Type I Interferon Signaling Promotes Defense Against Gram-negative Pneumonia

Saturday, February 13, 2016
Kathryn Michels, University of Virginia, Charlottesville, VA
Background: Klebsiella pneumoniae is a gram-negative bacterium which can cause severe pneumonia in healthcare-associated settings.  Some K. pneumoniae strains have developed high resistance to multiple antibiotics, including carbapenems, drastically reducing treatment options for patients.  Type I interferons (IFNs) are a class of cytokines that signal via a single receptor, the type I IFN receptor (IFNAR), and are best-known for mediating antiviral host defense.  Much less is known about the role of type I IFNs during pneumonia.  Hypothesis: We hypothesized that type I IFN signaling is important to host outome in Klebsiella infection.  Methods: We infected wildtype and Ifnar1-/- mice intratracheally with K. pneumoniae to test the role of type I interferon on disease outcome.  Following infection, we harvested the lungs, blood, and spleen to determine bacterial burden and cytokine response.  We analyzed leucocyte recruitment to infection sites using flow cytometry.  Results: We found a marked induction of type I interferon transcript in the lungs of wildtype mice in the first 3 days after onset of pneumonia. As compared to wildtpye mice, Ifnar-/- hosts suffered higher bacterial burdens in the lungs and blood, and had reduced survival following K. pneumoniae infection.  Wildtype and Ifnar1-/- mice displayed similar levels of IL-12p70, TNF-α, IL-17, and Ifn-γ cytokine responses in the lung.  As expected, we found significantly more neutrophils in the lungs and blood of Ifnar1-/- mice compared to wildtype mice following infection, which we attributed to a response to higher bacterial burden.  Ifnar1-/- , but not wildtype, mice developed marked splenomegaly and exhibited increased splenic bacterial content and hemoglobin, but not leucocyte expansion, in direct proportion to spleen mass. Conclusions: Type I IFN signaling is required for host defense against K. pneumoniae infection.  Our results suggest that absence of type I IFN signaling in the spleen may impede bacterial clearance from the blood.  Our findings support a novel, protective role of type I IFNs in gram negative bacterial pneumonia that centers on splenic function.