Details of a Researcher - Fujii, Hideki

Papers - Fujii, Hideki

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Immunological detection of severe acute respiratory syndrome coronavirus by monoclonal antibodies.

Ohnishi, K., Sakaguchi, M., Kaji, T., Akagawa, K., Taniyama, T., Kasai,M., Tsunetsugu-Yokota, Y., Ohshima, M., Yamamoto, K., Takasuka, N., Hashimoto, S., Ato, M., Fujii, H., Takahashi, Y., Morikawa, S., Ishii, K., Sata, T., Takagi, H., Itamura, S., Odagiri, T, Miyamura, T., Kurane, I., Tashiro, M., Kurata, T., Yoshikura, H. and Takemori, T

Jpn. J Infect. Dis. 58 ( 2 ) 88-94 - 94 2005.04

Research paper (scientific journal), Single Work, ISSN 1344-6304

In order to establish immunological detection methods for severe acute respiratory syndrome coronavirus (SARS-CoV), we established monoclonal antibodies directed against structural components of the virus. B cell hybridomas were generated from mice that were hyper-immunized with inactivated SARS-CoV virion. By screening 2,880 generated hybridomas, we established three hybridoma clones that secreted antibodies specific for nucleocapsid protein (N) and 27 clones that secreted antibodies specific for spike protein (S). Among these, four S-protein specific antibodies had in vitro neutralization activity against SARS-CoV infection. These monoclonal antibodies enabled the immunological detection of SARS-CoV by immunofluorescence staining, Western blot or immunohistology. Furthermore, a combination of monoclonal antibodies with different specificities allowed the establishment of a highly sensitive antigen-capture sandwich ELISA system. These monoclonal antibodies would be a useful tool for rapid and specific diagnosis of SARS and also for possible antibody-based treatment of the disease.

Double-Stranded RNA Poly(I:C) Combined with Mucosal Vaccine Protects against Influenza Virus Infection.

Ichinohe T, Watanabe I, Ito S, Fujii H, Moriyama M, Tamura S, Takahashi H, Sawa H, Chiba J, Kurata T, Sata T, Hasegawa H.

J Virol. 79 ( 5 ) 2910-2919 - 2919 2005.03

Research paper (scientific journal), Joint Work, Accepted

A subcutaneously injected UV-inactivated SARS coronavirus vaccine elicits systemic humoral immunity in mice

Takasuka N, Fujii H, Takahashi Y, Kasai M, Morikawa S, Itamura S, Ishii K, Sakaguchi M, Ohnishi K, Ohshima M, Hashimoto S, Odagiri T, Tashiro M, Yoshikura H, Takemori T, Tsunetsugu-Yokota Y.

Int Immunol. 16 ( 10 ) 1423-1430 2004.10

Research paper (scientific journal), Joint Work, Accepted

2-methacryloyloxyethyl phosphorylcholine polymer treatment prevents Candida albicans biofilm formation on acrylic resin.

Adityakrisna Yoshi Putra Wigianto, Yuichi Ishida, Yuki Iwawaki, Takaharu Goto, Megumi Watanabe, Kazumitsu Sekine, Kenichi Hamada, Keiji Murakami, Hideki Fujii, Tetsuo Ichikawa

Journal of prosthodontic research 2022.10

Research paper (scientific journal), Joint Work, Lead author, Last author, Corresponding author, Accepted

