Abstract
Bacterial co-infections represent a major clinical complication of influenza. Host-derived interferon (IFN) increases susceptibility to bacterial infections following influenza, but the relative roles of type-I versus type-II IFN remain poorly understood. We have used novel mouse models of co-infection in which colonizing pneumococci were inoculated into the upper respiratory tract; subsequent sublethal influenza virus infection caused the bacteria to enter the lungs and mediate lethal disease. Compared to wild-type mice or mice deficient in only one pathway, mice lacking both IFN pathways demonstrated the least amount of lung tissue damage and mortality following pneumococcal-influenza virus superinfection. Therapeutic neutralization of both type-I and type-II IFN pathways similarly provided optimal protection to co-infected wild-type mice. The most effective treatment regimen was staggered neutralization of the type-I IFN pathway early during co-infection combined with later neutralization of type-II IFN, which was consistent with the expression and reported activities of these IFNs during superinfection. These results are the first to directly compare the activities of type-I and type-II IFN during superinfection and provide new insights into potential host-directed targets for treatment of secondary bacterial infections during influenza.
Highlights
Influenza A virus is a leading cause of respiratory infection in the United States
We have used two novel mouse models of co-infection in which pneumococci were inoculated into the upper respiratory tract followed two days later by influenza virus infection
Nasopharyngeal carriage of S. pneumoniae in humans often leads to pneumococcal disease [20]
Summary
Complications involving secondary infections with bacterial pathogens, such as Streptococcus pneumoniae, significantly exacerbate the risk of severe disease and result in considerably increased rates of hospitalization and death [1]. It is estimated that at least 95% of the deaths that occurred during the 1918 pandemic were due to influenza-associated pneumococcal lung infection [2]. Approximately half of hospitalized patients during the 1957 and 2009 influenza pandemics presented with bacterial co-infections [3,4]. Influenza can promote bacterial pneumonia through epithelial damage, inflammation in the respiratory tract, and suppression of innate lung immune responses [5,6]. Evidence from human and mouse studies indicates that influenza infection compromises both the host immune response and lung barrier function to promote increased susceptibility to bacterial superinfection
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