Staphylococcus aureus activates type I IFN signaling in mice and humans through the Xr repeated sequences of protein A
Francis J. Martin, … , Christian Schindler, Alice Prince
Francis J. Martin, … , Christian Schindler, Alice Prince
Published June 15, 2009
Citation Information: J Clin Invest. 2009;119(7):1931-1939. https://doi.org/10.1172/JCI35879.
View: Text | PDF
Research Article Infectious disease

Staphylococcus aureus activates type I IFN signaling in mice and humans through the Xr repeated sequences of protein A

Abstract

The activation of type I IFN signaling is a major component of host defense against viral infection, but it is not typically associated with immune responses to extracellular bacterial pathogens. Using mouse and human airway epithelial cells, we have demonstrated that Staphylococcus aureus activates type I IFN signaling, which contributes to its virulence as a respiratory pathogen. This response was dependent on the expression of protein A and, more specifically, the Xr domain, a short sequence–repeat region encoded by DNA that consists of repeated 24-bp sequences that are the basis of an internationally used epidemiological typing scheme. Protein A was endocytosed by airway epithelial cells and subsequently induced IFN-β expression, JAK-STAT signaling, and IL-6 production. Mice lacking IFN-α/β receptor 1 (IFNAR-deficient mice), which are incapable of responding to type I IFNs, were substantially protected against lethal S. aureus pneumonia compared with wild-type control mice. The profound immunological consequences of IFN-β signaling, particularly in the lung, may help to explain the conservation of multiple copies of the Xr domain of protein A in S. aureus strains and the importance of protein A as a virulence factor in the pathogenesis of staphylococcal pneumonia.

Authors

Francis J. Martin, Marisa I. Gomez, Dawn M. Wetzel, Guido Memmi, Maghnus O’Seaghdha, Grace Soong, Christian Schindler, Alice Prince

×

Figure 3

SpA is internalized and induces type 1 IFN signaling in airway epithelial cells.

Options: View larger image (or click on image) Download as PowerPoint
SpA is internalized and induces type 1 IFN signaling in airway epithelia...
(A–E) Airway cells were incubated with SpA or SpA Xr and (A) internalization monitored by flow cytometry (ΔMFI, change in mean fluorescence intensity) or (B) by confocal microscopy for SpA (green) and transferrin (red) at 1 hour (original magnification, ×80). (C) SpA-induced IFN-β production was measured at 2 hours by real-time PCR in the presence of Dynasore (Dyn), (D) in response to transfection of an SpA Xr plasmid (Xr) or empty vector (CV), and (E) in the presence of 50 μg/ml polymixin B. (F) STAT1 and STAT3 phosphorylation in response to SpA (S) or LPS (L) after 1 and 2 hours was monitored in murine nasal epithelial cells from WT or trif–/– mice. (G) STAT1 and STAT3 phosphorylation was monitored in airway cells in response to SpA Xr (30 min., n = 2; 60 and 120 min., n = 3), in the presence of Dyn (n = 3), pan-JAK inhibitor (Pan, n = 3), JAK2 inhibitor (JAK2, n = 3), or neutralizing antibody to IFN-β (n = 2). Thin vertical lines between bands indicate data spliced together from original blot. Red arrows indicate that the same bands from the 120 min. Xr treatment were used as the control for pan-JAK and JAK2 inhibitor treatments. U, M, or Unstim. indicates unstimulated control. Unless otherwise indicated, data shows mean values of triplicate samples from 1 representative experiment out of 3, and error bars indicate standard deviations. *P < 0.001; **P < 0.05.