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Immunological and molecular-biological studies on pathogenesis and treatments of intractable obits media

Research Project

Project/Area Number 17591797
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Otorhinolaryngology
Research InstitutionWakayama Medical University

Principal Investigator

YAMANAKA Noboru  Wakayama Medical University, Otolaryngology, Professor, 医学部, 教授 (10136963)

Co-Investigator(Kenkyū-buntansha) FUJIHARA Keiji  Wakayama Medical University, Otolaryngology, Associate Professor, 医学部, 助教授 (80326371)
TAMURA Shinji  Wakayama Medical University, Otolaryngology, Assistant Professor, 医学部, 講師 (10244724)
HOTOMI Muneki  Wakayama Medical University, Otolaryngology, Assistant Professor, 医学部, 講師 (90336892)
YAMAUCHI Kazuma  Wakayama Medical University, Otolaryngology, Instructor, 医学部, 助手 (80336891)
Project Period (FY) 2005 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
Keywordsotitis media / anti-microbial resistance / Streptococcus pneumoniae / Haemophilus influenzae / penicillin binding protein / genotype analysis / vaccine / maternal intranasal immunization / 中耳炎 / ペニシリン耐性 / マクロライド耐性 / 分子生物学
Research Abstract

S.pneumoniae and H.influenzae have been major pathogens in acute otitis media of children. Almost 75.8% strains had mutation in their penicillin binding protein la, 2b and 2x (PBP) and they were classified into seven genotypic classes after PCR identification of abnormal pbp1a, pbp2x, and pbp2b genes: (i) penicillin-susceptible S. pneumoniae (PSSP) isolates with no abnormal pbp genes (24.2%), (ii) genotypic penicillin-intermediate S. pneumoniae (gPISP) isolates with only an abnormal pbp2x gene [gPISP (2x)] (26%), (iii) with only an abnormal pbp1a gene [gPISP (/a)](0.1%) (iv) with only an abnormal pbp2b gene [gPISP (2b)](2.2%) (V) gPISP isolates with abnormal pbp1a and pbp2x genes (2.8%), (vi) gPISP isolates with abnormal pbp2x and pbp2b genes (2.2%), and (vii) genotypic penicillin-resistant S. pneumoniae (gPRSP) isolates with three abnormal pbp genes (38.5%). H. influenzae isolates were divided into 61.0% susceptible strains (MIC less than or equal 1 pg/ml), 37 (14.0%) intermediately r … More esistant strains (MIC =2 μg/ml) and 66 (25.0%) resistant strains (MIC greater than or equal 4 pg/ml). Five strains produced TEM type β-lactamase. They were divided into 3 (1.2%) strains with mutations in fts1 gene (gBLPACR: genetically β-lactamase producing amoxicillin-clavulanate resistant) and 2 (0.8%) strains without mutations infts1 gene gBLPAR (genetically β-lactamase producing ampicillin resistant). According to PCR-based genotyping, 172 (65.1%) isolates had mutations in fts1 gene without producing β-lactamase (gBLNAR: genetically β-lactamase nonproducing ampicillin resistant). They were 98 (37.1%) strains with group I/II mutations in variable mutated region (Group 1/II gBLNAR) and 74 (28.0%) strains with group III mutations in highly mutated region (Group III gBLNAR). The rest of 87 (33.0%) isolate were gBLNAS (genetically β-lactamase non-producing ampicillin susceptible) strains with neither mutations in fts1 gene nor bla gene. The Group III gBLNAR strains showed resistance to both penicillin and cephalosporin. PBP gene mutated H. influenzae not only resistance to ampicillin but also had reduce susceptibility to cephalosporin. The high prevalence of gBLNAR strains of H. influenzae should be taken into account when treating the upper respiratory tract infectious diseases.
It is very important to induce effective protective immunity among children younger than 2 years of age. In this study, we evaluated the maternal immunization of P6 of H.influenzae to evoke specific antibody to P6 and to transfer it to offspring. We intranasally immunized mother mice with P6 and investigated the induction of specific antibody in sera and breast milk. The specific antibody among offspring delivered from immunized mother was also investigated according to the nursing status to evaluate the importance of breast feedings by immunized mothers. Our findings strongly suggest that maternal intranasal immunization with P6 would be an attractive strategy against NTHi infections during early childhood. It can supply protective antibodies via transplacental during pregnancy and via breast milk after birth. Less

Report

(3 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • Research Products

    (29 results)

All 2007 2006 2005

All Journal Article (28 results) Book (1 results)

