Abstract
An overt pro-inflammatory immune response is a key factor contributing to lethal pneumococcal infection in an influenza pre-infected host and represents a potential target for therapeutic intervention. However, there is a paucity of knowledge about the level of contribution of individual cytokines. Based on the predictions of our previous mathematical modeling approach, the potential benefit of IFN-γ- and/or IL-6-specific antibody-mediated cytokine neutralization was explored in C57BL/6 mice infected with the influenza A/PR/8/34 strain, which were subsequently infected with the Streptococcus pneumoniae strain TIGR4 on day 7 post influenza. While single IL-6 neutralization had no effect on respiratory bacterial clearance, single IFN-γ neutralization enhanced local bacterial clearance in the lungs. Concomitant neutralization of IFN-γ and IL-6 significantly reduced the degree of pneumonia as well as bacteremia compared to the control group, indicating a positive effect for the host during secondary bacterial infection. The results of our model-driven experimental study reveal that the predicted therapeutic value of IFN-γ and IL-6 neutralization in secondary pneumococcal infection following influenza infection is tightly dependent on the experimental protocol while at the same time paving the way toward the development of effective immune therapies.
Highlights
Influenza A virus (IAV) infected individuals are predisposed to severe secondary bacterial infections as observed in a substantial number of fatal cases during influenza outbreaks [1]
In a data-driven mathematical modeling approach [27], we have addressed the hierarchical contribution of different pro-inflammatory cytokines on bacterial outgrowth in a mouse model of secondary pneumococcal infection following influenza infection and have identified IFN-γ and interleukin6 (IL-6) dynamics as strong and time-dependent factors for bacterial invasion [27]
The co-infected mice were treated with a neutralizing IL-6-specific antibody administered to the respiratory tract together with the secondary pneumococcal infection on day 7 post influenza infection (Figure 2A)
Summary
Influenza A virus (IAV) infected individuals are predisposed to severe secondary bacterial infections as observed in a substantial number of fatal cases during influenza outbreaks [1]. Such complications due to bacterial super-infection substantially contribute to morbidity and mortality and are frequently caused by the gram-positive bacterium Streptococcus pneumoniae (S. pn.) [2]. Dysregulated cytokine responses during the underlying viral infection as well as in response to the secondary bacterial pathogen have been described and include both immunesuppressive as well as exaggerated pro-inflammatory responses [2, 5,6,7]
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