PURPOSE: We aimed to evaluate the effectiveness of photoreactive 2-methacryloyloxyethyl phosphorylcholine (MPC) in inhibiting Candida albicans biofilm formation on polymethyl methacrylate (PMMA) and assess its mechanism and need for re-application by evaluating its interaction with salivary mucin and durability during temperature changes. METHODS: PMMA discs were used as specimens. The MPC coating was applied using the spray and cure technique for the treatment groups, whereas no coating was applied to the control. The MPC treatment (MT) groups were further differentiated based on the number of thermal cycles involved (0, 1000, 2500, and 5000). The optical density was measured to assess mucin adsorption (MA). Contact angle (CA) was calculated to evaluate surface hydrophilicity. The presence of MPC components on the PMMA surface was assessed using X-ray photoelectron spectroscopy (XPS). C. albicans biofilms were evaluated qualitatively (scanning electron microscope images) and quantitatively (colony-forming units (CFUs)). Statistical analysis was conducted using two-way analysis of variance and Tukey's multiple comparison test. RESULTS: MA rate and CA increased significantly in the MT groups, which exhibited significantly fewer CFUs and thinner biofilms than those of the control group. Based on the XPS, MA, and CFU evaluations, the durability and efficacy of the MPC coating were considered stable up to 2500 thermal cycles. Additionally, a significant interaction was observed between mucin concentration and MPC efficacy. CONCLUSIONS: The photoreactive MPC coating, which was resistant to temperature changes for approximately 3 months, effectively prevented C. albicans biofilm formation by modifying surface hydrophilicity and increasing mucin adsorption.

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Porphyromonas gingivalis Outer Membrane Vesicles Stimulate Gingival Epithelial Cells to Induce Pro-Inflammatory Cytokines via the MAPK and STING Pathways

Yuta Uemura, Yuka Hiroshima, Ayano Tada, Keiji Murakami, Kaya Yoshida, Yuji Inagaki, Tomomi Kuwahara, Akikazu Murakami, Hideki Fujii, Hiromichi Yumoto

Biomedicines (MDPI AG) 10 ( 10 ) 2643 - 2643 2022.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 2227-9059

Porphyromonas gingivalis (Pg) is a keystone pathogen associated with chronic periodontitis and produces outer membrane vesicles (OMVs) that contain lipopolysaccharide (LPS), gingipains, and pathogen-derived DNA and RNA. Pg-OMVs are involved in the pathogenesis of periodontitis. Pg-OMV-activated pathways that induce the production of the pro-inflammatory cytokines, interleukin (IL)-6, and IL-8 in the human gingival epithelial cell line, OBA-9, were investigated. The role of mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB in levels of Pg-OMV-induced pro-inflammatory cytokines was investigated using Western blot analysis and specific pathway inhibitors. Pg-OMVs induced IL-6 and IL-8 production via the extracellular signal-regulated kinase (Erk) 1/2, c-Jun N-terminal kinase (JNK), p38 MAPK, and NF-κB signaling pathways in OBA-9 cells. In addition, the stimulator of interferon genes (STING), an essential innate immune signaling molecule, was triggered by a cytosolic pathogen DNA. Pg-OMV-induced IL-6 and IL-8 mRNA expression and production were significantly suppressed by STING-specific small interfering RNA. Taken together, these results demonstrated that Pg-OMV-activated Erk1/2, JNK, p38 MAPK, STING, and NF-κB signaling pathways resulting in increased IL-6 and IL-8 expression in human gingival epithelial cells. These results suggest that Pg-OMVs may play important roles in periodontitis exacerbation by stimulating various pathways.

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Regulatory roles of fibronectin and integrin α5 in reorganization of the actin cytoskeleton and completion of adipogenesis.

Uetaki M, Onishi N, Oki Y, Shimizu T, Sugihara E, Sampetrean O, Watanabe T, Yanagi H, Suda K, Fujii H, Kano K, Saya H, Nobusue H

Molecular biology of the cell 33 ( 9 ) ar78 2022.08

Research paper (scientific journal), Joint Work, Lead author, Last author, Corresponding author, Accepted, ISSN 1059-1524

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First reported case of Lachnoanaerobaculum gingivalis bacteremia in an acute myeloid leukemia patient with oral mucositis during high dose chemotherapy.

