title: Induction of type I interferon signaling determines the relative pathogenicity of Staphylococcus aureus strains.
abstract: The tremendous success of S. aureus as a human pathogen has been explained primarily by its array of virulence factors that enable the organism to evade host immunity. Perhaps equally important, but less well understood, is the importance of the intensity of the host response in determining the extent of pathology induced by S. aureus infection, particularly in the pathogenesis of pneumonia. We compared the pathogenesis of infection caused by two phylogenetically and epidemiologically distinct strains of S. aureus whose behavior in humans has been well characterized. Induction of the type I IFN cascade by strain 502A, due to a NOD2-IRF5 pathway, was the major factor in causing severe pneumonia and death in a murine model of pneumonia and was associated with autolysis and release of peptidogylcan. In contrast to USA300, 502A was readily eliminated from epithelial surfaces in vitro. Nonetheless, 502A caused significantly increased tissue damage due to the organisms that were able to invade systemically and trigger type I IFN responses, and this was ameliorated in Ifnar⁻/⁻ mice. The success of USA300 to cause invasive infection appears to depend upon its resistance to eradication from epithelial surfaces, but not production of specific toxins. Our studies illustrate the important and highly variable role of type I IFN signaling within a species and suggest that targeted immunomodulation of specific innate immune signaling cascades may be useful to prevent the excessive morbidity associated with S. aureus pneumonia.
authors.affiliation: Department of Pediatrics, Columbia University, New York, New York, United States of America.
authors.forename: Dane
authors.initials: D
authors.lastname: Parker
authors.affiliation: Department of Pediatrics, Columbia University, New York, New York, United States of America ; Sackler Institute for Comparative Genomics, American Museum of Natural History, New York, New York, United States of America.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Planet
authors.affiliation: Department of Pediatrics, Columbia University, New York, New York, United States of America.
authors.forename: Grace
authors.initials: G
authors.lastname: Soong
authors.affiliation: Sackler Institute for Comparative Genomics, American Museum of Natural History, New York, New York, United States of America.
authors.forename: Apurva
authors.initials: A
authors.lastname: Narechania
authors.affiliation: Department of Pediatrics, Columbia University, New York, New York, United States of America.
authors.forename: Alice
authors.initials: A
authors.lastname: Prince
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D015151:Immunoblotting; D007370:Interferon Type I / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D013203:Staphylococcal Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013211:Staphylococcus aureus / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D014774:Virulence
chemical_list: D007370:Interferon Type I