  • [Journal Article] In vitro induction and selection of fluoroquinolone-resistant mutants of Streptococcus pyogenes strains with multiple emm types2007

    • Author(s)
      Billal DS, Yamanaka N, et al.
    • Journal Title

      J Antimicrob Chemother 59

      Pages: 28-34

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Rapid identification of nontypeable and serotype b Haemophilus influenzae from nasopharyngeal secretions by the multiplex PCR2007

    • Author(s)
      Billal DS, Yamanaka N, et al.
    • Journal Title

      Int J Pediatr Otorhinolaryngol 71

      Pages: 269-274

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Antimicrobial resistance in Haemophilus influenzae isolated from the nasopharynx among Japanese children with acute otitis media.2006

    • Author(s)
      Hotomi M, Yamanaka N, et al.
    • Journal Title

      Acta Otolaryngol 126(2)

      Pages: 130-137

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] High Prevalence of Streptococcus pneumoniae with Mutations in pbpla, pbp2x, and pbp2b Genes of Penicillin-Binding Proteins in the Nasopharynx in Children in Japan.2006

    • Author(s)
      Hotomi M, Yamanaka N, et al.
    • Journal Title

      ORL J Otorhinolarynogol Relat Spec 68(3)

      Pages: 139-145

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Evaluation of serotypes of Streptococcus pneumoniae isolated from otitis media patients by multiplex polymerase chain reaction2006

    • Author(s)
      Billal DS, Yamanaka N, et al.
    • Journal Title

      ORL J Otorhinolaryngol Relat Spec 68

      Pages: 135-138

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Maternal intranasal immunization with outer membrane protein P6 maintains specific antibody level of derived offspring2006

    • Author(s)
      Yamauchi K, Yamanaka N, et al.
    • Journal Title

      Vaccine 24

      Pages: 5294-5299

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Study of upper respiratory tract bacterial flora : first report. Variations in upper respiratory tract bacterial flora in patients with acute upper respiratory tract infection and healthy subjects and variations by subject age.2006

    • Author(s)
      Konno M, et al.
    • Journal Title

      J Infect Chemother. 12

      Pages: 83-96

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Antimicrobial resistance of Haemophilus influenzae isolated from the nasopharynx of Japanese children with acute otitis media.2006

    • Author(s)
      Hotomi M, et al.
    • Journal Title

      Acta Otolaryngol. 126

      Pages: 240-247

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] High prevalence of Streptococcus pneumoniae with mutations in pbp1a, pbp2x, and pbp2b genes of penicillin-binding proteins in the nasopharynx in children in Japan.2006

    • Author(s)
      Hotomi M, et al.
    • Journal Title

      ORL J Otorhinolaryngol Relat Spec. 68

      Pages: 139-145

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Evaluation of serotypes of Streptococcus pneumoniae isolated from otitis media patients by multiplex polymerase chain reaction.2006

    • Author(s)
      Billal DS, et al.
    • Journal Title

      ORL J Otorhinolaryngol Relat Spec. 68

      Pages: 135-138

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Functions of tonsils in the mucosal immune system of the upper respiratory tract using a novel animal model, Suncus murinus.2006

    • Author(s)
      Suzumoto M, et al.
    • Journal Title

      Acta Oto-Laryngologica 126

      Pages: 1164-1170

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Maternal intranasal immunization with outer membrane protein P6 maintains specific antibody level of derived offspring.2006

    • Author(s)
      Yamauchi K, et al.
    • Journal Title

      Vaccine 24(25)

      Pages: 5294-5299

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Antimicrobial resistance in Haemophilus influenzae isolated from the nasopharynx among Japanese children with acute otitis media2006

    • Author(s)
      Hatomi M, Yamanaka N, et al.
    • Journal Title

      Acta Otolaryngol 126

      Pages: 240-247

    • Related Report
      2006 Annual Research Report
  • [Journal Article] High prevalence of Streptococcus pneumoniae with mutations in pbpla, pbp2x, and pbp2b genes of penicillin-binding proteins in the nasopharynx in children in Japan.2006

    • Author(s)
      Hatomi M, Yamanaka N, et al.
    • Journal Title

      ORL J Otorhinolaryngol Relat Spec 68

      Pages: 139-145

    • Related Report
      2006 Annual Research Report
  • [Journal Article] High Prevalence of Streptococcus pneumoniae with Mutations in pbp1a, pbp2x, and pbp2b Genes of Penicillin-Binding Proteins in the Nasopharynx in Children in Japan.2006

