38 results on '"Hideki Hasegawa"'
Search Results
2. A Numerical Method of Tracing a Vortical Axis along Local Topological Axis Line.
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Katsuyuki Nakayama and Hideki Hasegawa
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NUMERICAL analysis , *TOPOLOGICAL dynamics , *EIGENVECTORS , *EIGENVALUES , *TOPOLOGY - Abstract
A new numerical method is presented to trace or identify a vortical axis in flow, which is based on Galilean invariant flow topology. We focus on the local flow topology specified by the eigenvalues and eigenvectors of the velocity gradient tensor, and extract the axis component from its flow trajectory. Eigen-vortical-axis line is defined from the eigenvector of the real eigenvalue of the velocity gradient tensor where the tensor has the conjugate complex eigenvalues. This numerical method integrates the eigen-vortical-axis line and traces a vortical axis in terms of the invariant flow topology, which enables to investigate the feature of the topology-based vortical axis. [ABSTRACT FROM AUTHOR]
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- 2016
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3. Apple-shaped obesity: A risky soil for cytokine-accelerated severity in COVID-19.
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Tadashi Hosoya, Seiya Oba, Yoji Komiya, Daisuke Kawata, Mari Kamiya, Hideyuki Iwai, Sho Miyamoto, Michiyo Kataoka, Minoru Tobiume, Takayuki Kanno, Akira Ainai, Hiroyuki Sato, Akihiro Hirakawa, Yuichi Mitsui, Takashi Satoh, Kenji Wakabayashi, Tetsuya Yamada, Yasuhiro Otomo, Yasunari Miyazaki, and Hideki Hasegawa
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COVID-19 , *JAPANESE people , *RATES , *VIRAL proteins , *COVID-19 treatment , *PREVENTION of obesity , *LEPTIN receptors , *OVERWEIGHT persons - Abstract
Obesity has been recognized as one of the most significant risk factors for the deterioration and mortality associated with COVID-19, but the significance of obesity itself differs among ethnicity. Multifactored analysis of our single institute-based retrospective cohort revealed that high visceral adipose tissue (VAT) burden, but not other obesity-associated markers, was related to accelerated inflammatory responses and the mortality of Japanese COVID-19 patients. To elucidate the mechanisms how VAT-dominant obesity induces severe inflammation after severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection, we infected two different strains of obese mice, C57BL/6JHamSlc-ob/ob (ob/ob), C57BLKS/J-db/db (db/db), genetically impaired in the leptin ligand and receptor, respectively, and control C57BL/6 mice with mouse-adapted SARS-CoV-2. Here, we revealed that VAT-dominant ob/ob mice were extremely more vulnerable to SARS-CoV-2 due to excessive inflammatory responses when compared to SAT-dominant db/db mice. In fact, SARS-CoV-2 genome and proteins were more abundant in the lungs of ob/ob mice, engulfed in macrophages, resulting in increased cytokine production including interleukin (IL)-6. Both an anti-IL-6 receptor antibody treatment and the prevention of obesity by leptin replenishment improved the survival of SARS-CoV-2-infected ob/ob mice by reducing the viral protein burden and excessive immune responses. Our results have proposed unique insights and clues on how obesity increases the risk of cytokine storm and death in patients with COVID-19. Moreover, earlier administration of antiinflammatory therapeutics including anti-IL-6R antibody to VAT-dominant patients might improve clinical outcome and stratification of the treatment for COVID-19, at least in Japanese patients. [ABSTRACT FROM AUTHOR]
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- 2023
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4. Impact of Reinfection with SARS-CoV-2 Omicron Variants in Previously Infected Hamsters.
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Nozomi Shiwa-Sudo, Yusuke Sakai, Naoko Iwata-Yoshikawa, Shinji Watanabe, Souichi Yamada, Yudai Kuroda, Tsukasa Yamamoto, Masayuki Shirakura, Seiichiro Fujisaki, Kaya Miyazaki, Hideka Miura, Shiho Nagata, Shuetsu Fukushi, Ken Maeda, Hideki Hasegawa, Tadaki Suzuki, and Noriyo Nagata
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SARS-CoV-2 Omicron variant , *HAMSTERS , *GOLDEN hamster , *REINFECTION , *SARS-CoV-2 , *RESPIRATORY infections , *SARS-CoV-2 Delta variant , *PLANT viruses - Abstract
The diversity of SARS-CoV-2 mutations raises the possibility of reinfection of individuals previously infected with earlier variants, and this risk is further increased by the emergence of the B.1.1.529 Omicron variant. In this study, we used an in vivo, hamster infection model to assess the potential for individuals previously infected with SARS-CoV-2 to be reinfected with Omicron variant and we also investigated the pathology associated with such infections. Initially, Syrian hamsters were inoculated with a lineage A, B.1.1.7, B.1.351, B.1.617.2 or a subvariant of Omicron, BA.1 strain and then reinfected with the BA.1 strain 5 weeks later. Subsequently, the impact of reinfection with Omicron subvariants (BA.1 and BA.2) in individuals previously infected with the BA.1 strain was examined. Although viral infection and replication were suppressed in both the upper and lower airways, following reinfection, virus-associated RNA was detected in the airways of most hamsters. Viral replication was more strongly suppressed in the lower respiratory tract than in the upper respiratory tract. Consistent amino acid substitutions were observed in the upper respiratory tract of infected hamsters after primary infection with variant BA.1, whereas diverse mutations appeared in hamsters reinfected with the same variant. Histopathology showed no acute pneumonia or disease enhancement in any of the reinfection groups and, in addition, the expression of inflammatory cytokines and chemokines in the airways of reinfected animals was only mildly elevated. These findings are important for understanding the risk of reinfection with new variants of SARS-CoV-2. IMPORTANCE The emergence of SARS-CoV-2 variants and the widespread use of COVID19 vaccines has resulted in individual differences in immune status against SARS-CoV-2. A decay in immunity over time and the emergence of variants that partially evade the immune response can also lead to reinfection. In this study, we demonstrated that, in hamsters, immunity acquired following primary infection with previous SARS-CoV-2 variants was effective in preventing the onset of pneumonia after reinfection with the Omicron variant. However, viral infection and multiplication in the upper respiratory tract were still observed after reinfection. We also showed that more diverse nonsynonymous mutations appeared in the upper respiratory tract of reinfected hamsters that had acquired immunity from primary infection. This hamster model reveals the within-host evolution of SARS-CoV-2 and its pathology after reinfection, and provides important information for countermeasures against diversifying SARS-CoV-2 variants. [ABSTRACT FROM AUTHOR]
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- 2023
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5. Screening transplant donors for HTLV-1 and -2.
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Gallo, Robert C., Willems, Luc, and Hideki Hasegawa
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HTLV-I , *HTLV-II (Virus) , *ADULT T-cell leukemia , *PARAPARESIS , *SPINAL cord diseases , *TRANSPLANTATION of organs, tissues, etc. - Abstract
The article focuses on human T-cell leukemia virus-1 (HTLV-1) which causes adult T-cell leukemia-lymphoma (ATL) and a neurological disorder, HTLV-1–associated myelopathy and tropical spastic paraparesis. It mentions that HTLV-1 and HTLV-2 infection may remain asymptomatic for years while being transmitted from person-to-person through host cells in body fluids and breast milk, blood cell transfusions, and solid organ transplantation.
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- 2016
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6. Suberoyl Bis-Hydroxamic Acid Reactivates Kaposi's Sarcoma-Associated Herpesvirus through Histone Acetylation and Induces Apoptosis in Lymphoma Cells.