Naoto Okada, Akikazu Murakami, Masami Sato, Shingen Nakamura, Shiro Fujii, Kimiko Sogabe, Mamiko Takahashi, Asami Okada, Akane Abe, Hideki Fujii, Masahiro Abe, Momoyo Azuma, Keisuke Ishizawa

Anaerobe (Anaerobe) 76 102610 - 102610 2022.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 10759964

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pruR and PA0065 Genes Are Responsible for Decreasing Antibiotic Tolerance by Autoinducer Analog-1 (AIA-1) in Pseudomonas aeruginosa.

Muhammad Reza Pahlevi, Keiji Murakami, Yuka Hiroshima, Akikazu Murakami, Hideki Fujii

Antibiotics (Basel, Switzerland) (Antibiotics) 11 ( 6 ) 2022.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 2079-6382

Pseudomonas aeruginosa infection is considered a high-risk nosocomial infection and is very difficult to eradicate because of its tolerance to antibiotic treatment. A new compound, autoinducer analog-1 (AIA-1), has been demonstrated to reduce antibiotic tolerance, but its mechanisms remain unknown. This study aimed to investigate the mechanisms of AIA-1 in the antibiotic tolerance of P. aeruginosa. A transposon mutant library was constructed using miniTn5pro, and screening was performed to isolate high tolerant mutants upon exposure to biapenem and AIA-1. We constructed a deletion mutant and complementation strain of the genes detected in transposon insertion site determination, pruR and PA0066-65-64, and performed killing assays with antibiotics and AIA-1. Gene expression upon exposure to biapenem and AIA-1 and their relationship to stress response genes were analyzed. High antibiotic tolerance was observed in Tn5-pruR and Tn5-PA0065 transposon mutants and their deletion mutants, ΔpruR and ΔPA0066-65-64. Complemented strains of pruR and PA0066-65-64 with their respective deletion mutants exhibited suppressed antibiotic tolerance. It was determined that deletion of PA0066-65-64 increased rpoS expression, and PA0066-65-64 affects antibiotic tolerance via the rpoS pathway. Additionally, antibiotics and AIA-1 were found to inhibit pruR and PA0066-65-64. This study proposed that pruR and PA0066-65-64 are members of the antibiotic tolerance suppressors.

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Proton pump inhibitors affect capecitabine efficacy in patients with stage II-III colorectal cancer: a multicenter retrospective study.

Kitazume Y, Kawazoe H, Uozumi R, Yoshizawa T, Iihara H, Fujii H, Takahashi M, Arai T, Murachi Y, Sato Y, Mikami T, Hashiguchi K, Yamazaki T, Takahashi K, Fujita Y, Hosokawa Y, Morozumi I, Tsuchiya M, Yokoyama A, Hashimoto H, Yamaguchi M

Scientific reports 12 ( 1 ) 6561 2022.04

Research paper (scientific journal), Joint Work, Lead author, Last author, Corresponding author, Accepted

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IgM to IgG Class Switching Is a Necessary Step for Pemphigus Phenotype Induction in Desmoglein 3-Specific B Cell Receptor Knock-in Mouse.

Hisashi Nomura, Naoko Wada, Hayato Takahashi, Yuko Kase, Jun Yamagami, Shohei Egami, Hisato Iriki, Miho Mukai, Aki Kamata, Hiromi Ito, Hideki Fujii, Tomoyuki Ishikura, Haruhiko Koseki, Takashi Watanabe, Taketo Yamada, Osamu Ohara, Shigeo Koyasu, Masayuki Amagai

Journal of immunology (Baltimore, Md. : 1950) (Journal of Immunology) 208 ( 3 ) 582 - 593 2022.02

