permanent joint dysfunction is a devastating complication in patients with septic arthritis. Staphylococcus aureus (S. aureus) lipoproteins (Lpp), the predominant ligands for TLR2, are known to be arthritogenic and induce bone destruction when introduced directly into the joint. Here, we aim to investigate the importance of S. aureus Lpp and TLR2 in a hematogenous septic arthritis model, which is the most common route of infection in humans. C57BL/6 wild-type and TLR2 deficient mice were intravenously inoculated with S. aureus Newman parental strain or its lipoprotein-deficient Δlgt mutant strain. the clinical course of septic arthritis, radiological changes, and serum levels of cytokines and chemokines, were assessed. newman strain induced more severe and frequent clinical septic polyarthritis compared to its Δlgt mutant in TLR2 deficient mice, but not in wild-type controls. Bone destruction, however, did not differ between groups. Lpp expression was associated with higher mortality, weight loss as well as impaired bacterial clearance in mouse kidneys independent of TLR2. Furthermore, Lpp expression induced increased systemic pro-inflammatory cytokine and neutrophil chemokine release. Staphylococcal Lpp are potent virulence factors in S. aureus systemic infection independent of host TLR2 signalling. However, they have a limited impact on bone erosion in hematogenous staphylococcal septic arthritis. Septic arthritis remains a devastating and invasive joint disease. Due to its rapidly progressing nature, septic arthritis is considered a medical emergency 1 with a poor prognosis. Despite advances in understanding and treatment of infectious diseases, the prospect of patients with septic arthritis has remained poor. Almost half of the patients will suffer from permanent joint destruction 2 , if treatment is not initiated immediately 3. The estimated incidence of septic arthritis in the general population is approximately 6-10 cases per 100,000 individuals per year 4. However, in patients with an underlying joint disease, such as rheumatoid arthritis (RA), the incidence of septic arthritis is nearly 10 times higher than in the general population 4. Septic arthritis is most often caused by Staphylococcus aureus (S. aureus), a pathogenic Gram-positive bacterium 5. S. aureus-induced septic arthritis has been extensively studied for the past few decades; several virulence factors as well as various host-factors targeted by the bacterium have been identified 6-11. However, much still remains elusive regarding the bacteria-host interaction in S. aureus septic arthritis. Staphylococcal lipoproteins (Lpp), important bacterial molecules in S. aureus, consist of a lipid-moiety and a protein-part, and are anchored in the bacterial cytoplasmic membrane 12. Lpp are important for bacterial survival during infection due to their role in maintaining the metabolic activity of the bacteria 13,14. The lipid structure of Lpp is known to stimulate the innate immune system through activation of pattern recognition receptors 15 , and bacte...

Despite being a major bacterial factor in alerting the human immune system, the role of Staphylococcus aureus (S. aureus) lipoproteins (Lpp) in skin infections remains largely unknown. Here, we demonstrated that subcutaneous injection of S. aureus Lpp led to infiltration of neutrophils and monocytes/macrophages and induced skin lesions in mice. Lipid-moiety of S. aureus Lpp and host TLR2 was responsible for such effect. Lpp-deficient S. aureus strains exhibited smaller lesion size and reduced bacterial loads than their parental strains; the altered phenotype in bacterial loads was TLR2-independent. Lpp expression in skin infections contributed to imbalanced local hemostasis toward hypercoagulable state. Depletion of leukocytes or fibrinogen abrogated the effects induced by Lpp in terms of skin lesions and bacterial burden. Our data suggest that S. aureus Lpp induce skin inflammation and promote abscess formation that protects bacteria from innate immune killing. This suggests an intriguing bacterial immune evasion mechanism.

Staphylococcal aureus (S. aureus), a Gram-positive bacteria, is known to cause various infections. Extracellular vesicles (EVs) are a heterogeneous array of membranous structures secreted by cells from all three domains of life, i.e., eukaryotes, bacteria, and archaea. Bacterial EVs are implied to be involved in both bacteria–bacteria and bacteria–host interactions during infections. It is still unclear how S. aureus EVs interact with host cells and induce inflammatory responses. In this study, EVs were isolated from S. aureus and mutant strains deficient in either prelipoprotein lipidation (Δlgt) or major surface proteins (ΔsrtAB). Their immunostimulatory capacities were assessed both in vitro and in vivo. We found that S. aureus EVs induced pro-inflammatory responses both in vitro and in vivo. However, this activity was dependent on lipidated lipoproteins (Lpp), since EVs isolated from the Δlgt showed no stimulation. On the other hand, EVs isolated from the ΔsrtAB mutant showed full immune stimulation, indicating the cell wall anchoring of surface proteins did not play a role in immune stimulation. The immune stimulation of S. aureus EVs was mediated mainly by monocytes/macrophages and was TLR2 dependent. In this study, we demonstrated that not only free Lpp but also EV-imbedded Lpp had high pro-inflammatory activity.

Alterations in cellular pathways related to both endocrine and vascular endothelial growth factors (VEGF) may contribute to breast cancer progression. Inhibition of the elevated levels of these pathways is associated with clinical benefits. However, molecular mechanisms by which endocrine-related pathways and VEGF signalling cooperatively promote breast cancer progression remain poorly understood. In the present study, we show that the A-type cyclin, cyclin A1, known for its important role in the initiation of leukemia and prostate cancer metastasis, is highly expressed in primary breast cancer specimens and metastatic lesions, in contrasting to its barely detectable expression in normal human breast tissues. There is a statistically significant correlation between cyclin A1 and VEGF expression in breast cancer specimens from two patient cohorts (p<0.01). Induction of cyclin A1 overexpression in breast cancer cell line MCF-7 results in an enhanced invasiveness and a concomitant increase in VEGF expression. In addition, there is a formation of protein–protein complexes between cyclin A1 and estrogen receptor ER-α cyclin A1 overexpression increases ER-α expression in MCF-7 and T47D cells. In mouse tumor xenograft models in which mice were implanted with MCF-7 cells that overexpressed cyclin A1 or control vector, cyclin A1 overexpression results in an increase in tumor growth and angiogenesis, which is coincident with an enhanced expression of VEGF, VEGFR1 and ER-α Our findings unravel a novel role for cyclin A1 in growth and progression of breast cancer, and suggest that multiple cellular pathways, including cell cycle regulators, angiogenesis and estrogen receptor signalling, may cooperatively contribute to breast cancer progression.

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