseases - Abstract
Background. We compared the clinical effectiveness of oseltamivir and zanamivir in children with influenza A (H1N1) virus, influenza A (H3N2) virus, and influenza B virus infections. Methods. Total febrile period and the duration of fever after the start of treatment were compared between an oseltamivir-treated group (mean age, 8.9 years; range, 4.0-15.9 years) and a zanamivir-treated group (mean age, 10.0 years; range, 4.0-15.7 years) in the pediatric outpatient clinics of our hospitals. Oseltamivir was used to treat 91 children with influenza A (H3N2) infection and 24 children with influenza A (H1N1) infection. Zanamivir was used to treat 35 children with influenza A (H3N2) infection and 12 children with influenza A (H1N1) infection. Oseltamivir was also used to treat 128 children with influenza B virus infection, and zanamivir was used to treat 59 with influenza B virus infection. Results. There was no statistically significant difference in total febrile period or duration of fever after the start of treatment between the oseltamivir-treated group and the zanamivir-treated group of children with influenza A (H3N2) infection (mean duration of febrile period, 2.40 days vs. 2.39 days; mean duration of fever after the start of treatment, 1.35 days vs. 1.40 days), influenza A (H1N1) (mean duration of febrile period, 2.60 days vs. 2.46 days; mean duration of fever after the start of treatment, 1.79 days vs, 1.54 days), or influenza B (mean duration of febrile period, 2.95 days vs. 2.84 days; mean duration of fever after the start of treatment, 1.86 days vs. 1.67 days). Oseltamivir was more effective against influenza A (H3N2) than against influenza A (H1N1) or influenza B. Conclusions. Oseltamivir and zanamivir were equally effective in reducing the febrile period of children with influenza A (H1N1), influenza A (H3N2), and influenza B virus infection. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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30. Ebola Virus (EBOV) VP24 Inhibits Transcription and Replication of the EBOV Genome.
- Author
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Watanabe, Shinji, Noda, Takeshi, Halfmann, Peter, Jasenosky, Luke, and Kawaoka, Yoshihiro
- Subjects
EBOLA virus disease ,HEMORRHAGIC fever ,VIRUS diseases ,VIRAL genomes ,MICROBIAL genomes ,LUCIFERASES ,OXIDOREDUCTASES ,MESSENGER RNA ,GENETICS - Abstract
The roles of Ebola virus (EBOV) VP24 in nucleocapsid (NC) formation and the effect of VP24 on transcription and replication of the viral genome during NC formation remain unknown. We therefore examined the effect of VP24 on the expression of a reporter gene (luciferase), viral RNA, and messenger RNA from the EBOV minigenome. VP24 inhibited the expression of luciferase and both RNAs in a dose-dependent manner, suggesting that VP24 inhibits transcription and replication of the EBOV genome. By contrast, FLAG-tagged VP24, which cannot support NC-like structure formation, did not appreciably decrease luciferase expression, indicating that association of VP24 with the ribonucleoprotein complex is required for inhibition. Glycoprotein and VP40 did not affect VP24-mediated inhibition of transcription and replication. Together, these results suggest that VP24 reduces transcription and replication of the EBOV genome by direct association with the ribonucleoprotein complex in virus-infected cells. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
31. Epitopes Required for Antibody-Dependent Enhancement of Ebola Virus Infection.
- Author
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Takada, Ayato, Ebihara, Hideki, Feldmann, Heinz, Geisbert, Thomas W., and Kawaoka, Yoshihiro
- Subjects
EBOLA virus disease ,HEMORRHAGIC fever ,VIRUS diseases ,COMMUNICABLE diseases ,EPITOPES ,PREVENTIVE medicine ,VACCINATION ,GLYCOPROTEINS ,IMMUNOGLOBULIN G - Abstract
We have shown that antibody-dependent enhancement (ADE) of infection with Zaire Ebola virus (ZEBOV) is mediated by interaction of virus-specific antibodies with Fc receptors or complement component C1q and its receptors in vitro. ADE activities of the antisera to the viral glycoprotein (GP) were virus species specific and were primarily correlated with immunoglobulin (Ig) G2a and IgM levels but not with IgG1 levels. Interestingly, compared with ZEBOV, Reston Ebola virus (REBOV) had substantially weaker potential to induce ADE antibodies. Using monoclonal antibodies, we identified ZEBOV-specific ADE epitopes. To confirm epitope specificity, we constructed a chimeric ZEBOV GP, the ADE epitopes of which were replaced with the corresponding regions of REBOV GP. We found that mouse antisera to the chimeric ZEBOV GP showed less potential to induce ADE activity than did mouse antisera to wild-type ZEBOV GP, although they retained neutralizing activity. These data suggest that GP lacking the ADE-inducing epitopes may crease the potential of GP as a vaccine antigen. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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32. Lower Clinical Effectiveness of Oseltamivir against Influenza B Contrasted with Influenza A Infection in Children.