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Shun Iida, Sohtaro Mine, Keiji Ueda, Tadaki Suzuki, Hideki Hasegawa, and Harutaka Katano
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KAPOSI'S sarcoma-associated herpesvirus , *HISTONE acetylation , *KAPOSI'S sarcoma , *LYMPHOPROLIFERATIVE disorders , *HISTONE deacetylase inhibitors , *CASTLEMAN'S disease - Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma as well as primary effusion lymphoma (PEL), an aggressive B-cell neoplasm that mostly arises in immunocompromised individuals. Lytic replication of KSHV is also associated with a subset of multicentric Castleman diseases. At present, there is no specific treatment available for PEL, and its prognosis is poor. In this study, we found that the histone deacetylase inhibitor suberoyl bis-hydroxamic acid (SBHA) induced KSHV reactivation in PEL cells in a dose-dependent manner. Nextgeneration sequencing analysis showed that .40% of all transcripts expressed in SBHA-treated PEL cells originated from the KSHV genome, compared with,1% in untreated cells. Chromatin immunoprecipitation assays demonstrated that SBHA induced histone acetylation targeting the promoter region of the KSHV replication and transcription activator gene. However, there was no significant change in the methylation status of the promoter region of this gene. In addition to its effect on KSHV reactivation, this study revealed that SBHA induces apoptosis in PEL cells in a dose-dependent manner, inducing the acetylation and phosphorylation of p53, cleavage of caspases, and expression of proapoptotic factors such as Bim and Bax. These findings suggest that SBHA reactivates KSHV from latency and induces apoptosis through the mitochondrial pathway in PEL cells. Therefore, SBHA can be considered a new tool for the induction of KSHV reactivation and could provide a novel therapeutic strategy against PEL. IMPORTANCE Kaposi's sarcoma and primary effusion lymphoma cells are latently infected with Kaposi's sarcoma-associated herpesvirus (KSHV), whereas KSHV replication is frequently observed in multicentric Castleman disease. Although KSHV replication can be induced by some chemical reagents (e.g., 12-O-tetradecanoylphorbol-13- acetate), the mechanism of KSHV replication is not fully understood. We found that the histone deacetylase inhibitor suberoyl bis-hydroxamic acid (SBHA) induced KSHV reactivation with high efficiency through histone acetylation in the promoter of the replication and transcription activator gene, compared with 12-O-tetradecanoylphorbol- 13-acetate. SBHA also induced apoptosis through the mitochondrial pathway in KSHV-infected cells, with a lower half-maximal effective concentration (EC50) than that measured for viral reactivation. SBHA could be used in a highly efficient replication system for KSHV in vitro and as a tool to reveal the mechanism of replication and pathogenesis of KSHV. The ability of SBHA to induce apoptosis at lower levels than those needed to stimulate KSHV reactivation indicates its therapeutic potential. [ABSTRACT FROM AUTHOR]
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- 2021
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7. Integrating genotypes and phenotypes improves long-term forecasts of seasonal influenza A/H3N2 evolution.
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Huddleston, John, Barnes, John R., Rowe, Thomas, Xiyan Xu, Kondor, Rebecca, Wentworth, David E., Whittaker, Lynne, Ermetal, Burcu, Daniels, Rodney Stuart, McCauley, John W., Seiichiro Fujisaki, Kazuya Nakamura, Noriko Kishida, Shinji Watanabe, Hideki Hasegawa, Barr, Ian, Subbarao, Kanta, Barrat-Charlaix, Pierre, Neher, Richard A., and Bedford, Trevor
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PHENOTYPES , *GENOTYPES , *VACCINE effectiveness , *CAUSES of death , *FORECASTING , *SEASONAL influenza , *INFLUENZA - Abstract
Seasonal influenza virus A/H3N2 is a major cause of death globally. Vaccination remains the most effective preventative. Rapid mutation of hemagglutinin allows viruses to escape adaptive immunity. This antigenic drift necessitates regular vaccine updates. Effective vaccine strains need to represent H3N2 populations circulating one year after strain selection. Experts select strains based on experimental measurements of antigenic drift and predictions made by models from hemagglutinin sequences. We developed a novel influenza forecasting framework that integrates phenotypic measures of antigenic drift and functional constraint with previously published sequence-only fitness estimates. Forecasts informed by phenotypic measures of antigenic drift consistently outperformed previous sequence-only estimates, while sequence-only estimates of functional constraint surpassed more comprehensive experimentally-informed estimates. Importantly, the best models integrated estimates of both functional constraint and either antigenic drift phenotypes or recent population growth. [ABSTRACT FROM AUTHOR]
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- 2020
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8. Haplotype networks of SARS-CoV-2 infections in the Diamond Princess cruise ship outbreak.
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Tsuyoshi Sekizuka, Kentaro Itokawa, Tsutomu Kageyama, Shinji Saito, Ikuyo Takayama, Hideki Asanuma, Naganori Nao, Rina Tanaka, Masanori Hashino, Takuri Takahashi, Hajime Kamiya, Takuya Yamagishi, Kensaku Kakimoto, Motoi Suzuki, Hideki Hasegawa, Takaji Wakita, and Makoto Kuroda
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SARS-CoV-2 , *COVID-19 , *CRUISE ships , *DIAMONDS , *PRINCESSES - Abstract
The Diamond Princess cruise ship was put under quarantine offshore Yokohama, Japan, after a passenger who disembarked in Hong Kong was confirmed as a coronavirus disease 2019 case. We performed whole-genome sequencing of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly from PCR+ clinical specimens and conducted a phylogenetic analysis of the outbreak. All tested isolates exhibited a transversion at G11083T, suggesting that SARS-CoV-2 dissemination on the Diamond Princess originated from a single introduction event before the quarantine started. Although further spreading might have been prevented by quarantine, some progeny clusters could be linked to transmission through mass-gathering events in the recreational areas and direct transmission among passengers who shared cabins during the quarantine. This study demonstrates the usefulness of haplotype network/phylogeny analysis in identifying potential infection routes. [ABSTRACT FROM AUTHOR]
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- 2020
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9. Severe Fever with Thrombocytopenia Syndrome, Japan, 2013-2017.
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Yusuke Kobayashi, Hirofumi Kato, Takuya Yamagishi, Tomoe Shimada, Tamano Matsui, Tomoki Yoshikawa, Takeshi Kurosu, Masayuki Shimojima, Shigeru Morikawa, Hideki Hasegawa, Masayuki Saijo, Kazunori Oishi, Kobayashi, Yusuke, Kato, Hirofumi, Yamagishi, Takuya, Shimada, Tomoe, Matsui, Tamano, Yoshikawa, Tomoki, Kurosu, Takeshi, and Shimojima, Masayuki
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THROMBOCYTOPENIA , *FEVER , *PETS , *SYNDROMES , *FERAL cats , *LYME disease , *ANIMAL experimentation - Abstract
We conducted an epidemiologic study of severe fever with thrombocytopenia syndrome (SFTS) in Japan during 2013-2017. Of 303 cases reported during that period, 133 (44%) were included in this study. The median time between onset of illness and diagnosis of SFTS shortened, from 11.5 to 3.0 days, but the case-fatality rate remained high, at 27%. In 64 patients (48%), a close contact with companion animals was reported within 2 weeks of disease onset. Of these 64 patients, 40 were surveyed further, and we confirmed that 3 had direct contact with body fluids of ill companion animals; 2 had direct contact with the saliva of an ill feral cat or pet dog. These patients reported no history of tick bite, suggesting that ill companion animals might be a source of SFTS virus transmission. Direct contact with the body fluids of ill companion animals should be avoided. [ABSTRACT FROM AUTHOR]
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- 2020
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10. Severe fever with thrombocytopenia syndrome virus targets B cells in lethal human infections.
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Tadaki Suzuki, Yuko Sato, Kaori Sano, Takeshi Arashiro, Harutaka Katano, Noriko Nakajima, Masayuki Shimojima, Michiyo Kataoka, Kenta Takahashi, Yuji Wada, Shigeru Morikawa, Shuetsu Fukushi, Tomoki Yoshikawa, Masayuki Saijo, Hideki Hasegawa, Suzuki, Tadaki, Sato, Yuko, Sano, Kaori, Arashiro, Takeshi, and Katano, Harutaka
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B cells , *PATHOLOGY , *HEMORRHAGIC fever , *SYNDROMES , *B cell differentiation - Abstract
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging hemorrhagic fever caused by a tick-borne banyangvirus and is associated with high fatality. Despite increasing incidence of SFTS and serious public health concerns in East Asia, the pathogenesis of lethal SFTS virus (SFTSV) infection in humans is not fully understood. Numbers of postmortem examinations to determine target cells of the viral infection have so far been limited. Here we showed that B cells differentiating into plasmablasts and macrophages in secondary lymphoid organs were targets for SFTSV at the end stage of lethal infection, and the majority of SFTSV-infected cells were B cell-lineage lymphocytes. In affected individuals, B cell-lineage lymphocytes with SFTSV infection were widely distributed in both lymphoid and nonlymphoid organs, and infiltration of these cells into the capillaries of the organs could be observed occasionally. Moreover, a human plasmablastic lymphoma cell line, PBL-1, was susceptible to SFTSV propagation and had a similar immunophenotype to that of target cells of SFTSV in fatal SFTS. PBL-1 can therefore provide a potential in vitro model for human SFTSV infection. These results extend our understanding of the pathogenesis of human lethal SFTSV infection and can facilitate the development of SFTSV countermeasures. [ABSTRACT FROM AUTHOR]
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- 2020
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11. Candidatus Mycoplasma haemohominis in Human, Japan.
