Details of a Researcher - YOKOTA Shinichi

Papers - YOKOTA Shinichi

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Mitochondrial proteins NIP-SNAP-1 and-2 are a target for the immunomodulatory activity of clarithromycin, which involves NF-kappa B-mediated cytokine production

Soh Yamamoto, Noriko Ogasawara, Keisuke Yamamoto, Chika Uemura, Yoshiaki Takaya, Tsukasa Shiraishi, Toyotaka Sato, Shin Hashimoto, Hiroyuki Tsutsumi, Kenichi Takano, Tetsuo Himi, Shin-ichi Yokota

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS ( ACADEMIC PRESS INC ELSEVIER SCIENCE ) 483 ( 3 ) 911 - 916 2017.02 [Refereed]

Macrolide antibiotics have immunomodulatory activities, including suppression of cytokine production, cell adhesion molecule expression, and mucin production. These immunomodulatory activities improve the symptoms of respiratory diseases associated with chronic inflammation. However, the underlying molecular mechanism(s) is not well understood yet. To address this, we prepared clarithromycin (CAM)-conjugated Sepharose and examined bound cellular proteins by proteome analysis. We identified mitochondrial proteins 4-nitrophenylphosphatase domain and non-neuronal synaptosomal associated protein 25-like protein homolog (NIP-SNAP)-1 and -2 and very long-chain acyl-CoA dehydrogenase (VLCAD) as CAM-binding proteins. Production of proinflammatory cytokines (IL-8 and IL-6) induced by lipopolysaccharides (LPSs) and Pam(3)-CSK4 in human epithelial cell lines BEAS-2B and T24 were suppressed by knockdown of NIP-SNAP -1 or -2, and partly by knockdown of VLCAD. Also, knockdown of NIP SNAP-1 or -2 in various cell lines suppressed LPS-induced expression of IL-8 and IL-6 mRNA and NF-kappa B activity. Thus, CAM suppresses NF-kappa B-mediated proinflammatory cytokine production by interacting with mitochondrial proteins, NIP-SNAP-1 and -2. (C) 2016 The Authors. Published by Elsevier Inc.

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NIP-SNAP-1 and-2 mitochondrial proteins are maintained by heat shock protein 60

Soh Yamamoto, Tomoya Okamoto, Noriko Ogasawara, Shin Hashimoto, Tsukasa Shiraishi, Toyotaka Sato, Keisuke Yamamoto, Hiroyuki Tsutsumi, Kenichi Takano, Testuo Himi, Hideaki Itoh, Shin-ichi Yokota

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS ( ACADEMIC PRESS INC ELSEVIER SCIENCE ) 483 ( 3 ) 917 - 922 2017.02 [Refereed]

NIP-SNAP-1 and -2 are ubiquitous proteins thought to be associated with maintenance of mitochondrial function, neuronal transmission, and autophagy. However, their physiological functions remain largely unknown. To elucidate their functional importance, we screened for proteins that interact with NIP SNAP-1 and -2, resulting in identification of HSP60 and P62/SQSTMI as binding proteins. NIP-SNAP-1 and -2 localized in the mitochondrial inner membrane space, whereas HSP60 localized in the matrix. Native gel electrophoresis and filter trap assays revealed that human HSP60 prevented aggregation of newly synthesized NIP-SNAP-2 in an in vitro translation system. Moreover, expression levels of NIP SNAP-1 and -2 in cells were decreased by knockdown of HSP60, but not HSP10. These findings indicate that HSP60 promotes folding and maintains the stability of NIP-SNAP-1 and -2. (C) 2016 Elsevier Inc. All rights reserved.

