title: A mouse model of lethal synergism between influenza virus and Haemophilus influenzae.
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.
authors.affiliation: Viral Immunology, Torrey Pines Institute for Molecular Studies, San Diego, CA 92121, USA.
authors.forename: Lian Ni
authors.initials: LN
authors.lastname: Lee
authors.forename: Peter
authors.initials: P
authors.lastname: Dias
authors.forename: Dongun
authors.initials: D
authors.lastname: Han
authors.forename: Sorah
authors.initials: S
authors.lastname: Yoon
authors.forename: Ashley
authors.initials: A
authors.lastname: Shea
authors.forename: Vladislav
authors.initials: V
authors.lastname: Zakharov
authors.forename: David
authors.initials: D
authors.lastname: Parham
authors.forename: Sally R
authors.initials: SR
authors.lastname: Sarawar
mesh_terms: D056704:Adaptive Immunity / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004285:Dogs; D006192:Haemophilus Infections / Q000150:complications / Q000401:mortality* / Q000473:pathology / Q000821:virology; D006193:Haemophilus influenzae / Q000502:physiology*; D006801:Humans; D009980:Influenza A virus / Q000502:physiology*; D008168:Lung / Q000473:pathology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000150:complications / Q000401:mortality* / Q000473:pathology / Q000821:virology; D015163:Superinfection / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000821:virology; D019562:Viral Load