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A mouse model of lethal synergism between influenza virus and Haemophilus influenzae
Lian Ni Lee1, Peter Dias, Dongun Han
1Viral Immunology, Torrey Pines Institute for Molecular Studies, San Diego, CA 92121, USA.
Abstract:
Secondary bacterial infections that follow infection with influenza virus result in considerable morbidity and mortality in young children, the elderly, and immunocompromised individuals and may also significantly increase mortality in normal healthy adults during influenza pandemics. We herein describe a mouse model for investigating the interaction between influenza virus and the bacterium Haemophilus influenzae. Sequential infection with sublethal doses of influenza and H. influenzae resulted in synergy between the two pathogens and caused mortality in immunocompetent adult wild-type mice. Lethality was dependent on the interval between administration of the bacteria and virus, and bacterial growth was prolonged in the lungs of dual-infected mice, although influenza virus titers were unaffected. Dual infection induced severe damage to the airway epithelium and confluent pneumonia, similar to that observed in victims of the 1918 global influenza pandemic. Increased bronchial epithelial cell death was observed as early as 1 day after bacterial inoculation in the dual-infected mice. Studies using knockout mice indicated that lethality occurs via a mechanism that is not dependent on Fas, CCR2, CXCR3, interleukin-6, tumor necrosis factor, or Toll-like receptor-4 and does not require T or B cells. This model suggests that infection with virulent strains of influenza may predispose even immunocompetent individuals to severe illness on secondary infection with H. influenzae by a mechanism that involves innate immunity, but does not require tumor necrosis factor, interleukin-6, or signaling via Toll-like receptor-4.
Insights
Influenza virus and Haemophilus influenzae coinfection cause severe lung damage and mortality in mice. This suggests influenza may increase susceptibility to bacterial pneumonia through innate immune pathways.
Area of Science:
- Infectious Diseases
- Immunology
- Microbiology
- Pathology
Background:
- Secondary bacterial infections post-influenza increase morbidity and mortality, particularly in vulnerable populations and during pandemics.
- Understanding the interaction between influenza virus and bacteria like Haemophilus influenzae is crucial for public health.
Purpose of the Study:
- To develop and characterize a mouse model for studying the synergistic interaction between influenza virus and Haemophilus influenzae.
- To investigate the mechanisms underlying mortality and lung pathology in dual-infected mice.
Main Methods:
- Sequential infection of immunocompetent adult wild-type mice with sublethal doses of influenza virus and Haemophilus influenzae.
- Analysis of pathogen titers, lung histopathology, and epithelial cell death.
- Studies utilizing knockout mice to investigate the role of specific immune factors (Fas, CCR2, CXCR3, IL-6, TNF, TLR-4) and adaptive immunity (T and B cells).
Main Results:
- Dual infection resulted in synergistic lethality in immunocompetent mice, dependent on the timing of pathogen administration.
- Prolonged bacterial growth and severe airway epithelial damage, including confluent pneumonia, were observed in dual-infected lungs.
- Lethality was independent of Fas, CCR2, CXCR3, IL-6, TNF, TLR-4, and T/B cells, suggesting an innate immunity mechanism.
Conclusions:
- The developed mouse model effectively replicates severe outcomes of influenza and H. influenzae coinfection, mimicking aspects of the 1918 pandemic.
- Virulent influenza infection can predispose even immunocompetent individuals to severe secondary bacterial pneumonia via innate immune pathways.
- The mechanism of lethality involves innate immunity but does not require key inflammatory mediators like TNF, IL-6, or TLR-4 signaling.