- Author
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Sugaya, Norio, Mitamura, Keiko, Yamazaki, Masahiko, Tamura, Daisuke, Ichikawa, Masataka, Kimura, Kazuhiro, Kawakami, Chiharu, Kiso, Maki, Ito, Mutsumi, Hatakeyama, Shuji, and Kawaoka, Yoshihiro
- Subjects
VIRUS diseases ,INFLUENZA ,RESPIRATORY infections ,THERAPEUTICS ,INFECTION in children ,MICROORGANISMS - Abstract
Background. Recently, many Japanese physicians have claimed that oseltamivir is less effective in children with influenza B virus infection. This study assesses the effectiveness of oseltamivir against influenza A (H3N2) and influenza B in children on the basis of the duration of febrile illness. Methods. We used oseltamivir to treat 127 children with influenza A (H3N2; mean age, 6.97 years [range, 1–15 years]) and 362 children with influenza B (mean age, 5.16 years [range, 1–15 years]) in outpatient clinics. The duration of fever after the start of oseltamivir therapy was compared in the influenza A group and the influenza B group. Results. The mean duration of fever after the start of oseltamivir therapy was significantly greater in the influenza B group than in the influenza A (H3N2) group (2.18 days vs. 1.31 days, respectively; P<.001 ). The difference was marked in young children (1-5 years old; 2.37 days for the influenza B group vs. 1.42 days for the influenza A group) but was not significant among older children (11–15 years old). The 50% inhibitory concentration of oseltamivir against influenza B virus was nmol/L and was substantially higher than that for 75.4±41.7 type A (H3N2) virus ( nmol/L). Only 3 (1.6%) of 192 influenza B viruses were resistant to oseltamivir. 0.3±0.1 Conclusions. Oseltamivir is much less effective against influenza B virus infection in young children, probably because of the low sensitivity of influenza B viruses to oseltamivir. The effectiveness of oseltamivir against influenza B is influenced by age and host immunity. A few oseltamivir-resistant influenza B strains were isolated before the start of oseltamivir therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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33. Gargle Lavage as a Safe and Sensitive Alternative to Swab Samples to Diagnose COVID-19: A Case Report in Japan.
- Author
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Saito, Makoto, Adachi, Eisuke, Yamayoshi, Seiya, Koga, Michiko, Iwatsuki-Horimoto, Kiyoko, Kawaoka, Yoshihiro, and Yotsuyanagi, Hiroshi
- Subjects
MOUTHWASHES ,PHYSIOLOGIC salines ,COVID-19 - Published
- 2020
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34. High Frequency of Resistant Viruses Harboring Different Mutations in Amantadine-Treated Children with Influenza.
- Author
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Shiraishi, Kyoko, Mitamura, Keiko, Sakai-Tagawa, Yuko, Goto, Hideo, Sugaya, Norio, and Kawaoka, Yoshihiro
- Subjects
AMANTADINE ,GENETIC mutation ,RNA viruses ,REVERSE transcriptase ,POLYMERASE chain reaction ,PLASMIDS - Abstract
Clinical samples from 15 amantadine-treated children were collected serially -- before, during, and/or after treatment -- and were studied to determine the actual prevalence, timing, and clinical implications of M2 mutational events. After viral RNA extraction and reverse-transcriptase polymerase chain reaction amplification of the viral RNA encoding the M2 protein, the products were cloned into plasmids, and their sequences were determined. Five mutations known to confer amantadine resistance in clinical samples were identified in 12 (80%) of 15 evaluable patients, and 9 patients had > (2-4) mutant virus. The pattern of emergence of mutant strains was clarified from the study of 6 patients with at least 4 serial samples. Although viruses with M2 mutations tended to become the dominant populations, in 2 cases, wild-type viruses became dominant after decreasing to low levels. These results suggest that resistant viruses emerge in a much higher proportion of amantadine-treated patients than has been suggested by previous studies. [ABSTRACT FROM AUTHOR]
- Published
- 2003
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35. Interspecies Transmission and Reassortment of Influenza A Viruses in Pigs and Turkeys in the United States.
- Author
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Wright, Stephen M., Kawaoka, Yoshihiro, Sharp, Gerold B., Senne, Dennis A., and Webster, Robert G.
- Published
- 1992
- Full Text
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36. 2748. Single Intranasal (IN) Dose of M2SR (M2-Deficient Single Replication) Live Influenza Vaccine Protects Adults Against Subsequent Challenge with a Substantially Drifted H3N2 Strain.
