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.