Abstract
Pathogen activation of innate immune pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) stimulates cellular signaling pathways. This often leads to outcomes that contribute to pathogen clearance. Alternatively, activation of specific PRR pathways can aid pathogen survival. The human pathogen Staphylococcus aureus is a case in point, employing strategies to escape innate immune recognition and killing by the host. As for other bacteria, PRR-stimulated type I interferon (IFN-I) induction has been proposed as one such immune escape pathway that may favor S. aureus. Cell wall components of S. aureus elicit TLR2-dependent cellular responses, but the exact signaling pathways activated by S. aureus–TLR2 engagement and the consequences of their activation for the host and bacterium are not fully known. We previously showed that TLR2 activates both a cytoplasmic and an endosome-dependent signaling pathway, the latter leading to IFN-I production. Here, we demonstrate that S. aureus infection of human monocytes activates a TLR2-dependent endosomal signaling pathway, leading to IFN-I induction. We mapped the signaling components of this pathway and identified roles in IFN-I stimulation for the Toll-interleukin-1 receptor (TIR) adaptor Myd88 adaptor-like (Mal), TNF receptor-associated factor 6 (TRAF6), and IκB kinase (IKK)-related kinases, but not for TRIF-related adaptor molecule (TRAM) and TRAF3. Importantly, monocyte TLR2-dependent endosomal signaling enabled immune escape for S. aureus, because this pathway, but not IFN-I per se, contributed to intracellular bacterial survival. These results reveal a TLR2-dependent mechanism in human monocytes whereby S. aureus manipulates innate immune signaling for its survival in cells.
Highlights
Pathogen activation of innate immune pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) stimulates cellular signaling pathways
We have previously shown in mouse bone marrow– derived macrophages (BMDMs) that TLR2induced IFN-I utilized an endosomal signaling pathway that required the adaptors Toll/IL-1R domain– containing adaptor inducing IFN (TRIF)-related adaptor molecule (TRAM) and Myd88 adaptor-like (Mal), whereas TLR2-induced tumor necrosis factor (TNF)␣ was via a nonendosomal Mal-dependent pathway [24]
It has been known for some time that TLR2 has a major role in detection of Grampositive bacteria, such as S. aureus, and that lipoteichoic acid (LTA) is a major S. aureus pathogen-associated molecular patterns (PAMPs) that is recognized by TLR2 [11, 42]
Summary
We have previously shown in mouse BMDMs that TLR2induced IFN-I utilized an endosomal signaling pathway that required the adaptors TRAM and Mal, whereas TLR2-induced TNF␣ was via a nonendosomal Mal-dependent pathway [24]. VIPER is a peptide derived from the poxviral TIR antagonist protein A46, which inhibits Mal- and TRAM-dependent cellular responses in mouse BMDMs [34] Both LTA and S. aureus IFN-I and TNF␣ responses in THP-1s and primary monocytes were significantly inhibited by pretreatment of cells with VIPER, compared with control peptide (Fig. 4, A–D), consistent with the notion that Mal and/or TRAM are required for both the cytoplasmic TNF␣ response and the endosomal IFN-I response pathways. TLR2 utilizes different sorting adaptors for IFN-I induction in human monocytes compared with mouse BMDMs. As expected, siRNA targeting MyD88 and Mal, and not TRAM and TRIF, significantly inhibited the LTAstimulated cytoplasmic TNF␣ response (Fig. 4G). The rate of phagocytosis of S. aureus by the THP-1 cells was not affected by inhibitor treatment (Fig. 8, D and E) Taken together, these data suggest that S. aureus manipulates the endosomal TLR2 signaling pathway to promote its survival in human monocytes. Despite the lack of effect of IFN-I on intracellular survival, we wondered whether other cell-intrinsic outcomes regulated by the TLR2-
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