No 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.

No abstract

Secondary bacterial pneumonia is responsible for significant morbidity and mortality during seasonal and pandemic influenza. Due to the unpredictability of influenza A virus evolution and the time-consuming process of manufacturing strain-specific influenza vaccines, recent efforts have been focused on developing anti-Streptococcus pneumoniae immunity to prevent influenza-related illness and death. Bacterial vaccination to prevent viral-bacterial synergistic interaction during co-infection is a promising concept that needs further investigation. Here, we show that immunization with pneumococcal surface protein A (PspA) fully protects mice against low-dose, but not high-dose, secondary bacterial challenge using a murine model of influenza A virus-S. pneumoniae co-infection. We further show that immunization with PspA is more broadly protective than the pneumococcal conjugate vaccine (Prevnar). These results demonstrate that PspA is a promising vaccine target that can provide protection against a physiologically relevant dose of S. pneumoniae following influenza infection.

Significance The regulation of functional immune cell plasticity is poorly understood. Host environmental cues are critical, but the possible influence of pathogen-derived virulence factors has not been described. We have used reverse-engineered influenza A viruses that differ in PB1-F2 activity to analyze influenza in mice in the presence or absence of host interferon (IFN)-γ. In the absence of functional PB1-F2 and IFN-γ, lung ILC2s initiated robust IL-5 responses following viral challenge, which led to improved tissue integrity and survival. Conversely, functional PB1-F2 suppressed IL-5 + ILC2 responses and induced a dominant IL-13 + CD8 T cell response regardless of host IFN-γ. These findings demonstrate the critical interplay between the viral virulence factors and host cytokines in regulating protective pulmonary immunity during influenza virus infection.