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Norimichi Hattori, Makoto Kuroda, Harutaka Katano, Takahiro Takuma, Takayoshi Ito, Nana Arai, Ryo Yanai, Tsuyoshi Sekizuka, Sho Ishii, Yoko Miura, Takahiro Tokunaga, Hiroyuki Watanabe, Norihiro Nomura, Junichi Eguchi, Hideki Hasegawa, Tsuyoshi Nakamaki, Takaji Wakita, Yoshihito Niki, Hattori, Norimichi, and Kuroda, Makoto
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CANDIDATUS , *MYCOPLASMA , *NEEDLESTICK injuries , *BONE marrow , *ELECTRON microscopy , *RESEARCH , *MYCOPLASMA diseases , *SEQUENCE analysis , *ERYTHEMA , *SKIN , *RESEARCH methodology , *MEDICAL cooperation , *EVALUATION research , *COMPARATIVE studies , *ITCHING - Abstract
Hemotropic mycoplasmas are common pathogens in animals, but it remains unclear what role these pathogens play in human infections. We report clinical and biologic characterization of Candidatus Mycoplasma haemohominis infection in a 42-year-old man in Japan. The patient had severe hemophagocytic syndrome 1 month after an accidental needlestick injury. Metagenomic deep sequencing identified Candidatus M. haemohominis and determined its draft genome for an isolate from serum of the patient. A high copy number of the Candidatus M. haemohominis genome was detected in serum and bone marrow samples. Electron microscopy examination showed morphologic characteristics of Candidatus M. haemohominis. Levofloxacin monotherapy induced resistance caused by a gyrase A gene mutation in the quinolone resistance-determining region, but a combination treatment with moxifloxacin and minocycline was effective. We identified Candidatus M. haemohominis in a patient who had life-threatening symptoms related to multiple organ infection. Human infection with this mycoplasma might occur more frequently than has been generally recognized. [ABSTRACT FROM AUTHOR]
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- 2020
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12. Immune-Focusing Properties of Virus-like Particles Improve Protective IgA Responses.
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Taishi Onodera, Kana Hashi, Rajni Kant Shukla, Motohiro Miki, Reiko Takai-Todaka, Akira Fujimoto, Masayuki Kuraoka, Tatsuya Miyoshi, Kazuo Kobayashi, Hideki Hasegawa, Manabu Ato, Kelsoe, Garnett, Kazuhiko Katayama, and Yoshimasa Takahashi
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VIRUS-like particles , *VACCINES , *EPITOPES - Abstract
Virus-like particles (VLPs) provide a well-established vaccine platform; however, the immunogenic properties acquired by VLP structure remain poorly understood. In this study, we showed that systemic vaccination with norovirus VLP recalls human IgA responses at higher magnitudes than IgG responses under a humanized mouse model that was established by introducing human PBMCs in severely immunodeficient mice. The recall responses elicited by VLP vaccines depended on VLP structure and the dis- ruption of VLP attenuated recall responses, with a more profound reduction being observed in IgA responses. The IgA-focusing property was also conserved in a murine norovirus-primed model under which murine IgA responses were recalled in a manner dependent on VLP structure. Importantly, the VLP-driven IgA response preferentially targeted virus-neutralizing epitopes located in the receptor-binding domain. Consequently, VLP-driven IgA responses were qualitatively superior to IgG responses in terms of the virus-neutralizing activity in vitro. Furthermore, the IgA in mucosa obtained remarkable protective function toward orally administrated virus in vivo. Thus, our results indicate the immune-focusing properties of the VLP vaccine that improve the quality/quantity of mucosal IgA responses, a finding with important implications for developing mucosal vaccines. [ABSTRACT FROM AUTHOR]
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- 2019
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13. Human-to-Human Transmission of Influenza A(H3N2) Virus with Reduced Susceptibility to Baloxavir, Japan, February 2019.
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Emi Takashita, Masataka Ichikawa, Hiroko Morita, Rie Ogawa, Seiichiro Fujisaki, Masayuki Shirakura, Hideka Miura, Kazuya Nakamura, Noriko Kishida, Tomoko Kuwahara, Hiromi Sugawara, Aya Sato, Miki Akimoto, Keiko Mitamura, Takashi Abe, Masahiko Yamazaki, Shinji Watanabe, Hideki Hasegawa, Takato Odagiri, and Takashita, Emi
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HUMAN-to-human transmission , *INFLUENZA A virus, H3N2 subtype , *INFLUENZA , *INFLUENZA transmission , *DISEASE susceptibility , *ANTIVIRAL agents , *INFLUENZA epidemiology , *SULFUR compounds , *PYRIDINE , *GENETIC mutation , *HETEROCYCLIC compounds , *PHARMACODYNAMICS - Abstract
In 2019, influenza A(H3N2) viruses carrying an I38T substitution in the polymerase acidic gene, which confers reduced susceptibility to baloxavir, were detected in Japan in an infant without baloxavir exposure and a baloxavir-treated sibling. These viruses' whole-genome sequences were identical, indicating human-to-human transmission. Influenza virus isolates should be monitored for baloxavir susceptibility. [ABSTRACT FROM AUTHOR]
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- 2019
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14. Serial Section Array Scanning Electron Microscopy Analysis of Cells from Lung Autopsy Specimens following Fatal A/H1N1 2009 Pandemic Influenza Virus Infection.
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Michiyo Kataoka, Kinji Ishida, Katsutoshi Ogasawara, Takayuki Nozaki, Yoh-Ichi Satoh, Tetsutaro Sata, Yuko Sato, Hideki Hasegawa, and Noriko Nakajima
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VIRUS diseases , *CELL analysis , *INFLUENZA viruses , *SCANNING electron microscopy , *VIRAL antigens , *THREE-dimensional modeling , *AUTOPSY - Abstract
A/H1N1 2009 pandemic influenza virus (A/H1N1/pdm09) was first identified as a novel pandemic influenza A virus (IAV) in 2009. Previously, we reported that many viral antigens were detected in type II alveolar epithelial cells (AEC-IIs) within autopsied lung tissue from a patient with A/H1N1/pdm09 pneumonia. It is important to identify the association between the virus and host cells to elucidate the pathogenesis of IAV pneumonia. To investigate the distribution of virus particles and morphological changes in host cells, the autopsied lung specimens from this patient were examined using transmission electron microscopy (TEM) and a novel scanning electron microscopy (SEM) method. We focused on AEC-IIs as viral antigen-positive cells and on monocytes/macrophages (Ms/Mϕs) and neutrophils (Neus) as innate immune cells. We identified virus particles and intranuclear dense tubules, which are associated with matrix 1 (M1) proteins from IAV. Large-scale two-dimensional observation was enabled by digitally "stitching" together contiguous SEM images. A single whole-cell analysis using a serial section array (SSA)-SEM identified virus particles in vesicles within the cytoplasm and/or around the surfaces of AEC-IIs, Ms/Mϕs, and Neus; however, intranuclear dense tubules were found only in AEC-IIs. Computer-assisted processing of SSA-SEM images from each cell type enabled three-dimensional (3D) modeling of the distribution of virus particles within an ACE-II, a M/Mϕ, and a Neu. [ABSTRACT FROM AUTHOR]
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- 2019
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15. Acute respiratory inf ection in human dipeptidyl peptidase 4-transgenic mice infected with Middle East respiratory syndrome coronavirus.