Research paper (scientific journal), Joint Work, Accepted, ISSN 00221767

Pemphigus vulgaris is an autoimmune blistering disease caused by IgG targeting desmoglein 3 (Dsg3), an adhesion molecule of keratinocytes. Anti-Dsg3 IgG production is prevented in healthy individuals, but it is unclear how Dsg3-specific B cells are regulated. To clarify the immunological condition regulating Dsg3-specific B cells, a pathogenic anti-Dsg3 Ig (AK23) knock-in mouse was generated. AK23 knock-in B cells developed normally without undergoing deletion or acquiring an anergic phenotype in vivo. The knock-in B cells showed Ca2+ influx upon IgM cross-linking and differentiated into AK23-IgG+ B cells after LPS and IL-4 stimulation in vitro that induced a pemphigus phenotype after adoptive transfer into Rag2 -/- mice. However, the knock-in mouse itself produced AK23-IgM but little IgG without blisters in vivo. Dsg3 immunization and skin inflammation caused AK23-IgG production and a pemphigus phenotype in vivo. Furthermore, Fcgr2b deficiency or haploinsufficiency spontaneously induced AK23-IgG production and a pemphigus phenotype with poor survival rates in AK23 knock-in mice. To assess Fcgr2b involvement in Ig class-switch efficiency, postswitch transcripts of B cells were quantified and significantly higher in Fcgr2b -/- and Fcgr2b +/- mice than wild-type mice in a gene dose-dependent manner. Finally, RNA sequencing revealed reduced expression of FCGR2B and FcγRIIB-related genes in patient B cells. These results indicated that Dsg3-specific B cells do not spontaneously perform pathogenic class switching in vivo, and pemphigus phenotype induction was prevented under normal conditions. Attenuated FcγRIIB signaling is also one of the drivers for pathogenic class switching and is consistent with immunological features identified from clinical samples. This study unveiled a characteristic immune state silencing autoreactive B cells in mice.

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Autoinducer Analogs Can Provide Bactericidal Activity to Macrolides in Pseudomonas aeruginosa through Antibiotic Tolerance Reduction.

Mizuki Abe, Keiji Murakami, Yuka Hiroshima, Takashi Amoh, Mayu Sebe, Keiko Kataoka, Hideki Fujii

Antibiotics (Basel, Switzerland) (Antibiotics) 11 ( 1 ) 2022.01

Research paper (scientific journal), Joint Work, Accepted

Macrolide antibiotics are used in treating Pseudomonas aeruginosa chronic biofilm infections despite their unsatisfactory antibacterial activity, because they display several special activities, such as modulation of the bacterial quorum sensing and immunomodulatory effects on the host. In this study, we investigated the effects of the newly synthesized P. aeruginosa quorum-sensing autoinducer analogs (AIA-1, -2) on the activity of azithromycin and clarithromycin against P. aeruginosa. In the killing assay of planktonic cells, AIA-1 and -2 enhanced the bactericidal ability of macrolides against P. aeruginosa PAO1; however, they did not affect the minimum inhibitory concentrations of macrolides. In addition, AIA-1 and -2 considerably improved the killing activity of azithromycin and clarithromycin in biofilm cells. The results indicated that AIA-1 and -2 could affect antibiotic tolerance. Moreover, the results of hydrocarbon adherence and cell membrane permeability assays suggested that AIA-1 and -2 changed bacterial cell surface hydrophobicity and accelerated the outer membrane permeability of the hydrophobic antibiotics such as azithromycin and clarithromycin. Our study demonstrated that the new combination therapy of macrolides and AIA-1 and -2 may improve the therapeutic efficacy of macrolides in the treatment of chronic P. aeruginosa biofilm infections.

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Optimizing antiemetic treatment for chemotherapy-induced nausea and vomiting in Japan: Update summary of the 2015 Japan Society of Clinical Oncology Clinical Practice Guidelines for Antiemesis.

Aogi K, Takeuchi H, Saeki T, Aiba K, Tamura K, Iino K, Imamura CK, Okita K, Kagami Y, Tanaka R, Nakagawa K, Fujii H, Boku N, Wada M, Akechi T, Iihara H, Ohtani S, Okuyama A, Ozawa K, Kim YI, Sasaki H, Shima Y, Takeda M, Nagasaki E, Nishidate T, Higashi T, Hirata K

International journal of clinical oncology 26 ( 1 ) 1 - 17 2021.01

Research paper (scientific journal), Joint Work, Lead author, Last author, Corresponding author, Accepted, ISSN 1341-9625

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Clinical Significance of Carbapenem-Tolerant Pseudomonas aeruginosa Isolated in the Respiratory Tract.

