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Dual Acting Neuraminidase Inhibitors Open New Opportunities to Disrupt the Lethal Synergism between Streptococcus pneumoniae and Influenza Virus

Secondary infections with Streptococcus pneumoniae cause severe pneumonia and enhance lethality during influenza epidemics and pandemics. Structural and functional similarities with viral neuraminidase (NA) suggest that the highly prevalent pneumococcal NAs, NanA and NanB, might contribute to this l...

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Autores principales: Walther, Elisabeth, Xu, Zhongli, Richter, Martina, Kirchmair, Johannes, Grienke, Ulrike, Rollinger, Judith M., Krumbholz, Andi, Saluz, Hans P., Pfister, Wolfgang, Sauerbrei, Andreas, Schmidtke, Michaela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800182/
https://www.ncbi.nlm.nih.gov/pubmed/27047471
http://dx.doi.org/10.3389/fmicb.2016.00357
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author Walther, Elisabeth
Xu, Zhongli
Richter, Martina
Kirchmair, Johannes
Grienke, Ulrike
Rollinger, Judith M.
Krumbholz, Andi
Saluz, Hans P.
Pfister, Wolfgang
Sauerbrei, Andreas
Schmidtke, Michaela
author_facet Walther, Elisabeth
Xu, Zhongli
Richter, Martina
Kirchmair, Johannes
Grienke, Ulrike
Rollinger, Judith M.
Krumbholz, Andi
Saluz, Hans P.
Pfister, Wolfgang
Sauerbrei, Andreas
Schmidtke, Michaela
author_sort Walther, Elisabeth
collection PubMed
description Secondary infections with Streptococcus pneumoniae cause severe pneumonia and enhance lethality during influenza epidemics and pandemics. Structural and functional similarities with viral neuraminidase (NA) suggest that the highly prevalent pneumococcal NAs, NanA and NanB, might contribute to this lethal synergism by supporting viral replication and that dual acting NA inhibitors (NAIs) will disrupt it. To verify this hypothesis, NanA and NanB were expressed in E. coli. After confirming their activity in enzyme assays, in vitro models with influenza virus A/Jena/8178/09 (Jena/8178) and the recombinant NanA or NanB (rNanA and rNanB) were established in A549 and MDCK cells to mimic the role of these pneumococcal NAs during co-infection. Studies on the influence of both NAs on viral receptor expression, spread, and yield revealed a distinct effect of NanA and NanB on viral replication in these in vitro models. Both enzymes were able to support Jena/8178 replication at certain concentrations. This synergism was disrupted by the NAIs oseltamivir, DANA, katsumadain A, and artocarpin exerting an inhibitory effect on viral NA and NanA. Interestingly, katsumadain A and artocarpin inhibited rNanA and rNanB similarly. Zanamivir did not show activity. These results demonstrate a key role of pneumococcal NAs in the lethal synergism with influenza viruses and reveal opportunities for its effective disruption.
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spelling pubmed-48001822016-04-04 Dual Acting Neuraminidase Inhibitors Open New Opportunities to Disrupt the Lethal Synergism between Streptococcus pneumoniae and Influenza Virus Walther, Elisabeth Xu, Zhongli Richter, Martina Kirchmair, Johannes Grienke, Ulrike Rollinger, Judith M. Krumbholz, Andi Saluz, Hans P. Pfister, Wolfgang Sauerbrei, Andreas Schmidtke, Michaela Front Microbiol Microbiology Secondary infections with Streptococcus pneumoniae cause severe pneumonia and enhance lethality during influenza epidemics and pandemics. Structural and functional similarities with viral neuraminidase (NA) suggest that the highly prevalent pneumococcal NAs, NanA and NanB, might contribute to this lethal synergism by supporting viral replication and that dual acting NA inhibitors (NAIs) will disrupt it. To verify this hypothesis, NanA and NanB were expressed in E. coli. After confirming their activity in enzyme assays, in vitro models with influenza virus A/Jena/8178/09 (Jena/8178) and the recombinant NanA or NanB (rNanA and rNanB) were established in A549 and MDCK cells to mimic the role of these pneumococcal NAs during co-infection. Studies on the influence of both NAs on viral receptor expression, spread, and yield revealed a distinct effect of NanA and NanB on viral replication in these in vitro models. Both enzymes were able to support Jena/8178 replication at certain concentrations. This synergism was disrupted by the NAIs oseltamivir, DANA, katsumadain A, and artocarpin exerting an inhibitory effect on viral NA and NanA. Interestingly, katsumadain A and artocarpin inhibited rNanA and rNanB similarly. Zanamivir did not show activity. These results demonstrate a key role of pneumococcal NAs in the lethal synergism with influenza viruses and reveal opportunities for its effective disruption. Frontiers Media S.A. 2016-03-21 /pmc/articles/PMC4800182/ /pubmed/27047471 http://dx.doi.org/10.3389/fmicb.2016.00357 Text en Copyright © 2016 Walther, Xu, Richter, Kirchmair, Grienke, Rollinger, Krumbholz, Saluz, Pfister, Sauerbrei and Schmidtke. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Microbiology
Walther, Elisabeth
Xu, Zhongli
Richter, Martina
Kirchmair, Johannes
Grienke, Ulrike
Rollinger, Judith M.
Krumbholz, Andi
Saluz, Hans P.
Pfister, Wolfgang
Sauerbrei, Andreas
Schmidtke, Michaela
Dual Acting Neuraminidase Inhibitors Open New Opportunities to Disrupt the Lethal Synergism between Streptococcus pneumoniae and Influenza Virus
title Dual Acting Neuraminidase Inhibitors Open New Opportunities to Disrupt the Lethal Synergism between Streptococcus pneumoniae and Influenza Virus
title_full Dual Acting Neuraminidase Inhibitors Open New Opportunities to Disrupt the Lethal Synergism between Streptococcus pneumoniae and Influenza Virus
title_fullStr Dual Acting Neuraminidase Inhibitors Open New Opportunities to Disrupt the Lethal Synergism between Streptococcus pneumoniae and Influenza Virus
title_full_unstemmed Dual Acting Neuraminidase Inhibitors Open New Opportunities to Disrupt the Lethal Synergism between Streptococcus pneumoniae and Influenza Virus
title_short Dual Acting Neuraminidase Inhibitors Open New Opportunities to Disrupt the Lethal Synergism between Streptococcus pneumoniae and Influenza Virus
title_sort dual acting neuraminidase inhibitors open new opportunities to disrupt the lethal synergism between streptococcus pneumoniae and influenza virus
topic Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800182/
https://www.ncbi.nlm.nih.gov/pubmed/27047471
http://dx.doi.org/10.3389/fmicb.2016.00357
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