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Naoko Iwata-Yoshikawa, Tadashi Okamura, Yukiko Shimizu, Osamu Kotani, Hironori Sato, Hanako Sekimukai, Shuetsu Fukushi, Tadaki Suzuki, Yuko Sato, Makoto Takeda, Masato Tashiro, Hideki Hasegawa, and Noriyo Nagata
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PEPTIDASE , *MERS coronavirus - Abstract
Middle East respiratory syndrome coronavirus (MERS-CoV) infection can manifest as a mild illness, acute respiratory distress, organ failure, or death. Several animal models have been established to study disease pathogenesis and to develop vaccines and therapeutic agents. Here, we developed transgenic (Tg) mice on a C57BL/6 background; these mice expressed human CD26/dipeptidyl peptidase 4 (hDPP4), a functional receptor for MERS-CoV, under the control of an endogenous hDPP4 promoter. We then characterized this mouse model of MERS-CoV. The expression profile of hDPP4 in these mice was almost equivalent to that in human tissues, including kidney and lung; however, hDPP4 was overexpressed in murine CD3-positive cells within peripheral blood and lymphoid tissues. Intranasal inoculation of young and adult Tg mice with MERS-CoV led to infection of the lower respiratory tract and pathological evidence of acute multifocal interstitial pneumonia within 7 days, with only transient loss of body weight. However, the immunopathology in young and adult Tg mice was different. On Day 5 or 7 post-inoculation, lungs of adult Tg mice contained higher levels of pro-inflammatory cytokines and chemokines associated with migration of macrophages. These results suggest that the immunopathology of MERS infection in the Tg mouse is age-dependent. The mouse model described herein will increase our understanding of disease pathogenesis and host mediators that protect against MERS-CoV infection. [ABSTRACT FROM AUTHOR]
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- 2019
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16. TMPRSS2 contributes to virus spread and immunopathology in the airways of murine models after coronavirus infection.
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Naoko Iwata-Yoshikawa, Tadashi Okamura, Yukiko Shimizu, Hideki Hasegawa, Makoto Takeda, and Noriyo Nagata
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CORONAVIRUS diseases , *TRANSGENIC mice - Abstract
Transmembrane serine protease TMPRSS2 activates the spike protein of highly pathogenic human coronaviruses such as severe acute respiratory syndrome-related coronavirus (SARS-CoV) and Middle East respiratory syndrome-related coronavirus (MERS-CoV). In vitro, activation induces virus-cell membrane fusion at the cell surface. However, the roles of TMPRSS2 during coronavirus infection in vivo are unclear. Here, we used animal models of SARS-CoV and MERS-CoV infection to investigate the role of TMPRSS2. Th-1-prone C57BL/6 mice and TMPRSS2-knockout (KO) mice were used for SARS-CoV infection, and transgenic mice expressing the human MERS-CoV receptor, hDPP4-Tg mice, and TMPRSS2-KO hDPP4-Tg mice were used for MERS-CoV infection. After experimental infection, TMPRSS2-deficient mouse strains showed reduced body weight loss and viral kinetics in the lungs. Lack of TMPRSS2 affected the primary sites of infection and virus spread within the airway, accompanied by less severe immunopathology. However, TMPRSS2-KO mice showed weakened inflammatory chemokine and/or cytokine responses to intranasal stimulation with poly (I:C), a Toll-like receptor 3 agonist. In conclusion, TMPRSS2 plays a crucial role in viral spread within the airway of murine models infected by SARS-CoV and MERS-CoV and in the resulting immunopathology. [ABSTRACT FROM AUTHOR]
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- 2019
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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. Syrian Hamster as an Animal Model for the Study of Human Influenza Virus Infection.
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Kiyoko Iwatsuki-Horimoto, Noriko Nakajima, Yurie Ichiko, Yuko Sakai-Tagawa, Takeshi Noda, Hideki Hasegawa, and Yoshihiro Kawaoka
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GOLDEN hamster , *INFLUENZA viruses , *VIRUS diseases , *INFLUENZA A virus, H3N2 subtype , *FERRETS as laboratory animals - Abstract
Ferrets and mice are frequently used as animal models for influenza research. However, ferrets are demanding in terms of housing space and handling, whereas mice are not naturally susceptible to infection with human influenza A or B viruses. Therefore, prior adaptation of human viruses is required for their use in mice. In addition, there are no mouse-adapted variants of the recent H3N2 viruses, because these viruses do not replicate well in mice. In this study, we investigated the susceptibility of Syrian hamsters to influenza viruses with a view to using the hamster model as an alternative to the mouse model. We found that hamsters are sensitive to influenza viruses, including the recent H3N2 viruses, without adaptation. Although the hamsters did not show weight loss or clinical signs of H3N2 virus infection, we observed pathogenic effects in the respiratory tracts of the infected animals. All of the H3N2 viruses tested replicated in the respiratory organs of the hamsters, and some of them were detected in the nasal washes of infected animals. Moreover, a 2009 pandemic (pdm09) virus and a seasonal H1N1 virus, as well as one of the two H3N2 viruses, but not a type B virus, were transmissible by the airborne route in these hamsters. Hamsters thus have the potential to be a small-animal model for the study of influenza virus infection, including studies of the pathogenicity of H3N2 viruses and other strains, as well as for use in H1N1 virus transmission studies. [ABSTRACT FROM AUTHOR]
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- 2018
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19. Characterization of a Feline Influenza A(H7N2) Virus.
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Masato Hatta, Gongxun Zhong, Yuwei Gao, Noriko Nakajima, Shufang Fan, Shiho Chiba, Deering, Kathleen M., Mutsumi Ito, Masaki Imai, Maki Kiso, Sumiho Nakatsu, Lopes, Tiago J., Thompson, Andrew J., McBride, Ryan, Suarez, David L., Macken, Catherine A., Shigeo Sugita, Gabriele Neumann, Hideki Hasegawa, and Paulson, James C.
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INFLUENZA A virus , *ANIMAL shelters , *INFLUENZA transmission , *CAT diseases , *EPIDEMICS - Abstract
During December 2016-February 2017, influenza A viruses of the H7N2 subtype infected ≈500 cats in animal shelters in New York, NY, USA, indicating virus transmission among cats. A veterinarian who treated the animals also became infected with feline influenza A(H7N2) virus and experienced respiratory symptoms. To understand the pathogenicity and transmissibility of these feline H7N2 viruses in mammals, we characterized them in vitro and in vivo. Feline H7N2 subtype viruses replicated in the respiratory organs of mice, ferrets, and cats without causing severe lesions. Direct contact transmission of feline H7N2 subtype viruses was detected in ferrets and cats; in cats, exposed animals were also infected via respiratory droplet transmission. These results suggest that the feline H7N2 subtype viruses could spread among cats and also infect humans. Outbreaks of the feline H7N2 viruses could, therefore, pose a risk to public health. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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20. Emergence of Oseltamivir-Resistant H7N9 Influenza Viruses in Immunosuppressed Cynomolgus Macaques.
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Maki Kiso, Kiyoko Iwatsuki-Horimoto, Seiya Yamayoshi, Ryuta Uraki, Mutsumi Ito, Noriko Nakajima, Shinya Yamada, Masaki Imai, Eiryo Kawakami, Yuriko Tomita, Satoshi Fukuyama, Yasushi Itoh, Kazumasa Ogasawara, Lopes, Tiago J. S., Tokiko Watanabe, Moncla, Louise H., Hideki Hasegawa, Friedrich, Thomas C., Neumann, Gabriele, and Yoshihiro Kawaoka
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OSELTAMIVIR , *INFLUENZA , *VIRUSES , *MACAQUES , *VIROCAP (Medical test) - Abstract
Antiviral compounds (eg, the neuraminidase inhibitor oseltamivir) are invaluable for the treatment of individuals infected with influenza A viruses of the H7N9 subtype (A[H7N9]), which have infected and killed hundreds of persons. However, oseltamivir treatment often leads to the emergence of resistant viruses in immunocompromised individuals. To better understand the emergence and properties of oseltamivir-resistant A(H7N9) viruses in immunosuppressed individuals, we infected immunosuppressed cynomolgus macaques with an A(H7N9) virus and treated them with oseltamivir. Disease severity and mortality were higher in immunosuppressed than in immunocompetent animals. Oseltamivir treatment at 2 different doses reduced A(H7N9) viral titers in infected animals, but even high-dose oseltamivir did not block viral replication sufficiently to suppress the emergence of resistant variants. Some resistant variants were not appreciably attenuated in cultured cells, but an oseltamivir-resistant A(H7N9) virus did not transmit among ferrets. These findings are useful for the control of A(H7N9) virus infections in clinical settings. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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21. Conserved sequences of BART and BHRF regions encoding viral microRNAs in Epstein-Barr virus-associated lymphoma.