DOI

Tigecycline Nonsusceptibility Occurs Exclusively in Fluoroquinolone-Resistant Escherichia coli Clinical Isolates, Including the Major Multidrug-Resistant Lineages O25b:H4-ST131-H30R and O1-ST648

Toyotaka Sato, Yuuki Suzuki, Tsukasa Shiraishi, Hiroyuki Honda, Masaaki Shinagawa, Soh Yamamoto, Noriko Ogasawara, Hiroki Takahashi, Satoshi Takahashi, Yutaka Tamura, Shin-ichi Yokota

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY ( AMER SOC MICROBIOLOGY ) 61 ( 2 ) e01654-16 2017.02 [Refereed]

Tigecycline (TGC) is a last-line drug for multidrug-resistant Enterobacteriaceae. We investigated the mechanism(s) underlying TGC nonsusceptibility (TGC resistant/ intermediate) in Escherichia coli clinical isolates. The MIC of TGC was determined for 277 fluoroquinolone-susceptible isolates (ciprofloxacin [CIP] MIC, < 0.125 mg/ liter) and 194 fluoroquinolone- resistant isolates (CIP MIC, > 2 mg/ liter). The MIC50 and MIC90 for TGC in fluoroquinolone- resistant isolates were 2-fold higher than those in fluoroquinolone-susceptible isolates (MIC50, 0.5 mg/liter versus 0.25 mg/liter; MIC90, 1 mg/ liter versus 0.5 mg/ liter, respectively). Two fluoroquinolone-resistant isolates (O25b:H4-ST131-H30R and O125:H37-ST48) were TGC resistant (MICs of 4 and 16 mg/liter, respectively), and four other isolates of O25b:H4-ST131-H30R and an isolate of O1-ST648 showed an intermediate interpretation (MIC, 2 mg/liter). No TGC-resistant/ intermediate strains were found among the fluoroquinolone-susceptible isolates. The TGC- resistant/ intermediate isolates expressed higher levels of acrA and acrB and had lower intracellular TGC concentrations than susceptible isolates, and they possessed mutations in acrR and/or marR. The MICs of acrAB-deficient mutants were markedly lower (0.25 mg/liter) than those of the parental strain. After continuous stepwise exposure to CIP in vitro, six of eight TGC-susceptible isolates had reduced TGC susceptibility. Two of them acquired TGC resistance (TGC MIC, 4 mg/liter) and exhibited expression of acrA and acrB and mutations in acrR and/or marR. In conclusion, a population of fluoroquinolone-resistant E. coli isolates, including major extraintestinal pathogenic lineages O25b: H4-ST131-H30R and O1-ST648, showed reduced susceptibility to TGC due to overexpression of the efflux pump AcrAB- TolC, leading to decreased intracellular concentrations of the antibiotics that may be associated with the development of fluoroquinolone resistance.

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タゾバクタム/ピペラシリン耐性大腸菌の耐性機構の解析

鈴木裕樹, 佐藤豊孝, 山本聡, 小笠原徳子, 白石宗, 品川雅明, 高橋聡, 横田伸一

日本細菌学雑誌 ( 日本細菌学会 ) 72 ( 1 ) 138 - 138 2017.02

Helicobacter pylori感染症におけるTLR10の役割(Toll-like receptor 10 in Helicobacter pylori infection)

永島裕之, 横田伸一, 山岡吉生

日本細菌学雑誌 ( 日本細菌学会 ) 72 ( 1 ) 147 - 147 2017.02 [Refereed]

日本のダイズ発酵食品である納豆由来ペプチドの新規の抗菌活性(Novel antimicrobial activities of a peptide derived from a Japanese soy-bean fermented food, Natto)

北川学, 白石宗, 山本聡, 久富亮佑, 佐藤豊孝, 小笠原徳子, 宮本篤, 横田伸一

日本細菌学雑誌 ( 日本細菌学会 ) 72 ( 1 ) 145 - 145 2017.02

Lactobacillus gasseri種に共通するリポテイコ酸の特異的構造

久富亮佑, 白石宗, 佐藤耶舞羽, 森田直樹, 吹谷智, 佐藤豊孝, 横田篤, 横田伸一

日本細菌学雑誌 ( 日本細菌学会 ) 72 ( 1 ) 86 - 86 2017.02

Adaptive Cross-Resistance to Aminoglycoside Antibiotics in Pseudomonas aeruginosa Induced by Topical Dosage of Neomycin

