Herbsttagung Programm & Abstracts - Deutsche Gesellschaft für ...
Herbsttagung Programm & Abstracts - Deutsche Gesellschaft für ... Herbsttagung Programm & Abstracts - Deutsche Gesellschaft für ...
A single point mutation (Y89F) within the non- structural protein 1 of influenza A viruses dramatically limits lung epithelial cell tropism and virulence in mice. Hrincius E.R. 1 , Henneke A.K. 1 , Gensler L. 1 , Anhlan D. 1 , Vogel P. 2 , McCullers J. 3 , Ludwig S. 1 and Ehrhardt C. 1 * 1 Institute of Molecular Virology (IMV), ZMBE, Von Esmarch-Str. 56, D-48149 Muenster, Germany 2 St. Jude Children's Research Hospital, Veterinary Pathology, 262 Danny Thomas Place, Memphis, TN 38105-3678 3 St. Jude Children's Research Hospital, Department of Infectious Diseases, 262 Danny Thomas Place, Memphis, TN 38105-3678 *presenting author Introduction The non-structural protein 1 (A/NS1) of influenza A viruses (IAV) harbors several src homology domain (SH)-binding motifs (bm) (one SH2bm and two SH3bm), which mediate interaction with cellular proteins. In contrast to the sequence variability of the second SH3bm, the tyrosine 89 within the SH2bm is highly conserved among different IAV strains. This prompted us to evaluate the necessity of this SH2bm for IAV virulence. Methods: In an in vivo mouse model, we investigated body weight-loss, survival, viral replication and changes in cytokine and chemokine expression upon infection with A/NS1 Y89F mutant in comparison to wildtype virus. Results: We observed a dramatically reduced body weight-loss and reduced mortality upon infection with the A/NS1 Y89F mutant in comparison to wild-type virus. Infectious titers in the lung and bronchoalveolarlavage fluid (BALF) were also reduced in comparison to wild-type virus. Concomitantly, we observed decreased cytokine, chemokine and immune cell levels in the lung and BALF as well as less severe pathological changes, reflecting reduced levels of virus-titers. Interestingly the replication of the A/NS1 mutant in mouse lung was overall reduced and strongly restricted to alveoli and if any marginally to bronchioli. In contrast, wild-type virus infection led to virus antigen positive areas in tracheal, bronchus, bronchiole and alveolar epithelium. Finally, wild-type virus infection resulted in a dramatic destruction of the bronchiole epithelium in clear contrast to infection with the A/NS1 mutant. Here, a slightly hypertrophic but entirely intact bronchiole epithelium was observed. Discussion: Taken together, we could show that disruption of the highly conserved SH2bm within the A/NS1 results in decreased virus distribution in the mouse lung and dramatically reduces virulence illustrating the necessity of the SH2bm for IAV induced pathogenicity. 22
A novel device for gaseous nitric oxide to treat antibiotic resistant bacterial and fungal lung infections in patients with cystic fibrosis Döring Gerd 1 , Deppisch Caroline 2 , Hermann Gloria 2 , Riethmüller Joachim 2 , Miller Christopher C 3 1 Institute of Medical Microbiology and Hygiene and 2 Children’s Clinic, Universitätsklinikum Tübingen, Tübingen, Germany, Univ British Columbia, Vancouver, Canada Introduction: Lower respiratory infections will be the fourth leading cause of death in 2020 globally. However, antibiotic therapies for patients with lung infections are hampered by drugresistant bacteria which are now ubiquitous in hospital settings and the community. A typical example are patients with the hereditary disease cystic fibrosis (CF) who are at a higher risk of suffering from lung infections caused by drug-resistant bacterial and fungal pathogens (2). Here we investigate a novel broad-spectrum treatment strategy for pulmonary infections caused by drug-resistant pathogens, based on gaseous nitric oxide (NO) because NO is highly bactericidal and fungicidal at concentrations of 160-200 ppm, and virtually no microorganism can develop resistance to NO at this dose. Methods: In an ongoing first-in-human open-label, standard care-controlled phase 1 trial, six adult CF patients chronically infected with various drug-resistant bacterial and fungal pathogens including P. aeruginosa, Mycobacterium abscessus and Aspergillus fumigatus receive 160 ppm of NO for 2x5 days trice daily for 30 min with 3.5 h recreation time by inhalation via a NO device (Linde AG, Munich, Germany). The primary endpoint is safety secondary endpoints are change of bacterial and or fungal load after completion of the treatment compared to baseline, change in lung function (FEV1) from baseline. Results: Preliminary data from 4 patients revealed that antibiotic-resistant bacteria and fungi such as Pseudomonas aeruginosa Escherichia coli (ESBL), Mycobacterium abscessus und Aspergillus fumigatus had been eradicated after therapy or had been reduced to several orders of magnitude. Lung function relative to baseline increased to approx. 