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Keishin Sunagawa, Tsunekazu Hishima, Hitomi Fukumoto, Hideki Hasegawa, and Harutaka Katano
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EPSTEIN-Barr virus , *LYMPHOMAS , *MICRORNA , *DNA mutational analysis , *NUCLEOTIDE sequencing - Abstract
Objective: Epstein-Barr virus (EBV) encodes at least 25 pri-microRNAs (miRNAs) in two regions of its DNA genome, BART and BHRF. B95-8, an EBV reference strain, has a deletion in the BART region. However, no information is available on the deletions or mutations in the BART and BHRF regions in clinical samples of EBV-associated lymphoma. Results: Nine DNA fragments encoding miR-BARTs and two coding miR-BHRF1s were amplified by PCR from DNA samples extracted from 16 cases of EBV-associated lymphoma. All the PCR products were sequenced directly. DNA fragments encoding miR-BARTs and miR-BHRF1-1 were successfully amplified from all samples. An adenine-toguanine mutation in the DNA fragment encoding miR-BART2-3p was detected in four of the 16 cases, and a cytosineto-thymidine mutation in the DNA fragment encoding miR-BART11-3p was detected in one of the 16 samples. These mutations were not associated with any histological categories of lymphoma. In conclusion, mutations were rarely observed in the DNA encoding viral miRNAs in cases of lymphoma. This suggests that the DNA sequences of EBV-encoded miR-BARTs and miR-BHRF1-1 are conserved in EBV-associated lymphoma. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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22. Unusual presentation of a severely ill patient having severe fever with thrombocytopenia syndrome: a case report.
- Author
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Masahiko Kaneko, Masaki Maruta, Hisaharu Shikata, Kengo Asou, Hiroto Shinomiya, Tadaki Suzuki, Hideki Hasegawa, Masayuki Shimojima, Masayuki Saijo, Kaneko, Masahiko, Maruta, Masaki, Shikata, Hisaharu, Asou, Kengo, Shinomiya, Hiroto, Suzuki, Tadaki, Hasegawa, Hideki, Shimojima, Masayuki, and Saijo, Masayuki
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THROMBOCYTOPENIA , *EXANTHEMA , *ALVARADO score , *GRAY platelet syndrome , *BLOOD platelet disorders - Abstract
Background: Severe fever with thrombocytopenia syndrome is an emerging infectious disease caused by a novel phlebovirus belonging to the family Bunyaviridate. Emergence of encephalitis/encephalopathy during severe fever with thrombocytopenia syndrome progression has been identified as a major risk factor associated with a poor prognosis. Here we report the case of a severely ill patient with severe fever with thrombocytopenia syndrome virus-associated encephalitis/encephalopathy characterized by a lesion of the splenium, which resolved later.Case Presentation: A 56-year-old Japanese man presented with fever and diarrhea, followed by dysarthria. Diffusion-weighted magnetic resonance imaging demonstrated high signal intensity in the splenium of the corpus callosum. The severe fever with thrombocytopenia syndrome virus genome was detected in our patient's serum, and the clinical course was characterized by convulsion, stupor, and hemorrhagic manifestations, with disseminated intravascular coagulation and hemophagocytic lymphohistiocytosis. Supportive therapy not including administration of corticosteroids led to gradual improvement of the clinical and laboratory findings, and magnetic resonance imaging demonstrated resolution of the splenial lesion. The serum severe fever with thrombocytopenia syndrome viral copy number, which was determined with the quantitative reverse-transcription polymerase chain reaction, rapidly decreased despite the severe clinical course. Our patient's overall condition improved, allowing him to be eventually discharged.Conclusions: Patients with encephalitis/encephalopathy due to severe fever with thrombocytopenia syndrome virus infection may have a favorable outcome, even if they exhibit splenial lesions and a severe clinical course; monitoring the serum viral load may be of value for prediction of outcome and potentially enables the avoidance of corticosteroids to intentionally cause opportunistic infection. [ABSTRACT FROM AUTHOR]- Published
- 2017
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23. The Microminipig as an Animal Model for Influenza A Virus Infection.
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Kiyoko Iwatsuki-Horimoto, Noriko Nakajima, Masatoshi Shibata, Kenta Takahashi, Yuko Sato, Maki Kiso, Seiya Yamayoshi, Mutsumi Ito, Satoko Enya, Masayoshi Otake, Akihisa Kangawa, da Silva Lopes, Tiago Jose, Hirotaka Ito, Hideki Hasegawa, and Yoshihiro Kawaoka
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INFLUENZA treatment , *SWINE housing , *ANIMAL models in research , *MEDICAL microbiology , *MEDICAL research - Abstract
Pigs are considered a mixing vessel for the generation of novel pandemic influenza A viruses through reassortment because of their susceptibility to both avian and human influenza viruses. However, experiments to understand reassortment in pigs in detail have been limited because experiments with regular-sized pigs are difficult to perform. Miniature pigs have been used as an experimental animal model, but they are still large and require relatively large cages for housing. The microminipig is one of the smallest miniature pigs used for experiments. Introduced in 2010, microminipigs weigh around 10 kg at an early stage of maturity (6 to 7 months old) and are easy to handle. To evaluate the microminipig as an animal model for influenza A virus infection, we compared the receptor distribution of 10-week-old male pigs (Yorkshire Large White) and microminipigs. We found that both animals have SAα2,3Gal and SAα2,6Gal in their respiratory tracts, with similar distributions of both receptor types. We further found that the sensitivity of microminipigs to influenza A viruses was the same as that of larger miniature pigs. Our findings indicate that the microminipig could serve as a novel model animal for influenza A virus infection. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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24. Deep-Sequence Identification and Role in Virus Replication of a JC Virus Quasispecies in Patients with Progressive Multifocal Leukoencephalopathy.
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Kenta Takahashi, Tsuyoshi Sekizuka, Hitomi Fukumoto, Kazuo Nakamichi, Tadaki Suzuki, Yuko Sato, Hideki Hasegawa, Makoto Kuroda, and Harutaka Katano
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VIRAL replication , *JOHN Cunningham virus , *PROGRESSIVE multifocal leukoencephalopathy , *IMMUNODEFICIENCY , *VIRAL genomes - Abstract
JC virus (JCV) is a DNA virus causing progressive multifocal leukoencephalopathy (PML) in immunodeficient patients. In the present study, 22 genetic quasispecies with more than 1.5% variant frequency were detected in JCV genomes from six clinical samples of PML by next-generation sequencing. A mutation from A to C at nucleotide (nt) 3495 in JCV Mad1 resulting in a V-to-G amino acid substitution at amino acid (aa) position 392 of the large T antigen (TAg) was identified in all six cases of PML at 3% to 19% variant frequencies. Transfection of JCV Mad1 DNA possessing the V392G substitution in TAg into IMR-32 and human embryonic kidney 293 (HEK293) cells resulted in dramatically decreased production of JCV-encoded proteins. The virus DNA copy number was also reduced in supernatants of the mutant virus-transfected cells. Transfection of the IMR-32 and HEK293 cells with a virus genome containing a revertant mutation recovered viral production and protein expression. Cotransfection with equal amounts of wild-type genome and mutated JCV genome did not reduce the expression of viral proteins or viral replication, suggesting that the mutation did not have any dominantnegative function. Finally, immunohistochemistry demonstrated that TAg was expressed in all six pathological samples in which the quasispecies were detected. In conclusion, the V392G amino acid substitution in TAg identified frequently in PML lesions has a function in suppressing JCV replication, but the frequency of the mutation was restricted and its role in PML lesions was limited. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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25. Intracerebral Inoculation of Mouse-Passaged Saffold Virus Type 3 Affects Cerebellar Development in Neonatal Mice.