Shuji Uemura, Shin-ichi Yokota, Tsukasa Shiraishi, Manabu Kitagawa, Suguru Hirayama, Ryoko Kyan, Hirotoshi Mizuno, Keigo Sawamoto, Hiroyuki Inoue, Atsushi Miyamoto, Eichi Narimatsu

CHEMOTHERAPY ( KARGER ) 62 ( 2 ) 121 - 127 2017 [Refereed]

Background: Topical antimicrobial formulations containing neomycin are commonly used to prevent and treat burn infections. However, Pseudomonas aeruginosa shows rapid acquisition of adaptive resistance to neomycin. This study aimed to evaluate the survival of P. aeruginosa during exposure to neomycin at high concentrations comparable to those used in topical formulations, and to investigate the effect of adaptive resistance to neomycin on the susceptibility to other aminoglycosides. Methods: Strain IID1130 [neomycin minimal inhibitory concentration (MIC) = 4 mu g/ml] was incubated on an agar medium containing neomycin at high concentrations (8-4,096 mu g/ml), and growing colonies were macroscopically observed. Acquisition of adaptive resistance was examined for 5 P. aeruginosa strains. Cells were sequentially passaged on agar medium containing neomycin with step-wise increased concentrations (82,048 mu g/ml). To assess reversion of antibiotic susceptibility, the resulting colonies were repeatedly subcultured on antibiotic-free agar plates. Results: Growing IID1130 colonies were macroscopically detected on a neomycin-containing ( 2,048 mu g/ml) agar plate for 48 h. These cells showed increasing MIC for not only neomycin, but also gentamicin and amikacin; the MIC values were occasionally higher than the breakpoints. When the adapted cells were subcultured on antibiotic-free agar, several passages were required for reversion of susceptibility. Conclusions: Our findings suggest that P. aeruginosa can survive in the presence of neomycin with a concentration typically used in topical dosage forms, and that the acquired adaptive resistance is persistent and is accompanied by cross-resistance to other aminoglycosides. (C) 2016 S. Karger AG, Basel

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Mechanism of Reduced Susceptibility to Fosfomycin in Escherichia coli Clinical Isolates

Yasuo Ohkoshi, Toyotaka Sato, Yuuki Suzuki, Soh Yamamoto, Tsukasa Shiraishi, Noriko Ogasawara, Shin-ichi Yokota

BIOMED RESEARCH INTERNATIONAL ( HINDAWI LTD ) 2017 5470241 2017 [Refereed]

In recent years, multidrug resistance of Escherichia coli has become a serious problem. However, resistance to fosfomycin (FOM) has been low. We screened E. coli clinical isolates with reduced susceptibility to FOM and characterized molecular mechanisms of resistance and reduced susceptibility of these strains. Ten strains showing reduced FOM susceptibility (MIC >= 8 mu g/mL) in 211 clinical isolates were found and examined. Acquisition of genes encoding FOM-modifying enzyme genes (fos genes) and mutations in murA that underlie high resistance to FOM were not observed. We examined ability of FOM incorporation via glucose-6phosphate (G6P) transporter and sn-glycerol-3-phosphate transporter. In ten strains, nine showed lack of growth on M9 minimum salt agar supplemented with G6P. Eight of the ten strains showed fluctuated induction by G6P of uhpT that encodes G6P transporter expression. Nucleotide sequences of the uhpT, uhpA, glpT, ptsI, and cyaA shared several deletions and amino acid mutations in the nine strains with lack of growth on G6P-supplemented M9 agar. In conclusion, reduction of uhpT function is largely responsible for the reduced sensitivity to FOM in clinical isolates that have not acquired FOM-modifying genes or mutations in murA. However, there are a few strains whose mechanisms of reduced susceptibility to FOM are still unclear.