15%. Conclusion: Provided further data confirm these preliminary results, the novel NO therapeutic strategy will be an alternative to current antibiotic therapy designed for pulmonary infections, avoid adverse effects caused by repeated antibiotic treatment courses in patients, improve quality of life, prognosis and life expectancies for infected patients, make convenient home therapy possible, reduce health care costs of treatment and hospital stay. 23
- Seite 1: Herbsttagung der Sektion Zellbiolog
- Seite 4 und 5: Freitag 16. November 2012 ab 12:15
- Seite 6 und 7: 16:30 - 16:40 Uhr A novel device fo
- Seite 8 und 9: Samstag, 17. November 2012 9:00 - 1
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- Seite 12 und 13: Role of TNFAIP2 in Legionella pneum
- Seite 14 und 15: Nontypeable Haemophilus influenzae
- Seite 16 und 17: Stammzellfaktor Krüppel-like Fakto
- Seite 18 und 19: Untersuchung des immunmodulatorisch
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- Seite 26 und 27: Die Gabe CD4 + T-Zellen verstärkt
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- Seite 36 und 37: Characterization of bronchioalveola
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- Seite 40 und 41: Biomechanischer Einfluss der chroni
- Seite 42 und 43: Bronchozentrische Granulomatose in
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A novel device for gaseous nitric oxide to treat antibiotic resistant bacterial<br />
and fungal lung infections in patients with cystic fibrosis<br />
Döring Gerd 1 , Deppisch Caroline 2 , Hermann Gloria 2 , Riethmüller Joachim 2 , Miller Christopher C 3<br />
1 Institute of Medical Microbiology and Hygiene and 2 Children’s Clinic, Universitätsklinikum Tübingen,<br />
Tübingen, Germany, Univ British Columbia, Vancouver, Canada<br />
Introduction: Lower respiratory infections will be the fourth leading cause of death in 2020<br />
globally. However, antibiotic therapies for patients with lung infections are hampered by drugresistant<br />
bacteria which are now ubiquitous in hospital settings and the community. A typical<br />
example are patients with the hereditary disease cystic fibrosis (CF) who are at a higher risk of<br />
suffering from lung infections caused by drug-resistant bacterial and fungal pathogens (2).<br />
Here we investigate a novel broad-spectrum treatment strategy for pulmonary infections caused<br />
by drug-resistant pathogens, based on gaseous nitric oxide (NO) because NO is highly<br />
bactericidal and fungicidal at concentrations of 160-200 ppm, and virtually no microorganism<br />
can develop resistance to NO at this dose.<br />
Methods: In an ongoing first-in-human open-label, standard care-controlled phase 1 trial, six<br />
adult CF patients chronically infected with various drug-resistant bacterial and fungal<br />
pathogens including P. aeruginosa, Mycobacterium abscessus and Aspergillus fumigatus<br />
receive 160 ppm of NO for 2x5 days trice daily for 30 min with 3.5 h recreation time by<br />
inhalation via a NO device (Linde AG, Munich, Germany). The primary endpoint is safety<br />
secondary endpoints are change of bacterial and or fungal load after completion of the<br />
treatment compared to baseline, change in lung function (FEV1) from baseline.<br />
Results: Preliminary data from 4 patients revealed that antibiotic-resistant bacteria and fungi<br />
such as Pseudomonas aeruginosa Escherichia coli (ESBL), Mycobacterium abscessus und<br />
Aspergillus fumigatus had been eradicated after therapy or had been reduced to several orders<br />
of magnitude. Lung function relative to baseline increased to approx. 15%.<br />
Conclusion: Provided further data confirm these preliminary results, the novel NO therapeutic<br />
strategy will be an alternative to current antibiotic therapy designed for pulmonary infections,<br />
avoid adverse effects caused by repeated antibiotic treatment courses in patients, improve<br />
quality of life, prognosis and life expectancies for infected patients, make convenient home<br />
therapy possible, reduce health care costs of treatment and hospital stay.<br />
23
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