Sequential targeting of interferon pathways for increased host resistance to bacterial superinfection during...

Area of Science:

• Immunology
• Virology
• Microbiology

Background:

• Bacterial co-infections are a significant complication of influenza.
• Host-derived interferon (IFN) signaling pathways, specifically type-I and type-II IFN, are implicated in increased susceptibility to secondary bacterial infections post-influenza, but their distinct roles are not fully elucidated.

Purpose of the Study:

• To investigate the differential roles of type-I and type-II interferon pathways in the context of pneumococcal-influenza virus superinfection.
• To evaluate the therapeutic potential of neutralizing these IFN pathways, individually and in combination, for treating secondary bacterial pneumonia following influenza.

Main Methods:

• Utilized novel mouse models to establish pneumococcal colonization followed by sublethal influenza virus infection, creating a superinfection scenario.
• Assessed lung tissue damage and mortality rates in wild-type mice and mice deficient in specific IFN pathways (type-I, type-II, or both).
• Administered therapeutic neutralization of type-I and type-II IFN pathways at different time points during the co-infection.

Main Results:

• Mice lacking both type-I and type-II IFN pathways exhibited significantly reduced lung damage and mortality compared to wild-type or single-pathway deficient mice.
• Therapeutic neutralization of both IFN pathways provided optimal protection against lethal superinfection in wild-type mice.
• A staggered neutralization strategy, targeting type-I IFN early and type-II IFN later, proved most effective, aligning with observed IFN expression patterns.

Conclusions:

• This study provides the first direct comparison of type-I and type-II interferon activities during influenza-bacterial superinfection.
• Simultaneous or strategically staggered neutralization of both type-I and type-II interferon pathways represents a promising host-directed therapeutic strategy for mitigating secondary bacterial infections during influenza.