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家族内発症のCrohn病３家系７症例における臨床的特徴の比較検討ならびに疾患関連遺伝子（TNFSF15）の解析

戸板成昭, 藤原伸一, 高橋美智子, 今野武津子, 横田伸一

臨牀小児医学 65 ( 1-6 ) 11 - 14 2017 [Refereed]

構造情報の蓄積から見えてきたリポテイコ酸の細菌種による構造多様性.

白石宗, 横田伸一, 吹谷智, 横田篤

日本乳酸菌学会誌 28 ( 3 ) 177 - 177 2017 [Invited]

Pathogenic Lineage of mcr-Negative Colistin-Resistant Escherichia coli, Japan, 2008-2015

Toyotaka Sato, Akira Fukuda, Yuuki Suzuki, Tsukasa Shiraishi, Hiroyuki Honda, Masaaki Shinagawa, Soh Yamamoto, Noriko Ogasawara, Masaru Usui, Hiroki Takahashi, Satoshi Takahashi, Yutaka Tamura, Shin-ichi Yokota

EMERGING INFECTIOUS DISEASES ( CENTERS DISEASE CONTROL ) 22 ( 12 ) 2223 - 2225 2016.12 [Refereed]

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Clarithromycin prevents human respiratory syncytial virus-induced airway epithelial responses by modulating activation of interferon regulatory factor-3

Keisuke Yamamoto, Soh Yamamoto, Noriko Ogasawara, Kenichi Takano, Tsukasa Shiraishi, Toyotaka Sato, Ryo Miyata, Takuya Kakuki, Ryuta Kamekura, Takashi Kojima, Hiroyuki Tsutsumi, Tetsuo Himi, Shin-ichi Yokota

PHARMACOLOGICAL RESEARCH ( ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD ) 111 804 - 814 2016.09 [Refereed]

Macrolide antibiotics exert immunomodulatory activity by reducing pro-inflammatory cytokine production by airway epithelial cells, fibroblasts, vascular endothelial cells, and immune cells. However, the underlying mechanism of action remains unclear. Here, we examined the effect of clarithromycin (CAM) on pro-inflammatory cytokine production, including interferons (IFNs), by primary human nasal epithelial cells and lung epithelial cell lines (A549 and BEAS-2B cells) after stimulation by Toll-like receptor (TLR) and RIG-I-like receptor (RLR) agonists and after infection by human respiratory syncytial virus (RSV). CAM treatment led to a significant reduction in poly I:C-and RSV-mediated IL-8, CCL5, IFN-beta and -lambda production. Furthermore, IFN-beta promoter activity (activated by poly I:C and RSV infection) was significantly reduced after treatment with CAM. CAM also inhibited IRF-3 dimerization and subsequent translocation to the nucleus. We conclude that CAM acts a crucial modulator of the innate immune response, particularly IFN production, by modulating IRF-3 dimerization and subsequent translocation to the nucleus of airway epithelial cells. This newly identified immunomodulatory action of CAM will facilitate the discovery of new macrolides with an anti-inflammatory role. (C) 2016 Elsevier Ltd. All rights reserved.

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Mumps Virus Induces Protein-Kinase-R-Dependent Stress Granules, Partly Suppressing Type III Interferon Production

Shin Hashimoto, Soh Yamamoto, Noriko Ogasawara, Toyotaka Sato, Keisuke Yamamoto, Hiroshi Katoh, Toru Kubota, Tsukasa Shiraishi, Takashi Kojima, Tetsuo Himi, Hiroyuki Tsutsumi, Shin-ichi Yokota

PLOS ONE ( PUBLIC LIBRARY SCIENCE ) 11 ( 8 ) e0161793 2016.08 [Refereed]

