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Cited by 143Influenza Virus Research StudiesPneumonia and Respiratory InfectionsRespiratory viral infections research

Lethal Synergism of 2009 Pandemic H1N1 Influenza Virus and Streptococcus pneumoniae Coinfection Is Associated with Loss of Murine Lung Repair Responses

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Kash, John C., Walters, Kathie-Anne, Davis, A. Sally, Sandouk, Aline, Schwartzman, Louis M., Jagger, Brett W., Chertow, Daniel S., Qi, Li +3 more·2011·mBio
DOI 10.1128/mbio.00172-11PMC PMC3175626
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Abstract

Secondary bacterial infections increase disease severity of influenza virus infections and contribute greatly to increased morbidity and mortality during pandemics. To study secondary bacterial infection following influenza virus infection, mice were inoculated with sublethal doses of 2009 seasonal H1N1 virus (NIH50) or pandemic H1N1 virus (Mex09) followed by inoculation with Streptococcus pneumoniae 48 h later. Disease was characterized by assessment of weight loss and survival, titration of virus and bacteria by quantitative reverse transcription-PCR (qRT-PCR), histopathology, expression microarray, and immunohistochemistry. Mice inoculated with virus alone showed 100% survival for all groups. Mice inoculated with Mex09 plus S. pneumoniae showed severe weight loss and 100% mortality with severe alveolitis, denuded bronchiolar epithelium, and widespread expression of apoptosis marker cleaved caspase 3. In contrast, mice inoculated with NIH50 plus S. pneumoniae showed increased weight loss, 100% survival, and slightly enhanced lung pathology. Mex09- S. pneumoniae coinfection also resulted in increased S. pneumoniae replication in lung and bacteremia late in infection. Global gene expression profiling revealed that Mex09- S. pneumoniae coinfection did not induce significantly more severe inflammatory responses but featured significant loss of epithelial cell reproliferation and repair responses. Histopathological examination for cell proliferation marker MCM7 showed significant staining of airway epithelial cells in all groups except Mex09- S. pneumoniae -infected mice. This study demonstrates that secondary bacterial infection during 2009 H1N1 pandemic virus infection resulted in more severe disease and loss of lung repair responses than did seasonal influenza viral and bacterial coinfection. Moreover, this study provides novel insights into influenza virus and bacterial coinfection by showing correlation of lethal outcome with loss of airway basal epithelial cells and associated lung repair responses. IMPORTANCE Secondary bacterial pneumonias lead to increased disease severity and have resulted in a significant percentage of deaths during influenza pandemics. To understand the biological basis for the interaction of bacterial and viral infections, mice were infected with sublethal doses of 2009 seasonal H1N1 and pandemic H1N1 viruses followed by infection with Streptococcus pneumoniae 48 h later. Only infection with 2009 pandemic H1N1 virus and S. pneumoniae resulted in severe disease with a 100% fatality rate. Analysis of the host response to infection during lethal coinfection showed a significant loss of responses associated with lung repair that was not observed in any of the other experimental groups. This group of mice also showed enhanced bacterial replication in the lung. This study reveals that the extent of lung damage during viral infection influences the severity of secondary bacterial infections and may help explain some differences in mortality during influenza pandemics.

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  • Direct viral infection of basal cells in fatal COVID-19 contrasts with fatal influenza viral infection, where viral replication does not occur in basal cells but associated secondary bacterial infections result in basal cell loss and lack of tissue repair and regeneration.

    “Direct viral infection of basal cells in fatal COVID-19 contrasts with fatal influenza viral infection, where viral replication does not occur in basal cells but associated secondary bacterial infections result in basal cell loss and lack of tissue repair and regeneration (42).”

    From Lung epithelial and endothelial damage, loss of tissue repair, inhibition of fibrinolysis, and cellular senescence in fatal COVID-19 (2021) · cites this paper as [42]

  • Poor disease outcome has been linked to lost lung repair function and loss of basal epithelial cells, including alveolar epithelial cells, which is associated with increased bacterial attachment and apoptosis.

    “Furthermore, poor disease outcome has been linked to lost lung repair function and loss of basal epithelial cells, including alveolar epithelial cells; which is associated with increased bacterial attachment and apoptosis (Kash et al., 2011).”

    From Secondary bacterial infections associated with influenza pandemics (2017) · cites this paper as Kash et al., 2011

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Authors
Kash, J. C., Walters, K.-A., Davis, A. S., Sandouk, A., Schwartzman, L. M., Jagger, B. W., Chertow, D. S., Qi, L., Kuestner, R. E., Ozinsky, A., & Taubenberger, J. K.
Affiliations
  • National Institutes of Health (US)
  • Institute for Systems Biology (US)
ORCID
Venue
mBio
Publisher
American Society for Microbiology
Published
2011-11
Volume
2
Issue
5
ISSN
  • 2150-7511 (ISSN-L)
  • 2161-2129
DOI
10.1128/mbio.00172-11
PMC
PMC3175626
OpenAlex
W2080737538
Cited by
143
References
35
Citations by year
2026: 4 · 2025: 4 · 2024: 4 · 2023: 9 · 2022: 8 · 2021: 8 · 2020: 6 · 2019: 20 · 2018: 7 · 2017: 6 · 2016: 14 · 2015: 11 · 2014: 17 · 2013: 15 · 2012: 9
FWCI
10.60
Type
journal article
Language
en
Open access
Licence
Locations
  • mBio (publishedVersion, cc-by-nc-sa)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health
  • Defense Threat Reduction Agency
  • National Institute of Allergy and Infectious Diseases
Topics
  • Health Sciences › Medicine › Epidemiology › Influenza Virus Research Studies
  • Health Sciences › Medicine › Epidemiology › Pneumonia and Respiratory Infections
  • Health Sciences › Medicine › Epidemiology › Respiratory viral infections research
Keywords
Streptococcus pneumoniae, bacterial co-infection, secondary bacterial pneumonia, lung repair, basal epithelial cells, alveolitis, apoptosis, bacteremia, viral-bacterial interactions, disease severity, MCM7, gene expression profiling, 2009 H1N1 pandemic, seasonal H1N1
MeSH terms
Animals, Female, Gene Expression Regulation, Humans, Influenza, Human, Lung, Mice, Inbred BALB C, Pneumococcal Infections, Streptococcus pneumoniae, Virulence, Weight Loss, Mice, Influenza A Virus, H1N1 Subtype, Pandemics, Coinfection

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