Momoyo Azuma, Keiji Murakami, Rina Murata, Keiko Kataoka, Hideki Fujii, Yoichiro Miyake, Yasuhiko Nishioka

Antibiotics (Basel, Switzerland) 9 ( 9 ) 2020.09

Research paper (scientific journal), Joint Work, Lead author, Last author, Corresponding author, Accepted

We often come across difficult to treat infections-even after administering appropriate antibiotics according to the minimal inhibitory concentration of the causative bacteria. Antibiotic tolerance has recently started to garner attention as a crucial mechanism of refractory infections. However, few studies have reported the correlation between clinical outcomes and antibiotic tolerance. This study aims to clarify the effect of antibiotic tolerance on clinical outcomes of respiratory tract infection caused by Pseudomonas aeuginosa (P. aeruginosa). We examined a total of 63 strains isolated from sputum samples of different patients and conducted a retrospective survey with the medical records of 37 patients with imipenem-sensitive P. aeruginosa infections. Among them, we selected 15 patients with respiratory infections, and they were divided into high-tolerance minimal bactericidal concentration for adherent bacteria (MBCAD)/minimal inhibitory concentration for adherent bacteria (MICAD) ≥ 32 (n = 9) group and low-tolerance MBCAD/MICAD ≤ 16 (n = 6) group for further investigations. The findings indicated that the high-tolerance group consisted of many cases requiring hospitalization. Chest computed tomography findings showed that the disease was more extensive in the high-tolerance group compared to the low-tolerance group. Regarding the bacterial phenotypic characterization, the high-tolerance group significantly upregulated the production of the virulence factors compared to the low-tolerance group. Our study provided evidence that carbapenem tolerance level is a potent prognostic marker of P. aeruginosa infections, and carbapenem tolerance could be a potential target for new antimicrobial agents to inhibit the progression of persistent P. aeruginosa infections.

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Suppressive effects of 2-methacryloyloxyethyl phosphorylcholine (MPC)-polymer on the adherence of Candida species and MRSA to acrylic denture resin.

Natsumi Fujiwara, Keiji Murakami, Kaya Yoshida, Shunsuke Sakurai, Yasusei Kudo, Kazumi Ozaki, Katsuhiko Hirota, Hideki Fujii, Maiko Suzuki, Yoichiro Miyake, Hiromichi Yumoto

Heliyon 6 ( 6 ) e04211 2020.06

Research paper (scientific journal), Joint Work, Lead author, Last author, Corresponding author, Accepted

OBJECTIVES: The effects of 2-methacryloyloxyethyl phosphorylcholine (MPC)-polymer on the adherence of microorganisms such as non-Candida albicans Candida (NCAC) and methicillin-resistant Staphylococcus aureus (MRSA), frequently detected in oral infections in immunocompromised and/or elderly people, to denture resin material, are still unclear. Here, we report the effects of MPC-polymer on the adherence of C. albicans, NCAC, and MRSA to acrylic denture resin. METHODS: Sixteen strains of C. albicans, seven strains of C. glabrata, two strains of C. tropicalis, one strain of C. parapsilosis, and six strains of MRSA were used. We cultured the fungal/bacterial strains and examined the cell growth and adherence of fungi/bacteria to mucin-coated acrylic denture resin plates (ADRP) with or without MPC-polymer coating, by scanning electron microscopy. The cell surface hydrophobicity of the fungal/bacterial strains was measured by the adsorption to hydrocarbons. RESULTS: MPC-polymer did not affect the growth of all strains of Candida species and MRSA, but significantly suppressed adherence to ADRP in most strains of C. albicans and all strains of NCAC and MRSA. A significant positive correlation was found between cell hydrophobicity and the reduction rates of microbial adherence to ADRP treated with 5% of MPC-polymer. CONCLUSIONS: MPC-polymer treatment for acrylic resin material suppresses the adherence of C. albicans, NCAC and MRSA via their hydrophilicity interaction. CLINICAL SIGNIFICANCE: The application of MPC-polymer for denture hygiene is potent to prevent oral candidiasis, denture stomatitis and opportunistic infection, caused by Candida species and MRSA, via suppressing the adherence of those fungus/bacteria.