Stress granules (SGs) are cytoplasmic granular aggregations that are induced by cellular stress, including viral infection. SGs have opposing antiviral and proviral roles, which depend on virus species. The exact function of SGs during viral infection is not fully understood. Here, we showed that mumps virus (MuV) induced SGs depending on activation of protein kinase R (PKR). MuV infection strongly induced interferon (IFN)-lambda 1, 2 and 3, and IFN-beta through activation of IFN regulatory factor 3 (IRF3) via retinoic acid inducible gene-I (RIG-I) and the mitochondrial antiviral signaling (MAVS) pathway. MuV-induced IFNs were strongly upregulated in PKR-knockdown cells. MuV-induced SG formation was suppressed by knockdown of PKR and SG marker proteins, Ras-GTPase-activating protein SH3-domain-binding protein 1 and T-cell-restricted intracellular antigen-1, and significantly increased the levels of MuV-induced IFN-lambda 1. However, viral titer was not altered by suppression of SG formation. PKR was required for induction of SGs by MuV infection and regulated type III IFN (IFN-lambda 1) mRNA stability. MuV-induced SGs partly suppressed type III IFN production by MuV; however, the limited suppression was not sufficient to inhibit MuV replication in cell culture. Our results provide insight into the relationship between SGs and IFN production induced by MuV infection.

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日本における大腸菌のプラスミド性コリスチン耐性遺伝子(mcr-1)保有状況とヒト医療に与える影響

福田昭, 佐藤豊孝, 鈴木裕樹, 臼井優, 浅井鉄夫, 横田伸一, 田村豊

日本獣医学会学術集会講演要旨集 ( (公社)日本獣医学会 ) 159回 415 - 415 2016.08

Measles Virus Genotype D Wild Strains Suppress Interferon-Stimulated Gene Expression More Potently than Laboratory Strains in SiHa Cells

Masaru Jinushi, Soh Yamamoto, Noriko Ogasawara, Hideki Nagano, Shin Hashimoto, Hiroyuki Tsutsumi, Tetsuo Himi, Shin-ichi Yokota

VIRAL IMMUNOLOGY ( MARY ANN LIEBERT, INC ) 29 ( 5 ) 296 - 306 2016.06 [Refereed]

Changes in interferon (IFN)-stimulated gene (ISG) expression in cells infected with measles virus (MeV), four wild strains (belonging to different genotypes), and the laboratory strain Edmonston were examined. ISGs [MxA, 2'-5'-oligoadenylate synthetase, and interferon regulatory factor-1] were upregulated in an MeV-infection- induced manner and in an IFN-induced manner. In MeV-infected SiHa cell lines, the MeV infection-induced expression levels were in the order of A>H1>D8>D5>D3. On the other hand, all infected cell lines abolished type I and III IFN-induced ISG expression. However, partial type II IFN-mediated induction was observed in the MeV-infected cells. The wild strain of genotype D3 was the most potent inhibitor of MeV infection-induced and IFN-induced ISG expression and generated the highest titer of infectious viral particles. Edmonston triggered the highest levels of MeV infection-induced ISG expression in SiHa cells and produced the lowest titer of infectious particles. Expression of the viral C protein was associated with suppression of MeV infection-induced and type II IFN-induced ISG expression.

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ヒト鼻粘膜上皮バリアにおけるp63の役割

小島隆, 角木拓也, 金子躍人, 高野賢一, 小笠原徳子, 横田伸一, 氷見徹夫, 幸野貴之

日本細胞生物学会大会講演要旨集 ( (一社)日本細胞生物学会 ) 68回 63 - 63 2016.05

Intrafamilial, Preferentially Mother-to-Child and Intraspousal, Helicobacter pylori Infection in Japan Determined by Mutilocus Sequence Typing and Random Amplified Polymorphic DNA Fingerprinting

Shin-ichi Yokota, Mutsuko Konno, Shin-ichi Fujiwara, Nariaki Toita, Michiko Takahashi, Soh Yamamoto, Noriko Ogasawara, Tsukasa Shiraishi

HELICOBACTER ( WILEY-BLACKWELL ) 20 ( 5 ) 334 - 342 2015.10 [Refereed]

