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.

Viral–bacterial interactions in the respiratory tract

“…Indeed, several studies point to distinct mechanisms of copathogenesis depending on the order of infection (Lee et al, 2010;McCullers & Rehg, 2002). In the host, however, the impact of sequential infections most likely does not stop there, as acute exposures to pathogens have been shown to trigger alterations in the local bacterial microbiome (Molyneaux et al, 2013;Tarabichi et al, 2015), which may impact on subsequent 'rounds' of infection.…”

Synergistic and feedback signaling mechanisms in the regulation of inflammation in respiratory infections

“…Interestingly, the mortality rate of the co-infections was critically dependent on the duration of time between the influenza and NTHi exposure, with incubations between 3 and 4 days showing the maximum lethality. 33 …”

Genome-wide fitness profiling reveals adaptations required by Haemophilus in coinfection with influenza A virus in the murine lung

“…More recently, pathogenic mechanisms associated with the mouse lung model of lethal IAV coinfection with H. influenzae type b (Hib) were investigated, implicating innate immunity in disease progression (8). Coinfection did not influence viral titers and yet led to dramatically increased multiplication and persistence of bacteria.…”