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The Pathogenic Factors from Oral Streptococci for Systemic Diseases.

Hiromichi Yumoto, Katsuhiko Hirota, Kouji Hirao, Masami Ninomiya, Keiji Murakami, Hideki Fujii, Yoichiro Miyake

International journal of molecular sciences 20 ( 18 ) 2019.09

Research paper (scientific journal), Joint Work, Lead author, Last author, Corresponding author, Accepted

The oral cavity is suggested as the reservoir of bacterial infection, and the oral and pharyngeal biofilms formed by oral bacterial flora, which is comprised of over 700 microbial species, have been found to be associated with systemic conditions. Almost all oral microorganisms are non-pathogenic opportunistic commensals to maintain oral health condition and defend against pathogenic microorganisms. However, oral Streptococci, the first microorganisms to colonize oral surfaces and the dominant microorganisms in the human mouth, has recently gained attention as the pathogens of various systemic diseases, such as infective endocarditis, purulent infections, brain hemorrhage, intestinal inflammation, and autoimmune diseases, as well as bacteremia. As pathogenic factors from oral Streptococci, extracellular polymeric substances, toxins, proteins and nucleic acids as well as vesicles, which secrete these components outside of bacterial cells in biofilm, have been reported. Therefore, it is necessary to consider that the relevance of these pathogenic factors to systemic diseases and also vaccine candidates to protect infectious diseases caused by Streptococci. This review article focuses on the mechanistic links among pathogenic factors from oral Streptococci, inflammation, and systemic diseases to provide the current understanding of oral biofilm infections based on biofilm and widespread systemic diseases.

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Obesity worsens the outcome of influenza virus infection associated with impaired type I interferon induction in mice.

Ho Namkoong, Makoto Ishii, Hideki Fujii, Takahiro Asami, Kazuma Yagi, Shoji Suzuki, Shuhei Azekawa, Sadatomo Tasaka, Naoki Hasegawa, Tomoko Betsuyaku

Biochemical and biophysical research communications 513 ( 2 ) 405 - 411 2019.05

Research paper (scientific journal), Joint Work, Lead author, Last author, Corresponding author, Accepted

Increasing evidence indicates that obesity is a risk factor for increased severity of influenza virus infection. However, its precise immunological mechanism is not fully understood. To investigate this, diet-induced obese (DIO) mice were established by feeding C57BL/6 male mice a high-fat diet for 16 weeks. DIO and lean control mice were infected intranasally with 3000 pfu of influenza A virus (IAV) (PR8/H1N1). Interestingly, we found adipose tissue located along the bronchus in naïve DIO mice. In addition, the Nos2 level was significantly higher and Arg1 level was significantly lower in lung macrophages of naïve DIO mice, consistent with an M1-skewed phenotype. The survival rate and body weight of DIO mice infected with IAV were significantly lower than those of lean control mice and associated with higher viral load in the lungs of DIO mice. Histopathological analysis demonstrated higher numbers of inflammatory cells in the lungs of DIO mice after IAV infection. Levels of cytokines, including TNF-α, IL-6, IL-10, and type I IFN (IFN-α and IFN-β), in bronchoalveolar lavage fluid (BALF) were altered after IAV infection; in particular, IFN-α and IFN-β levels were significantly suppressed in the BALF of DIO mice. In vitro, bone marrow-derived macrophages were stimulated with ligands of toll-like receptor (TLR) 7/8, a pattern recognition receptor for single-stranded RNA, and levels of TNF-α, IL-6, and IL-10 were similarly altered. In addition, levels of IFN-α and IFN-β were significantly lower in culture supernatants of alveolar macrophages sorted from naïve DIO mice and infected with IAV, compared to those in macrophages sorted from lean control mice. Collectively, these results suggest that macrophages may be the main contributors to poor outcomes of influenza virus infection in obesity.

