Dataset Information

Toll-Like Receptor 2 and Lipoprotein-Like Lipoproteins Enhance Staphylococcus aureus Invasion in Epithelial Cells.

ABSTRACT: Staphylococcus aureus contains a certain subclass of lipoproteins, the so-called lipoprotein-like lipoproteins (Lpl's), that not only represent Toll-like receptor 2 (TLR2) ligands but are also involved in host cell invasion. Here we addressed the question of which factors contribute to Lpl-mediated invasion of epithelial cells and keratinocytes. For this purpose, we compared the invasiveness of USA300 and its Δlpl mutant under different conditions. In the presence of the matrix proteins IgG, fibrinogen (Fg), and fibronectin (Fn), and of fetal bovine serum (FBS), the invasion ratio was increased in both strains, and always more in USA300 than in its Δlpl mutant. Interestingly, when we compared the invasion of HEK-0 and HEK-TLR2 cells, the cells expressing TLR2 showed a 9-times-higher invasion frequency. When HEK-TLR2 cells were additionally stimulated with a synthetic lipopeptide, Pam3CSK4 (P3C), the invasion frequency was further increased. A potential reason for the positive effect of TLR2 on invasion could be that TLR2 activation by P3C also activates F-actin formation. Here we show that S. aureus invasion depends on a number of factors, on the host side as well as on the bacterial side.

SUBMITTER: Nguyen MT

PROVIDER: S-EPMC6056871 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Toll-Like Receptor 2 and Lipoprotein-Like Lipoproteins Enhance Staphylococcus aureus Invasion in Epithelial Cells.

Nguyen Minh-Thu MT Peisl Loulou L Barletta Francesca F Luqman Arif A Götz Friedrich F

Infection and immunity 20180723 8

<i>Staphylococcus aureus</i> contains a certain subclass of lipoproteins, the so-called lipoprotein-like lipoproteins (Lpl's), that not only represent Toll-like receptor 2 (TLR2) ligands but are also involved in host cell invasion. Here we addressed the question of which factors contribute to Lpl-mediated invasion of epithelial cells and keratinocytes. For this purpose, we compared the invasiveness of USA300 and its Δ<i>lpl</i> mutant under different conditions. In the presence of the matrix pro ...[more]

PMID: 29844243

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Project description:BACKGROUND: Chlamydia trachomatis was previously shown to express a lipoprotein, the macrophage infectivity potentiator (Mip), exposed at the bacterial surface, and able to stimulate human primary monocytes/macrophages through Toll Like Receptor (TLR)2/TLR1/TLR6, and CD14. In PMA-differentiated THP-1 cells the proinflammatory activity of Mip was significantly higher in the absence than in the presence of serum. The present study aims to investigate the ability of different serum factors to attenuate Mip proinflammatory activity in PMA-differentiated THP-1 cells and in primary human differentiated macrophages. The study was also extend to another lipoprotein, the Borrelia burgdorferi outer surface protein (Osp)A. The proinflammatory activity was studied through Tumor Necrosis Factor alpha (TNF-?) and Interleukin (IL)-8 release. Finally, TLR1/2 human embryonic kidney-293 (HEK-293) transfected cells were used to test the ability of the serum factors to inhibit Mip and OspA proinflammatory activity. RESULTS: In the absence of any serum and in the presence of 10% delipidated FBS, production of Mip-induced TNF-? and IL-8 in PMA-differentiated THP-1 cells were similar whereas they were significantly decreased in the presence of 10% FBS suggesting an inhibiting role of lipids present in FBS. In the presence of 10% human serum, the concentrations of TNF-? and IL-8 were 2 to 5 times lower than in the presence of 10% FBS suggesting the presence of more potent inhibitor(s) in human serum than in FBS. Similar results were obtained in primary human differentiated macrophages. Different lipid components of human serum were then tested (total lipoproteins, HDL, LDL, VLDL, triglyceride emulsion, apolipoprotein (apo)A-I, B, E2, and E3). The most efficient inhibitors were LDL, VLDL, and apoB that reduced the mean concentration of TNF-? release in Mip-induced macrophages to 24, 20, and 2%, respectively (p < 0.0001). These lipid components were also able to prevent TLR1/2 induced activation by Mip, in HEK-293 transfected cells. Similar results were obtained with OspA. CONCLUSIONS: These results demonstrated the ability of serum lipids to attenuate proinflammatory activity of bacterial lipoproteins and suggested that serum lipoproteins interact with acyl chains of the lipid part of bacterial lipoproteins to render it biologically inactive.

Project description:Methicillin-resistant Staphylococcus aureus (MRSA) resists nearly all β-lactam antibiotics that have a bactericidal activity. However, whether the empirically used β-lactams enhance MRSA pathogenicity in vivo remains unclear. In this study, we showed that a cluster of lipoprotein-like genes (lpl, sa2275 to sa2273 [sa2275-sa2273]) was upregulated in MRSA in response to subinhibitory concentrations of β-lactam induction. The increasing expression of lpl by β-lactams was directly controlled by the global regulator SarA. The β-lactam-induced Lpls stimulated the production of interleukin-6 and tumor necrosis factor alpha in RAW 264.7 macrophages. The lpl deletion mutants (N315Δlpl and USA300Δlpl) decreased the proinflammatory cytokine levels in vitro and in vivo Purified lipidated SA2275-his proteins could trigger a Toll-like-receptor-2 (TLR2)-dependent immune response in primary mouse bone marrow-derived macrophages and C57BL/6 mice. The bacterial loads of N315Δlpl in the mouse kidney were lower than those of the wild-type N315. The β-lactam-treated MRSA exacerbated cutaneous infections in both BALB/c and C57BL/6 mice, presenting increased lesion size; destroyed skin structure; and easily promoted abscess formation compared with those of the untreated MRSA. However, the size of abscesses caused by the β-lactam-treated N315 was negligibly different from those caused by the untreated N315Δlpl in C57BL/6 TLR2-/- mice. Our findings suggest that β-lactams must be used carefully because they might aggravate the outcome of MRSA infection compared to inaction in treatment.IMPORTANCE β-Lactam antibiotics are widely applied to treat infectious diseases. However, certain poor disease outcomes caused by β-lactams remain poorly understood. In this study, we have identified a cluster of lipoprotein-like genes (lpl, sa2275-sa2273) that is upregulated in the major clinically prevalent MRSA clones in response to subinhibitory concentrations of β-lactam induction. The major highlight of this work is that β-lactams stimulate the expression of SarA, which directly binds to the lpl cluster promoter region and upregulates lpl expression in MRSA. Deletion of lpl significantly decreases proinflammatory cytokine levels in vitro and in vivo The β-lactam-induced Lpls enhance host inflammatory responses by triggering the Toll-like-receptor-2-mediated expressions of interleukin-6 and tumor necrosis factor alpha. The β-lactam-induced Lpls are important virulence factors that enhance MRSA pathogenicity. These data elucidate that subinhibitory concentrations of β-lactams can exacerbate the outcomes of MRSA infection through induction of lpl controlled by the global regulator SarA.

Dataset Information

Toll-Like Receptor 2 and Lipoprotein-Like Lipoproteins Enhance Staphylococcus aureus Invasion in Epithelial Cells.

Publications

Toll-Like Receptor 2 and Lipoprotein-Like Lipoproteins Enhance Staphylococcus aureus Invasion in Epithelial Cells.

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