Sequential Targeting Of Interferon Pathways For Increased Host Resistance To Bacterial Superinfection During Influenza

Author summaryBacterial co-infections represent a common and challenging clinical complication of influenza. Type-I and type-II interferon (IFN) pathways enhance susceptibility to influenza-pneumococcal co-infection, leading to increased lung pathology and mortality. However, the comparative importance of type-I versus type II IFN remains unclear. 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. Virus co-infection caused IFN-dependent inflammation that facilitated spreading of the colonizing bacteria into the lungs, followed by tissue damage and death. In this pneumococcal-influenza virus superinfection model, mice lacking both type-I and type-II IFN pathways demonstrated minimal lung pathology and increased survival compared to wild-type mice and mice deficient in only one pathway. Therapeutic neutralization of both type-I and type-II IFN pathways similarly provided optimal protection to superinfected wild-type mice. The most effective treatment regimen involved neutralization of the type-I IFN pathway early during co-infection combined with later neutralization of the type-II IFN pathway. These results provide new insights into potential host-directed therapy for management of bacterial-viral superinfections.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.