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Osamu Kotani, Tadaki Suzuki, Masaru Yokoyama, Naoko Iwata-Yoshikawa, Noriko Nakajima, Hironori Sato, Hideki Hasegawa, Fumihiro Taguchi, Hiroyuki Shimizu, and Noriyo Nagata
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INTRACEREBRAL hematoma , *MENINGITIS , *NEUROGLIA , *STRUCTURAL dynamics , *INFECTIOUS disease transmission - Abstract
Saffold virus (SAFV), a human cardiovirus, is occasionally detected in infants with neurological disorders, including meningitis and cerebellitis. We recently reported that SAFV type 3 isolates infect cerebellar glial cells, but not large neurons, in mice. However, the impact of this infection remained unclear. Here, we determined the neuropathogenesis of SAFV type 3 in the cerebella of neonatal ddY mice by using SAFV passaged in the cerebella of neonatal BALB/c mice. The virus titer in the cerebellum increased following the inoculation of each of five passaged strains. The fifth passaged strain harbored amino acid substitutions in the VP2 (H160R and Q239R) and VP3 (K62M) capsid proteins. Molecular modeling of the capsid proteins suggested that the VP2-H160R and VP3-K62M mutations alter the structural dynamics of the receptor binding surface via the formation of a novel hydrophobic interaction between the VP2 puff B and VP3 knob regions. Compared with the original strain, the passaged strain showed altered growth characteristics in human-derived astroglial cell lines and greater replication in the brains of neonatal mice. In addition, the passaged strain was more neurovirulent than the original strain, while both strains infected astroglial and neural progenitor cells in the mouse brain. Intracerebral inoculation of either the original or the passaged strain affected brain Purkinje cell dendrites, and a high titer of the passaged strain induced cerebellar hypoplasia in neonatal mice. Thus, infection by mouse-passaged SAFV affected cerebellar development in neonatal mice. This animal model contributes to the understanding of the neuropathogenicity of SAFV infections in infants. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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26. Fungus-Derived Neoechinulin B as a Novel Antagonist of Liver X Receptor, Identified by Chemical Genetics Using a Hepatitis C Virus Cell Culture System.
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Syo Nakajima, Koichi Watashi, Hirofumi Ohashi, Shinji Kamisuki, Izaguirre-Carbonell, Jesus, Tae-Jun Kwon, Andrew, Harukazu Suzuki, Michiyo Kataoka, Senko Tsukuda, Okada, Maiko, Meng Ling Moi, Toshifumi Takeuchi, Arita, Minetaro, Ryosuke Suzuki, Hideki Aizaki, Takanobu Kato, Tadaki Suzuki, Hideki Hasegawa, Tomohiko Takasaki, and Fumio Sugawara
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MYCOSES , *BIOCHEMICAL genetics , *HEPATITIS C virus , *CELL culture , *MOLECULES - Abstract
Cell culture systems reproducing virus replication can serve as unique models for the discovery of novel bioactive molecules. Here, using a hepatitis C virus (HCV) cell culture system, we identified neoechinulin B (NeoB), a fungus-derived compound, as an inhibitor of the liver X receptor (LXR). NeoB was initially identified by chemical screening as a compound that impeded the production of infectious HCV. Genome-wide transcriptome analysis and reporter assays revealed that NeoB specifically inhibits LXR-mediated transcription. NeoB was also shown to interact directly with LXRs. Analysis of structural analogs suggested that the molecular interaction of NeoB with LXR correlated with the capacity to inactivate LXR-mediated transcription and to modulate lipid metabolism in hepatocytes. Our data strongly suggested that NeoB is a novel LXR antagonist. Analysis using NeoB as a bioprobe revealed that LXRs support HCV replication: LXR inactivation resulted in dispersion of double-membrane vesicles, putative viral replication sites. Indeed, cells treated with NeoB showed decreased replicative permissiveness for poliovirus, which also replicates in double-membrane vesicles, but not for dengue virus, which replicates via a distinct membrane compartment. Together, our data suggest that LXR-mediated transcription regulates the formation of virus-associated membrane compartments. Significantly, inhibition of LXRs by NeoB enhanced the activity of all known classes of anti-HCV agents, and NeoB showed especially strong synergy when combined with interferon or an HCV NS5A inhibitor. Thus, our chemical genetics analysis demonstrates the utility of the HCV cell culture system for identifying novel bioactive molecules and characterizing the virushost interaction machinery. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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27. Establishing and characterizing a new primary effusion lymphoma cell line harboring Kaposi's sarcoma--associated herpesvirus.
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Madori Osawa, Sohtaro Mine, Shinichiro Ota, Kengo Kato, Tsuyoshi Sekizuka, Makoto Kuroda, Michiyo Kataoka, Hitomi Fukumoto, Yuko Sato, Takayuki Kanno, Hideki Hasegawa, Keiji Ueda, Masashi Fukayama, Takuya Maeda, Soichiro Kanoh, Akihiko Kawana, Yuji Fujikura, and Harutaka Katano
- Abstract
Background: Primary effusion lymphoma is a rare distinct large B-cell neoplasm that is associated with Kaposi's sarcoma--associated herpesvirus (KSHV) infection. Over recent years, 9 KSHV-positive/Epstein-Barr virus (EBV)-negative PEL cell lines have been established. Methods: Tumor cells were collected from the pleural effusion of a 49-year-old male with AIDS. Cells were grown in RPMI1640 culture medium supplemented with 10 % fetus bovine serum. Single cell cloning was performed successfully by a limiting dilution method in a 96-well plate. The cell line obtained was designated SPEL. Results: SPEL cells showed gourd-shaped morphology with a polarized nucleus, expressing CD38, CD138, and Blimp-1, but not B cell markers such as CD19 and CD20. Polymerase chain reaction analysis revealed that SPEL cells were positive for KSHV but negative for EBV. Tetradecanoylphorbol acetate induced expression of KSHV lytic proteins and the production of KSHV particles in SPEL cells. Subcutaneous inoculation of SPEL cells into severe combined immunodeficiency mice resulted in the formation of solid tumors. Next-generation sequencing revealed the 138 kbp genome sequence of KSHV in SPEL cells. Suberic bishydroxamate, a histone deacetylase inhibitor, induced the expression of KSHV-encoded lytic proteins and cell death in SPEL cells. Conclusions: A new KSHV-positive and EBV-negative PEL cell line, SPEL was established. This cell line may contribute to furthering our understanding of the pathogenesis of PEL and KSHV infection. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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28. The RNA- and TRIM25-Binding Domains of Influenza Virus NS1 Protein Are Essential for Suppression of NLRP3 Inflammasome-Mediated Interleukin-1β Secretion.
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Miyu Moriyama, I-Yin Chen, Atsushi Kawaguchi, Takumi Koshiba, Kyosuke Nagata, Haruko Takeyama, Hideki Hasegawa, and Takeshi Ichinohe
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TRIM proteins , *RNA-binding proteins , *INFLUENZA A virus , *NS1 viral protein , *INFLAMMASOMES , *INTERLEUKIN-1 , *OLIGOMERIZATION , *CASPASES - Abstract
Inflammasomes are cytosolic multimolecular protein complexes that stimulate the activation of caspase-1 and the release of mature forms of interleukin-1β (IL-1β) and IL-18. We previously demonstrated that the influenza A virus M2 protein stimulates IL-1β secretion following activation of the nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. The nonstructural protein 1 (NS1) of influenza virus inhibits caspase-1 activation and IL-1β secretion. However, the precise mechanism by which NS1 inhibits IL-1β secretion remains unknown. Here, we showed that J774A.1 macrophages stably expressing the NS1 protein inhibited IL-1β secretion after infection with recombinant influenza virus lacking the NS1 gene. Coimmunoprecipitation assay revealed that the NS1 protein interacts with NLRP3. Importantly, the NS1 protein inhibited the NLRP3/ASC-induced single-speck formation required for full activation of inflammasomes. The NS1 protein of other influenza virus strains, including a recent pandemic strain, also inhibited inflammasome-mediated IL-1β secretion. The NS1 RNA-binding domain (basic residues 38 and 41) and TRIM25-binding domain (acidic residues 96 and 97) were required for suppression of NLRP3 inflammasome-mediated IL-1β secretion. These results shed light on a mechanism by which the NS1 protein of influenza virus suppresses NLRP3 inflammasome-mediated IL-1β secretion. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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29. Adenovirus Type 7 Pneumonia in Children Who Died from Measles-Associated Pneumonia, Hanoi, Vietnam, 2014.
