3.3  Secondary bacterial infection in ferrets
A bacterial superinfection model was also established in ferrets, in which influenza more closely resembles that found in humans (Peltola et al., 2006). The goals of the study were to better understand the various sequelae of S. pneumoniae infection, including otitis media, sinusitis, and pneumonia, and to determine if the frequency and character of secondary pneumococcal infections differed depending on the strain of influenza virus that preceded bacterial challenge, as has been reported in humans. The viruses studied were A/Taiwan/1/86 (H1N1), the H3N2 viruses A/Sydney/5/97 and A/Fujian/411/02, and influenza B virus B/Singapore/222/79. In seven-week-old ferrets inoculated intranasally with virus and 5 days later with S. pneumoniae, all viruses increased bacterial colonization of the nasopharynx. However, 9 of 10 ferrets infected with H3N2 subtype influenza A viruses developed either sinusitis or otitis media, while only 1 of 11 infected with an H1N1 virus or an influenza B virus did so. These data support observations in humans that bacterial complication rates are higher during seasons when H3N2 viruses predominate (Bhat et al., 2005). This animal model could be useful for further study of the mechanisms that underlie viral–bacterial disease synergism.
Secondary infection by Staphylococcus aureus has also been evaluated in cotton rats (Braun et al., 2007). Although S. aureus superinfections are a relatively rare complication of influenza, the case fatality rate is extremely high. In addition, all three influenza pandemics of the 20th century included cases of co-infection with S. aureus in healthier and younger patients (Braun et al., 2007). Therefore, physiologic and pathologic changes in cotton rats infected with both S. aureus and influenza A/Wuhan/359/95 (H3N2) was evaluated and compared to the infections in cotton rats with each agent alone. Peribronchiolitis, interstitial pneumonitis as well as alveolitis were observed. Although pathology scores began to decline in the co-infected on day 7 p.i., they remained significantly higher than all other infected cohorts. This was true even in the cohort co-infected with inactivated S. aureus and influenza virus. Co-infection resulted in higher mortality than infection with either agent alone, and was associated with more marked hypothermia, lung pathology an enhancement of proinflammatory cytokine expression in the lungs (Braun et al., 2007). In addition, bacteremia was prolonged and bacterial lung titers were higher in co-infected cotton rats.