Background: The infection route of Helicobacter pylori has been recognized to be mainly intrafamilial, preferentially mother-to-child, especially in developed countries. To determine the transmission route, we examined whether multilocus sequence typing (MLST) was useful for analysis of intrafamilial infection. The possibility of intraspousal infection was also evaluated. Materials and Methods: Clonal relationships between strains derived from 35 index Japanese pediatric patients, and their family members were analyzed by two genetic typing procedures, MLST and random amplified polymorphic DNA (RAPD) fingerprinting. Results: Mostly coincident results were obtained by MLST and RAPD. By MLST, the allele of loci in the isolates mostly matched between the index child and both the father and mother for 9 (25.7%) of the 35 patients, between the index child and the mother for 25 (60.0%) of the 35 patients. Conclusions: MLST is useful for analyzing the infection route of H. pylori as a highly reproducible method. Intrafamilial, especially mother-to-children and sibling, infection is the dominant transmission route. Intraspousal infection is also thought to occur in about a quarter in the Japanese families.

DOI

Geranylgeranylacetone selectively binds to the HSP70 of Helicobacter pylori and alters its coccoid morphology

Ewa Grave, Shin-ichi Yokota, Soh Yamamoto, Arisa Tamura, Takako Ohtaki-Mizoguchi, Kenji Yokota, Keiji Oguma, Kazuhiko Fujiwara, Nobuaki Ogawa, Tomoya Okamoto, Michiro Otaka, Hideaki Itoh

SCIENTIFIC REPORTS ( NATURE PUBLISHING GROUP ) 5 13738 2015.09 [Refereed]

Geranylgeranylacetone (GGA) is used to treat patients suffering from peptic ulcers and gastritis. We examined the effect of GGA on Helicobacter pylori, which is a causative factor of gastrointestinal diseases. Previously, we have reported that GGA binds specifically to the molecular chaperone HSP70. In this paper, we report that GGA bounds to H. pylori HSP70 (product of the DnaK gene) with 26-times higher affinity than to human HSP70, and induced large conformational changes as observed from surface plasmon resonance and circular dichroism. Binding of GGA suppressed the activity of the H. pylori chaperone. GGA also altered several characteristics of H. pylori cells. GGA-treated cells elicited enhanced interleukin-8 production by gastric cancer cell lines and potentiated susceptibility to complement as compared to untreated cells. GGA also caused morphological alterations in H. pylori as reflected in fewer coccoid-like cells, suggesting that GGA converts H. pylori to an actively dividing, spiral state (vegetative form) from a non-growing, coccoid state. This morphological conversion by GGA resulted in accelerated growth of H. pylori. These results suggest a model in which GGA sensitizes H. pylori to antibiotic treatment by converting the cells to an actively growing state.

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扁桃・アデノイドはなぜあるのか?鼻はなにをしているのか? 粘膜免疫・粘膜防御の最前線を探る

氷見徹夫, 高野賢一, 山下恵司, 小笠原徳子, 山本圭佑, 堤裕幸, 小島隆, 一宮慎吾, 澤田典均, 横田伸一

顎顔面口腔育成会誌 ( 顎顔面口腔育成研究会 ) 3 ( 1 ) 3 - 6 2015.03

粘膜防御機構は自然免疫の最前線であり、上皮細胞に加えて免疫系細胞などを含む複合的なシステムで構築されている。耳鼻咽喉科領域では扁桃・アデノイドに代表される粘膜関連リンパ装置は、その抗原捕捉機構を駆使して、免疫記憶の形成と特異的抗体産生機構に関与している。一方、上気道の最前線である鼻粘膜もまた抗原捕捉に伴う免疫反応を行っているとともに、ウイルス・細菌感染やアレルギー炎症の場としても重要である。われわれは、扁桃やアデノイド、そして鼻粘膜の上皮についての研究を行い、機械的バリアを含む自然免疫の新しい概念を提唱してきた。ここでは、われわれの研究より得られた知見をもとに、扁桃、鼻粘膜の基本的な免疫臓器としての機能解析と、それぞれの類似性・相違性、自然免疫・獲得免疫での位置づけについて言及する。(著者抄録)

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Papers - YOKOTA Shinichi