Staphylococcus aureus Induces Type I IFN Signaling in Dendritic Cells Via TLR9

Abstract

The importance of type I IFN signaling in the innate immune response to viral and intracellular pathogens is well established, with an increasing literature implicating extracellular bacterial pathogens, including Staphylococcus aureus in this signaling pathway. Airway epithelial cells and especially dendritic cells (DC) contribute to the production of type I IFNs in the lung. We were interested in establishing how S. aureus activates the type I IFN cascade in DC. In vitro studies confirmed the rapid uptake of S. aureus by DC followed promptly by STAT1 phosphorylation and expression of IFN-β. Signaling occurred using heat-killed organism and in the absence of PVL and α-toxin. Consistent with the participation of endosomal and not cytosolic receptors, signaling was predominantly mediated by MyD88, TLR9 and IRF1 and blocked by cytochalasin D, dynasore and chloroquine. To determine the role of TLR9 signaling in the pathogenesis of S. aureus pneumonia we infected WT and Tlr9−/− mice with MRSA USA300. Tlr9−/− mice had significantly improved clearance of S. aureus from the airways and lung tissue. Ifnar−/− mice also had improved clearance. This enhanced clearance in Tlr9−/− mice was not due to differences in the numbers of recruited neutrophils into the airways, but instead correlated with decreased induction of TNF. Thus, we identified TLR9 as the critical receptor mediating the induction of type I IFN signaling in dendritic cells in response to S. aureus, illustrating an additional mechanism through which S. aureus exploits innate immune signaling to facilitate infection.

Toll-Like Receptor 9 Enhances Bacterial Clearance and Limits Lung Consolidation in Murine Pneumonia Caused by Methicillin-Resistant Staphylococcus aureus

“…Our data confirm and expand upon a previous study that examined the role of TLR9 in host defense during MRSA pneumonia (20). This former investigation reported reduced bacterial loads in lungs of tlr9 -/-mice at a single time point (24 h) after infection, accompanied by lower TNF-α levels.…”

“…including that of MRSA (20). Considering the central role of TLR9 in the recognition of extracellular DNA and the injurious host response associated with cellular damage and death during MRSA pneumonia, we here sought to determine the role of TLR9 in experimentally induced MRSA pneumonia.…”

TLR8 Senses Staphylococcus aureus RNA in Human Primary Monocytes and Macrophages and Induces IFN-β Production via a TAK1–IKKβ–IRF5 Signaling Pathway

“…Induction of type I IFNs by S. aureus has been examined in different human and murine cell types with different conclusions regarding the molecular mechanisms involved. S. aureus PAMPs suggested to be responsible for IFN-b induction include staphylococcal protein A, DNA, RNA, and lipoteichoic acid, and TLR2, TLR7, TLR9, and cytosolic PRRs were implicated (15)(16)(17)(18)(19)(20)(21)(22).…”

Розвиток Імунної Відповіді При Стафілококовій Пневмонії (Частина 3)

“…Индукция IFN-β в респираторном тракте Staphylococcus aureus осуществляется через возбуждение различных молекулярных путей, в том числе и через TLR9/IRF1 или NLRC2/RIP2/IRF5 пути [88].…”