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Clarithromycin expands CD11b+Gr-1+ cells via the STAT3/Bv8 axis to ameliorate lethal endotoxic shock and post-influenza bacterial pneumonia.

Ho Namkoong, Makoto Ishii, Hideki Fujii, Kazuma Yagi, Takahiro Asami, Takanori Asakura, Shoji Suzuki, Ahmed E Hegab, Hirofumi Kamata, Sadatomo Tasaka, Koji Atarashi, Nobuhiro Nakamoto, Satoshi Iwata, Kenya Honda, Takanori Kanai, Naoki Hasegawa, Shigeo Koyasu, Tomoko Betsuyaku

PLoS pathogens 14 ( 4 ) e1006955 2018.04

Research paper (scientific journal), Joint Work, Lead author, Last author, Corresponding author, Accepted

Macrolides are used to treat various inflammatory diseases owing to their immunomodulatory properties; however, little is known about their precise mechanism of action. In this study, we investigated the functional significance of the expansion of myeloid-derived suppressor cell (MDSC)-like CD11b+Gr-1+ cells in response to the macrolide antibiotic clarithromycin (CAM) in mouse models of shock and post-influenza pneumococcal pneumonia as well as in humans. Intraperitoneal administration of CAM markedly expanded splenic and lung CD11b+Gr-1+ cell populations in naïve mice. Notably, CAM pretreatment enhanced survival in a mouse model of lipopolysaccharide (LPS)-induced shock. In addition, adoptive transfer of CAM-treated CD11b+Gr-1+ cells protected mice against LPS-induced lethality via increased IL-10 expression. CAM also improved survival in post-influenza, CAM-resistant pneumococcal pneumonia, with improved lung pathology as well as decreased interferon (IFN)-γ and increased IL-10 levels. Adoptive transfer of CAM-treated CD11b+Gr-1+ cells protected mice from post-influenza pneumococcal pneumonia. Further analysis revealed that the CAM-induced CD11b+Gr-1+ cell expansion was dependent on STAT3-mediated Bv8 production and may be facilitated by the presence of gut commensal microbiota. Lastly, an analysis of peripheral blood obtained from healthy volunteers following oral CAM administration showed a trend toward the expansion of human MDSC-like cells (Lineage-HLA-DR-CD11b+CD33+) with increased arginase 1 mRNA expression. Thus, CAM promoted the expansion of a unique population of immunosuppressive CD11b+Gr-1+ cells essential for the immunomodulatory properties of macrolides.

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Antibiofilm and Anti-Inflammatory Activities of Houttuynia cordata Decoction for Oral Care.

Yasuko Sekita, Keiji Murakami, Hiromichi Yumoto, Kouji Hirao, Takashi Amoh, Natsumi Fujiwara, Katsuhiko Hirota, Hideki Fujii, Takashi Matsuo, Yoichiro Miyake, Yoshiki Kashiwada

Evidence-based complementary and alternative medicine : eCAM 2017 2850947 - 2850947 2017

Research paper (scientific journal), Joint Work, Lead author, Last author, Corresponding author, Accepted