- Author
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Eiden, Joseph, Volckaert, Bram, Rudenko, Oleg, Ellis, Ruth, Aitchison, Roger, Herber, Renee, Belshe, Robert, Greenberg, Harry, Coelingh, Kathleen, Kawaoka, Yoshihiro, Neumann, Gabriele, and Bilsel, Pamuk
- Subjects
INFLUENZA vaccines ,VIRAL vaccines ,VACCINE effectiveness ,VIRAL load ,RESPIRATORY infections - Abstract
Background Demonstration of protection by a M2SR (M2 deficient Single Replication) monovalent H3N2 vaccine was assessed in a phase 2a clinical trial in which the challenge virus was substantially drifted from the vaccine. M2SR is an investigational, live virus vaccine containing hemagglutinin (HA) and neuraminidase (NA) selected from targeted Type A influenza strains. M2SR undergoes only a single round of infection in the respiratory epithelium but evokes an immune response profile similar to wild-type influenza virus and protects ferrets against both homologous and heterologous influenza variants. Methods A blinded, randomized, placebo-controlled human challenge study (EudraCT #: 2017-004971-30) was conducted with M2SR containing HA and NA from A/Brisbane/10/2007 (H3N2). 18–55-year-old subjects received 1 IN dose of saline or 10
8 TCID50 of vaccine. 4 weeks later, 99 subjects were challenged IN with 106 TCID50 H3N2 A/Belgium/4217/2015 (Figures 1 and 2). Results Adverse events (AE) were similar between placebo (N = 51) and M2SR recipients (N = 48) during the 28 days after immunization. After challenge with A/Belgium/4217/2015, 35% of M2SR recipients experienced influenza infection and illness, compared with 49% of placebo subjects (Figure 3). An 18% reduction in viral load was noted after challenge for M2SR subjects. Serum microneutralization response to vaccine was detected in 54% of M2SR subjects (vs. 0/51 placebo subjects), and among these subjects a 34% reduction in viral load and 51% reduction in symptom scores was noted after challenge vs placebo. Among the 29% of subjects with post-vaccine response to both vaccine and challenge strains, a 62% reduction in viral load and 56% reduction in symptom scores was noted after challenge with highly drifted H3N2 (Figure 4). Conclusion One dose of M2SR protected healthy adults against influenza infection and illness with a highly drifted challenge strain. This is believed to be the first study to demonstrate protection against challenge with an influenza strain substantially different from the vaccine and indicates potential for improved breadth of protection by M2SR compared with current vaccines. The mild vaccine AE profile supports clinical trials of additional dose levels and regimens to enhance drifted strain protection by M2SR. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]- Published
- 2019
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37. Marburg and Ebola Viruses – Marking 50 Years Since Their Discovery.
- Author
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Becker, Stephan, Feldmann, Heinz, Geisbert, Tom, and Kawaoka, Yoshihiro
- Subjects
EBOLA virus ,MARBURG virus ,FILOVIRIDAE ,BIOTERRORISM ,VACCINES - Abstract
The article informs that Marburg and Ebola Viruses have marked 50 years of their discovery. Topics include family of viruses Filoviridae, comprising the genera Marburgvirus, concerns regarding bioterrorism seeking countermeasures such as diagnostics, vaccines, and research community with interest in all aspects of filoviruses.
- Published
- 2018
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38. Filoviruses: Recent Advances and Future Challenges.
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Feldmann, Heinz, Thomas Geisbert, and Kawaoka, Yoshihiro
- Subjects
VIRUSES ,GENETIC vectors ,EBOLA virus disease ,VIRUS diseases ,MARBURG virus ,RHABDOVIRUSES ,RNA viruses ,COMMUNICABLE diseases ,EPIDEMICS - Abstract
The article discusses the recent advances and future challenges in dealing with filoviruses, previewing the papers published within the issue. According to the authors, the fact that Marburg and Ebola viruses are highly pathogenic for humans and nonhuman primates makes these viruses feared pathogens worldwide today. They note that the collection of papers in within the issue focuses on these viruses. Among others, the papers bring up to date information on the mechanisms of how filoviruses emerge and re-emerge, and the molecular mechanisms of how these viruses replicate and cause disease.
- Published
- 2007
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39. Dedication: Jim Orzechowski (1944-2003) and Michael Kiley (1942-2004).
- Author
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Feldmann, Heinz, Geisbert, Thomas, Kawaoka, Yoshihiro, and Johnson, Karl M.
- Subjects
DEDICATIONS ,COMMUNICABLE diseases ,MEDICAL microbiology ,BIOSAFETY ,UNIVERSITIES & colleges ,PUBLIC health - Abstract
The article announces that the November 2007 supplemental issue of the "Journal of Infectious Diseases" is dedicated to the memories of Jim Orzechowski (1944-2003) and Michael Kiley (1942-2004). Orzechowski and Kiley were instrumental in bringing biosafety level 4 (BSL4) biocontainment into the 21st century. Orzechowski received a degree in architecture at the North Dakota State University in 1970, while Kiley received his degree at the Notre Dame University. Significant information relative to the life and career of these individuals are provided.
- Published
- 2007
- Full Text
- View/download PDF
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