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 5

SpA Xr activates STAT1/3 in vivo.

Options: View larger image (or click on image) Download as PowerPoint
SpA Xr activates STAT1/3 in vivo. (A) C57BL/6 mice were intranasally ino...
(A) C57BL/6 mice were intranasally inoculated with SpA Xr, S. aureus, or PBS (control). 4 hours later, p-STAT1 (Tyr701), p-STAT3 (Tyr705), and β-actin were detected in lung lysates by immunoblot. Data from 2 representative mice out of 6 are shown for both left quadrants and bottom right quadrant. Data from 2 representative mice out of 3 are shown for top right quadrant. The thin vertical line between bands within a group indicate data spliced from the original blot. (B) IL-6 mRNA in the lung of SpA Xr–treated mice was detected by real-time PCR, and the percentage of PMNs among total leukocytes in the lung was determined by flow cytometry following intranasal inoculation of SpA Xr in untreated or JAK inhibitor–treated mice (Inh). Each dot represents an individual mouse, and horizontal lines show the median value in each group. (C) IL-6 mRNA in the lung of S. aureus–infected mice was detected by real-time PCR. The median values of the percentage of PMNs corresponding to those mice are shown.