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Interferon Lambda Therapy Worsens Influenza, Staphylococcus Aureus Super-Infection
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A6235 - Interferon Lambda Therapy Worsens Influenza, Staphylococcus Aureus Super-Infection
Author Block: H. Rich, C. McCourt, W. Zheng, K. McHugh, J. F. Alcorn; Pulmonology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States.
Rationale: While pandemic influenza A H1N1 infection causes significant morbidity and mortality on its own, it also renders an individual more susceptible to secondary bacterial super-infection with pathogens such as Staphylococcus aureus. We have previously shown that type I interferons produced by influenza impair bacterial defense six to seven days post-influenza infection. Similarly, mice that lack the receptor for type III interferon (IFNL, IL-28A/B) exhibit better clearance of S. aureus bacterial pneumonia, with or without preceding influenza. As IFNL therapy has been proposed as a treatment for patients with influenza, we investigated the effect of overexpressing IFNL during influenza infection on S. aureus super-infection.
Methods: 6-8 week old male C57BL/6 mice were infected with 25 PFU of influenza H1N1 A/PR/8/34. Five days later, mice were treated with an adenoviral vector to overexpress mIL-28B or eGFP as control, one day later challenged with 5*107 CFU USA300 methicillin-resistant Staphylococcus aureus, and sacrificed twenty-four hours following bacterial challenge. Mouse lungs were lavaged with 1 mL sterile PBS, and infiltrating cells were counted on a hemocytometer. Lungs were homogenized and plated for bacterial CFU counting, and frozen for protein analysis.
Results: Mice showed a surprising decrease in weight loss after IFNL overexpression during influenza, S. aureus super-infection. IFNL overexpression did not alter bacterial burden during single S. aureus infection, but it increased bacterial burden during super-infection. Moreover, IFNL overexpression increased mortality from super-infection. While total cell counts were not different, IFNL overexpression decreased numbers of neutrophils in bronchoalveolar lavage fluid. Protein analysis showed a simultaneous increase in chemotactic cytokine levels in the lung.
Conclusions: IFNL overexpression decreases mouse weight loss during influenza, S. aureus super-infection, supporting the use of IFNL as a therapeutic for influenza. However, IFNL increased mortality and bacterial burden in the lungs of super-infected mice, concurrent with fewer neutrophils measured in bronchoalveolar lavage. It is likely that the lungs of these mice over-produce chemotactic cytokines in response to this lack of neutrophils. These data suggest that IFNL treatment for influenza poses significant risks for patients, as bacterial super-infection is not an uncommon complication, and mortality and morbidity are highly exacerbated by IFNL therapy.
Author Block: H. Rich, C. McCourt, W. Zheng, K. McHugh, J. F. Alcorn; Pulmonology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States.
Rationale: While pandemic influenza A H1N1 infection causes significant morbidity and mortality on its own, it also renders an individual more susceptible to secondary bacterial super-infection with pathogens such as Staphylococcus aureus. We have previously shown that type I interferons produced by influenza impair bacterial defense six to seven days post-influenza infection. Similarly, mice that lack the receptor for type III interferon (IFNL, IL-28A/B) exhibit better clearance of S. aureus bacterial pneumonia, with or without preceding influenza. As IFNL therapy has been proposed as a treatment for patients with influenza, we investigated the effect of overexpressing IFNL during influenza infection on S. aureus super-infection.
Methods: 6-8 week old male C57BL/6 mice were infected with 25 PFU of influenza H1N1 A/PR/8/34. Five days later, mice were treated with an adenoviral vector to overexpress mIL-28B or eGFP as control, one day later challenged with 5*107 CFU USA300 methicillin-resistant Staphylococcus aureus, and sacrificed twenty-four hours following bacterial challenge. Mouse lungs were lavaged with 1 mL sterile PBS, and infiltrating cells were counted on a hemocytometer. Lungs were homogenized and plated for bacterial CFU counting, and frozen for protein analysis.
Results: Mice showed a surprising decrease in weight loss after IFNL overexpression during influenza, S. aureus super-infection. IFNL overexpression did not alter bacterial burden during single S. aureus infection, but it increased bacterial burden during super-infection. Moreover, IFNL overexpression increased mortality from super-infection. While total cell counts were not different, IFNL overexpression decreased numbers of neutrophils in bronchoalveolar lavage fluid. Protein analysis showed a simultaneous increase in chemotactic cytokine levels in the lung.
Conclusions: IFNL overexpression decreases mouse weight loss during influenza, S. aureus super-infection, supporting the use of IFNL as a therapeutic for influenza. However, IFNL increased mortality and bacterial burden in the lungs of super-infected mice, concurrent with fewer neutrophils measured in bronchoalveolar lavage. It is likely that the lungs of these mice over-produce chemotactic cytokines in response to this lack of neutrophils. These data suggest that IFNL treatment for influenza poses significant risks for patients, as bacterial super-infection is not an uncommon complication, and mortality and morbidity are highly exacerbated by IFNL therapy.
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