- Author
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Le Thanh Hai, Thach, Hoang Ngoc, Ta Anh Tuan, Dao Huu Nam, Tran Minh Dien, Yuko Sato, Toshio Kumasaka, Tadaki Suzuki, Nozomu Hanaoka, Tsuguto Fujimoto, Harutaka Katano, Hideki Hasegawa, Shoji Kawachi, Noriko Nakajima, Hai, Le Thanh, Tuan, Ta Anh, Nam, Dao Huu, Dien, Tran Minh, Sato, Yuko, and Kumasaka, Toshio
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ADENOVIRUS diseases , *ADENOVIRUSES , *MEASLES , *PNEUMONIA , *EPIDEMIC research , *PUBLIC health - Abstract
During a 2014 measles outbreak in Vietnam, postmortem pathologic examination of hospitalized children who died showed that adenovirus type 7 pneumonia was a contributory cause of death in children with measles-associated immune suppression. Adenovirus type 7 pneumonia should be recognized as a major cause of secondary infection after measles. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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30. Relationship of the quaternary structure of human secretory IgA to neutralization of influenza virus.
- Author
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Tadaki Suzukia, Akira Kawaguchi, Akira Ainai, Shin-ichi Tamura, Ryo Ito, Multihartina, Pretty, Setiawaty, Vivi, Krisna Nur Andriana Pangesti, Takato Odagiri, Masato Tashiro, and Hideki Hasegawa
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INFLUENZA research , *INFLUENZA A virus , *VIRAL vaccines , *RESPIRATORY infections , *HYPOVENTILATION , *VACCINATION - Abstract
Secretory IgA (S-IgA) antibodies, the major contributors to humoral mucosal immunity to influenza virus infection, are polymeric Igs present in many external secretions. In the present study, the quaternary structures of human S-IgA induced in nasal mucosa after administration of intranasal inactivated influenza vaccines were characterized in relation to neutralization potency against influenza A viruses. Human nasal IgA antibodies have been shown to contain at least five quaternary structures. Direct and real-time visualization of S-IgA using high-speed atomic force microscopy (AFM) demonstrated that trimeric and tetrameric S-IgA had six and eight antigen-binding sites, respectively, and that these structures exhibited large-scale asynchronous conformational changes while capturing influenza HA antigens in solution. Furthermore, trimeric, tetrameric, and larger polymeric structures,which areminor fractions in human nasal IgA, displayed increased neutralizing potency against influenza A viruses comparedwith dimeric S-IgA, suggesting that the larger polymeric than dimeric forms of S-IgA play some important roles in protection against influenza A virus infection in the human upper respiratory tract. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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31. A Mutant H3N2 Influenza Virus Uses an Alternative Activation Mechanism in TMPRSS2 Knockout Mice by Loss of an Oligosaccharide in the Hemagglutinin Stalk Region.
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Kouji Sakai, Tsuyoshi Sekizuka, Yasushi Ami, Noriko Nakajima, Minori Kitazawa, Yuko Sato, Katsuhiro Nakajima, Masaki Anraku, Toru Kubota, Katsuhiro Komase, Kazuaki Takehara, Hideki Hasegawa, Takato Odagiri, Masato Tashiro, Makoto Kuroda, and Makoto Takeda
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PROTEASE inhibitors , *PROTEOLYTIC enzymes , *INFLUENZA A virus , *HEMAGGLUTININ , *MICROBIAL virulence , *OLIGOSACCHARIDES - Abstract
The host protease TMPRSS2 plays an essential role in proteolytic activation of the influenza A virus (IAV) hemagglutinin (HA) protein possessing a monobasic cleavage site. However, after passages in TMPRSS2 knockout mice, an H3N2 subtype IAV began to undergo cleavage activation of HA, showing high virulence in the mice due to the loss of an oligosaccharide at position 8 in the HA stalk region. Thus, the H3N2 IAV acquired cleavability by an alternative HA activation mechanism/protease(s). [ABSTRACT FROM AUTHOR]
- Published
- 2015
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32. Combatting infectious diseases; nanotechnology as a platform for rational vaccine design.
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van Riet, Elly, Akira Ainai, Tadaki Suzuki, Kersten, Gideon, and Hideki Hasegawa
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DRUG delivery systems , *PREVENTION of communicable diseases , *NANOTECHNOLOGY , *VACCINATION , *GENETIC engineering , *IMMUNOLOGY - Abstract
Currently, several successful vaccines are available. However, for pathogens with a highly variable genetic composition, and for which serum IgG antibodies are not a useful correlate of protection, effective vaccines are yet to be developed. This is due to a lack of both the understanding of the immunological pathways leading to long-term protection and the ability to translate the available knowledge into a suitable vaccine formulation. Regarding the latter, nanoparticles can be an attractive platform for vaccine development, as they offer multiple options for improving safety and efficacy. For example, side effects might be decreased upon encapsulation of the adjuvant and the concomitant delivery of antigen and adjuvant is a very promising tool for increasing efficacy. In addition to the many promises, the use of nanoparticles as vaccine carriers should be implemented with caution: the more sophisticated a particle, the more parameters need to be controlled during production and storage. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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33. Neutrophil Depletion Suppresses Pulmonary Vascular Hyperpermeability and Occurrence of Pulmonary Edema Caused by Hantavirus Infection in C.B-17 SCID Mice.
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Takaaki Koma, Kumiko Yoshimatsu, Noriyo Nagata, Yuko Sato, Kenta Shimizu, Yasuda, Shumpei P., Takako Amada, Sanae Nishio, Hideki Hasegawa, and Jiro Arikawa
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HANTAVIRUS diseases , *PULMONARY edema , *NEUTROPHILS , *PULMONARY blood vessels , *PERMEABILITY (Biology) , *SEVERE combined immunodeficiency , *POLYMERASE chain reaction - Abstract
Hantavirus infections are characterized by vascular hyperpermeability and neutrophilia. However, the pathogenesis of this disease is poorly understood. Here, we demonstrate for the first time that pulmonary vascular permeability is increased by Hantaan virus infection and results in the development of pulmonary edema in C.B-17 severe combined immunodeficiency (SCID) mice lacking functional T cells and B cells. Increases in neutrophils in the lung and blood were observed when pulmonary edema began to be observed in the infected SCID mice. The occurrence of pulmonary edema was inhibited by neutrophil depletion. Moreover, the pulmonary vascular permeability was also significantly suppressed by neutrophil depletion in the infected mice. Taken together, the results suggest that neutrophils play an important role in pulmonary vascular hyperpermeability and the occurrence of pulmonary edema after hantavirus infection in SCID mice. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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34. The Host Protease TMPRSS2 Plays a Major Role in In Vivo Replication of Emerging H7N9 and Seasonal Influenza Viruses.
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Kouji Sakai, Yasushi Ami, Maino Tahara, Toru Kubota, Masaki Anraku, Masako Abe, Noriko Nakajima, Tsuyoshi Sekizuka, Kazuya Shirato, Yuriko Suzaki, Akira Ainai, Yuichiro Nakatsu, Kazuhiko Kanou, Kazuya Nakamura, Tadaki Suzuki, Katsuhiro Komase, Eri Nobusawa, Katsumi Maenaka, Makoto Kuroda, and Hideki Hasegawa
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HEMAGGLUTININ , *INFLUENZA A virus , *ARGININE , *SERINE proteinases , *PLASMIDS - Abstract
Proteolytic cleavage of the hemagglutinin (HA) protein is essential for influenza A virus (IAV) to acquire infectivity. This process is mediated by a host cell protease(s) in vivo. The type II transmembrane serine protease TMPRSS2 is expressed in the respiratory tract and is capable of activating a variety of respiratory viruses, including low-pathogenic (LP) IAVs possessing a single arginine residue at the cleavage site. Here we show that TMPRSS2 plays an essential role in the proteolytic activation of LP IAVs, including a recently emerged H7N9 subtype, in vivo. We generated TMPRSS2 knockout (KO) mice. The TMPRSS2 KO mice showed normal reproduction, development, and growth phenotypes. In TMPRSS2 KO mice infected with LP IAVs, cleavage of HA was severely impaired, and consequently, the majority of LP IAV progeny particles failed to gain infectivity, while the viruses were fully activated proteolytically in TMPRSS2+/+ wild-type (WT) mice. Accordingly, in contrast to WT mice, TMPRSS2 KO mice were highly tolerant of challenge infection by LP IAVs (H1N1, H3N2, and H7N9) with⩾1,000 50% lethal doses (LD50) for WT mice. On the other hand, a high-pathogenic H5N1 subtype IAV possessing a multibasic cleavage site was successfully activated in the lungs of TMPRSS2 KO mice and killed these mice, as observed for WT mice. Our results demonstrate that recently emerged H7N9 as well as seasonal IAVs mainly use the specific protease TMPRSS2 for HA cleavage in vivo and, thus, that TMPRSS2 expression is essential for IAV replication in vivo. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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35. The prevalence of opportunistic infections and malignancies in autopsied patients with human immunodeficiency virus infection in Japan.
