TY - JOUR
T1 - Staphylococcus aureus activates type I IFN signaling in mice and humans through the Xr repeated sequences of protein A
AU - Martin, Francis J.
AU - Gomez, Marisa I.
AU - Wetzel, Dawn M.
AU - Memmi, Guido
AU - O'Seaghdha, Maghnus
AU - Soong, Grace
AU - Schindler, Christian
AU - Prince, Alice
PY - 2009/7/1
Y1 - 2009/7/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=68949146969&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=68949146969&partnerID=8YFLogxK
U2 - 10.1172/jci35879
DO - 10.1172/jci35879
M3 - Article
C2 - 19603548
AN - SCOPUS:68949146969
SN - 0021-9738
VL - 119
SP - 1931
EP - 1939
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 7
ER -