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Originally published online as doi:10.2353/ajpath.2010.090596 on December 30, 2009

Published online before print December 30, 2009
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(American Journal of Pathology. 2010;176:800-811.)
© 2010 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2010.090596

A Mouse Model of Lethal Synergism Between Influenza Virus and Haemophilus influenzae

Lian Ni Lee*, Peter Dias*, Dongun Han*, Sorah Yoon*, Ashley Shea*, Vladislav Zakharov{dagger}, David Parham{dagger} and Sally R. Sarawar*

From Viral Immunology,* Torrey Pines Institute for Molecular Studies, San Diego, California; and the Department of Pathology,{dagger} University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma

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.




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