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Harutaka Katano, Tsunekazu Hishima, Makoto Mochizuki, Yoshinori Kodama5, Naoki Oyaizu, Yasunori Ota, Sohtaro Mine, Toru Igari, Atsushi Ajisawa, Katsuji Teruya, Junko Tanuma, Yoshimi Kikuchi, Tomoko Uehira, Takuma Shirasaka, Tomohiko Koibuchi, Aikichi Iwamoto, Shinichi Oka, Hideki Hasegawa, Seiji Okada, and Akira Yasuoka
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OPPORTUNISTIC infections , *HIV infections , *FORENSIC medicine , *ANTIVIRAL agents , *HIGHLY active antiretroviral therapy - Abstract
Background Opportunistic infections and malignancies such as malignant lymphoma and Kaposi sarcoma are significant complications of human immunodeficiency virus (HIV) infection. However, following the introduction of antiretroviral therapy in Japan in 1997, the incidence of clinical complications has decreased. In the present study, autopsy cases of HIV infection in Japan were retrospectively investigated to reveal the prevalence of opportunistic infections and malignancies. Methods A total of 225 autopsy cases of HIV infection identified at 4 Japanese hospitals from 1985- 2012 were retrospectively reviewed. Clinical data were collected from patient medical records. Results Mean CD4 counts of patients were 77.0 cells/μL in patients who received any antiretroviral therapy during their lives (ART (+) patients) and 39.6 cells/μL in naïve patients (ART (-) patients). Cytomegalovirus infection (142 cases, 63.1%) and pneumocystis pneumonia (66 cases, 29.3%) were the most frequent opportunistic infections, and their prevalence was significantly lower in ART (+) patients than ART (-) patients. Non-Hodgkin lymphoma and Kaposi sarcoma were observed in 30.1% and 16.2% of ART (-) patients, and 37.9% and 15.2% of ART (+) patients, respectively. Malignant lymphoma was the most frequent cause of death, followed by cytomegalovirus infection regardless of ART. Non-acquired immunodeficiency syndrome (AIDS)-defining cancers such as liver and lung cancer caused death more frequently in ART (+) patients (9.1%) than in ART (-) patients (1.5%; P = 0.026). Conclusions The prevalence of infectious diseases and malignancies were revealed in autopsy cases of HIV infection in Japan. The prevalence of cytomegalovirus infection and pneumocystis pneumonia at autopsy were lower in ART (+) patients than ART (-) patients. Higher prevalence of non-AIDS defining malignancies among ART (+) patients than ART (-) patients suggests that onsets of various opportunistic infections and malignancies should be carefully monitored regardless of whether the patient is receiving ART. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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36. Plasma Antimicrobial Peptide LL-37 Level Is Inversely Associated with HDL Cholesterol Level in Patients with Type 2 Diabetes Mellitus.
- Author
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Shu Meguro, Masuomi Tomita, Takeshi Katsuki, Kiyoe Kato, Henpiru Oh, Akira Ainai, Ryo Ito, Toshihide Kawai, Hiroshi Itoh, and Hideki Hasegawa
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ATHEROSCLEROSIS , *ANTI-infective agents , *TYPE 2 diabetes , *CHOLESTEROL , *C-reactive protein - Abstract
Introduction. Relation between atherosclerosis and innate immunity has attracted attention. As the antimicrobial peptide, LL-37, could have an important role in atherosclerosis, we supposed that there could be a meaningful association of plasma LL-37 level with risk factors for cardiovascular disease in subjects with type 2 diabetes mellitus. Materials and Methods. We evaluated plasma LL-37 level and other clinical markers in Japanese subjects with type 2 diabetes mellitus (n = 133,115 men and 18 women; age 64.7 ± 11.5 years; HbA1c 8.1 ± 1.6%). Plasma level of LL-37 was measured by ELISA. Results. Mean plasma LL-37 level was 71.2 ± 22.3 ng/mL. Plasma LL-37 level showed significant correlations with HDL cholesterol (r = -0.450, P < 0.01), triglyceride (r = 0.445, P < 0.01), and high sensitive C-reactive protein (r = 0.316, P < 0.01) but no significant correlation with age, body mass index, HbA1c, estimated glomerular filtration rate, 25-hydroxy vitamin D, or vitamin D binding protein. Multiple linear regression analysis showed significant correlations of plasma LL-37 level with HDL cholesterol (ß = -0.411, P < 0.01) and high sensitive C-reactive protein (ß = 0.193, P < 0.05). Conclusion. Plasma LL-37 level waspositively correlated with inflammatory markers and negatively correlated with HDL cholesterol in patients with type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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37. Highly Frequent Mutations in Negative Regulators of Multiple Virulence Genes in Group A Streptococcal Toxic Shock Syndrome Isolates.
- Author
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Tadayoshi Ikebe, Manabu Ato, Takayuki Matsumura, Hideki Hasegawa, Tetsutaro Sata, Kazuo Kobayashi, and Haruo Watanabe
- Abstract
Streptococcal toxic shock syndrome (STSS) is a severe invasive infection characterized by the sudden onset of shock and multiorgan failure; it has a high mortality rate. Although a number of studies have attempted to determine the crucial factors behind the onset of STSS, the responsible genes in group A Streptococcus have not been clarified. We previously reported that mutations of csrS/csrR genes, a two-component negative regulator system for multiple virulence genes of Streptococcus pyogenes, are found among the isolates from STSS patients. In the present study, mutations of another negative regulator, rgg, were also found in clinical isolates of STSS patients. The rgg mutants from STSS clinical isolates enhanced lethality and impaired various organs in the mouse models, similar to the csrS mutants, and precluded their being killed by human neutrophils, mainly due to an overproduction of SLO. When we assessed the mutation frequency of csrS, csrR, and rgg genes among S. pyogenes isolates from STSS (164 isolates) and non-invasive infections (59 isolates), 57.3% of the STSS isolates had mutations of one or more genes among three genes, while isolates from patients with non-invasive disease had significantly fewer mutations in these genes (1.7%). The results of the present study suggest that mutations in the negative regulators csrS/csrR and rgg of S. pyogenes are crucial factors in the pathogenesis of STSS, as they lead to the overproduction of multiple virulence factors. [ABSTRACT FROM AUTHOR]
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- 2010
- Full Text
- View/download PDF
38. Herpes Simplex Virus 1 VP22 Regulates Translocation of Multiple Viral and Cellular Proteins and Promotes Neurovirulence.
- Author
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Michiko Tanaka, Akihisa Kato, Yuko Satoh, Takahiro Ide, Ken Sagou, Kayo Kimura, Hideki Hasegawa, and Yasushi Kawaguchi
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HERPES simplex virus , *CHROMOSOMAL translocation , *VIRAL proteins , *NEUROVIROLOGY , *CYTOPLASM , *AMINO acids , *GENE expression in viruses - Abstract
Herpes simplex virus 1 (HSV-1) protein VP22, encoded by the UL49 gene, is a major virion tegument protein. In the present study, we showed that VP22 was required for efficient redistribution of viral proteins VP16, VP26, ICP0, ICP4, and ICP27 and of cellular protein Hsc-70 to the cytoplasm of infected cells. We found that two dileucine motifs in VP22, at amino acids 235 and 236 and amino acids 251 and 252, were necessary for VP22 regulation of the proper cytoplasmic localization of these viral and cellular proteins. The dileucine motifs were also required for proper cytoplasmic localization of VP22 itself and for optimal expression of viral proteins VP16, VP22, ICP0, UL41, and glycoprotein B. Interestingly, a recombinant mutant virus with alanines substituted for the dileucines at amino acids 251 and 252 had a 50% lethal dose (LD50) for neurovirulence in mice following intracerebral inoculation about 103-fold lower than the LD50 of the repaired virus. Furthermore, the replication and spread of this mutant virus in the brains of mice following intracerebral inoculation were significantly impaired relative to those of the repaired virus. The ability of VP22 to regulate the localization and expression of various viral and cellular proteins, as shown in this study, was correlated with an increase in viral replication and neurovirulence in the experimental murine model. Thus, HSV-1 VP22 is a significant neurovirulence factor in vivo. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
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