Staphylococcus aureus activates type I IFN signaling in mice and humans through the Xr repeated sequences of protein A.
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-beta expression, JAK-STAT signaling, and IL-6 production. Mice lacking IFN-alpha/beta 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-beta 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.
Martin
Francis J
FJ
Department of Pharmacology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
Gomez
Marisa I
MI
Wetzel
Dawn M
DM
Memmi
Guido
G
O'Seaghdha
Maghnus
M
Soong
Grace
G
Schindler
Christian
C
Prince
Alice
A
D000818:Animals; D006801:Humans; D007370:Interferon Type I / Q000276:immunology* / Q000378:metabolism; D055624:Methicillin-Resistant Staphylococcus aureus / Q000276:immunology* / Q000472:pathogenicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D017434:Protein Structure, Tertiary; D053633:Receptor, Interferon alpha-beta / Q000276:immunology; D020449:Repetitive Sequences, Amino Acid; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013205:Staphylococcal Protein A / Q000737:chemistry / Q000276:immunology*
D007370:Interferon Type I; D050796:STAT3 Transcription Factor; D013205:Staphylococcal Protein A; C494087:Stat3 protein, mouse; D053633:Receptor, Interferon alpha-beta