    • Author(s)
      Hotomi M, Billal DS, Shimada J, Suzumoto M, Yamauchi K, Fujihara K, Yamanaka N
    • Journal Title

      ORL J Otorhinolarynogol Relat Spec 68(3)

      Pages: 139-145

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Antimicrobial resistance in Haemophilus influenzae isolated from the nasopharynx among Japanese children with acute otitis media.2006

    • Author(s)
      Hotomi M, Sakai A, Billal DS, Shimada J, Suzumoto M, Yamanaka N
    • Journal Title

      Acta Otolaryngol 126(2)

      Pages: 130-137

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Increase of macrolide-resistant Streptococcus pneumoniae-expressing mefE or ermB gene in the nasopharynx among children with otitis media.2005

    • Author(s)
      Hotomi M, Yamanaka N, et al.
    • Journal Title

      Laryngoscope 115(2)

      Pages: 317-320

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Evaluation of mutations in penicillin binding protein-3 gene of non-typeable Haemophilus influenzae isolated from the nasopharynx of children with acute otitic media2005

    • Author(s)
      Sakai A, Yamanaka N, et al.
    • Journal Title

      Acta Otolaryngol 125(2)

      Pages: 180-183

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Nasal colonization with Streptococcus pneumoniae includes subpopulations of surface and invasive pneumococci.2005

    • Author(s)
      Briles DE, et al.
    • Journal Title

      Infect Immun. 73(10)

      Pages: 6945-6951

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Evaluation of mutations in penicillin binding protein-3 gene of non-typeable Haemophilus influenzae isolated from the nasopharynx of children with acute otitis media.2005

    • Author(s)
      Sakai A, et al.
    • Journal Title

      Acta Otolaryngol. 125(2)

      Pages: 180-183

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] The Surveillance Subcommittee of the Japan Society for Infectious Diseases in Otolaryngology. Current status of antimicrobial susceptibility of clinical isolates of Streptococcus pyogenes in Japan : report of a countrywide surveillance study.2005

    • Author(s)
      Hotomi M, et al.
    • Journal Title

      J Infect Chemother. 11(1)

      Pages: 48-51

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Recent advances in otitis media. 6. Vaccine.2005

    • Author(s)
      Giebink GS, et al.
    • Journal Title

      Ann Otol Rhinol Laryngol Suppl. 194

      Pages: 86-103

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Increase of macrolide-resistant Streptococcus pneumoniae-expressing mefE or ermB gene in the nasopharynx among children with otitis media.2005

    • Author(s)
      Hotomi M, et al.
    • Journal Title

      Laryngoscope. 115(2)

      Pages: 317-320

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] A recombinant P4 protein of Haemophilus influenzae induces specific immune responses biologically active against nasopharyngeal colonization in mice after intranasal immunization.2005

    • Author(s)
      Hotomi M, et al.
    • Journal Title

      Vaccine. 26,23(10)

      Pages: 1294-1300

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Treatment and outcome of seven and non-severe acute otitis media.2005

    • Author(s)
      Hotomi M, et al.
    • Journal Title

      Eur J Pediatr. 164(1)

      Pages: 3-8

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Rapid diagnosis of pneumococcal meningitis : implications for treatment and measuring disease burden.2005

    • Author(s)
      Saha SK, et al.
    • Journal Title

      Pediatr Infect Dis J. 24(12)

      Pages: 1093-1098

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Evaluation of mutations in penicillin binding protein-3 gene of non-typeable Haemophilus influenzae isolated from the nasopharynx of children with acute otitis media.2005

    • Author(s)
      Sakai A, Hotomi M, Billal DS, Yamauchi K, Shimada J, Tamura S, Fujihara K, Yamanaka N
    • Journal Title

      Acta Otolaryngol 125(2)

      Pages: 180-183

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Increase of macrolide-resistant Streptococcus pneumoniae-expressing mefE or ermB gene in the nasopharynx among children with otitis media.2005

    • Author(s)
      Hotomi M, Billal DS, Shimada J, Suzumoto M, Yamauchi K, Fujihara K, Yamanaka N
    • Journal Title

      Laryngoscope 115(2)

      Pages: 317-320

    • Related Report
      2005 Annual Research Report
  • [Book] 小児中耳炎のマネジメント2006

    • Author(s)
      山中 昇, 保富宗城
    • Total Pages
      262
    • Publisher
      医薬ジャーナル社
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary

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Published: 2005-04-01   Modified: 2016-04-21  

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