Dental biofilms that form in the oral cavity play a critical role in the pathogenesis of several infectious oral diseases, including dental caries, periodontal disease, and oral candidiasis. Houttuynia cordata (HC, Saururaceae) is a widely used traditional medicine, for both internal and external application. A decoction of dried HC leaves (dHC) has long been consumed as a health-promoting herbal tea in Japan. We have recently reported that a water solution of HC poultice ethanol extract (wHCP) exerts antimicrobial and antibiofilm effects against several important oral pathogens. It also exhibits anti-inflammatory effects on human keratinocytes. In our current study, we examined the effects of dHC on infectious oral pathogens and inflammation. Our results demonstrated that dHC exerts moderate antimicrobial effects against methicillin-resistant Staphylococcus aureus (MRSA) and other oral microorganisms. dHC also exhibited antibiofilm effects against MRSA, Fusobacterium nucleatum (involved in dental plaque formation), and Candida albicans and inhibitory effects on interleukin-8, CCL20, IP-10, and GROα productions by human oral keratinocytes stimulated by Porphyromonas gingivalis lipopolysaccharide (a cause of periodontal disease), without cytotoxic effects. This suggests that dHC exhibits multiple activities in microorganisms and host cells. dHC can be easily prepared and may be effective in preventing infectious oral diseases.

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Corrigendum to 'Phagocytic cells contribute to the antibody-mediated elimination of pulmonary-infected SARS coronavirus' [Virology (2014) 157-168].

Fumihiko Yasui, Michinori Kohara, Masahiro Kitabatake, Tetsu Nishiwaki, Hideki Fujii, Chise Tateno, Misako Yoneda, Kouichi Morita, Kouji Matsushima, Shigeo Koyasu, Chieko Kai

Virology (ACADEMIC PRESS INC ELSEVIER SCIENCE BV) 499: 397 - 398 2016.12

Research paper (scientific journal), Joint Work, Lead author, Last author, Corresponding author, Accepted, ISSN 0042-6822

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Histone Deacetylase Inhibition Protects Mice Against Lethal Postinfluenza Pneumococcal Infection.

Kazuma Yagi, Makoto Ishii, Ho Namkoong, Hideki Fujii, Takahiro Asami, Shoji Suzuki, Takanori Asakura, Kosuke Mizoguchi, Tetsuro Kamo, Sadatomo Tasaka, Satoshi Iwata, Steven L Kunkel, Naoki Hasegawa, Tomoko Betsuyaku

Critical care medicine 44 ( 10 ) e980-7 2016.10

Research paper (scientific journal), Joint Work, Lead author, Last author, Corresponding author, Accepted

OBJECTIVES: Secondary bacterial pneumonia following influenza virus infection is associated with high mortality, but the mechanism is largely unknown. Epigenetic gene regulation appears to play key roles in innate and adaptive immunity. We hypothesized that histone acetylation, a major epigenetic mechanism associated with transcriptionally active chromatin, might contribute to the poor outcome of postinfluenza pneumonia. DESIGN: Prospective experimental study. SETTING: University research laboratory. SUBJECTS: C57BL/6 male mice. INTERVENTIONS: Mice were infected intranasally with 1.0 × 10 colony-forming units of Streptococcus pneumoniae, 7 days after intranasal inoculation with five plaque-forming units of influenza virus A/H1N1/PR8/34. The mice were intraperitoneally injected with the histone deacetylase inhibitor trichostatin A (1 mg/kg) or vehicle once a day from 1 hour after pneumococcal infection throughout the course of the experiment. The primary outcome was survival rate. MEASUREMENTS AND MAIN RESULTS: Trichostatin A significantly suppressed histone deacetylase activity and significantly improved the survival rate of mice (56.3%) after postinfluenza pneumococcal infection when compared with vehicle-treated mice (20.0%), which was associated with a significant decrease in the total cell count of the bronchoalveolar lavage fluid. The interleukin-1β level in the serum and the number of natural killer cells in the lungs were significantly lower in the trichostatin A-treated group. CONCLUSIONS: The histone deacetylase inhibitor trichostatin A protects mice against postinfluenza pneumonia possibly through multiple factors, including decreasing local cell recruitment into the lungs and suppressing systemic inflammation.

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