439 research outputs found

    FimH Adhesin of Type 1 Fimbriae Is a Potent Inducer of Innate Antimicrobial Responses Which Requires TLR4 and Type 1 Interferon Signalling

    Get PDF
    Components of bacteria have been shown to induce innate antiviral immunity via Toll-like receptors (TLRs). We have recently shown that FimH, the adhesin portion of type 1 fimbria, can induce the innate immune system via TLR4. Here we report that FimH induces potent in vitro and in vivo innate antimicrobial responses. FimH induced an innate antiviral state in murine macrophage and primary MEFs which was correlated with IFN-Ξ² production. Moreover, FimH induced the innate antiviral responses in cells from wild type, but not from MyD88βˆ’/βˆ’, Trifβˆ’/βˆ’, IFNβˆ’Ξ±/Ξ²Rβˆ’/βˆ’ or IRF3βˆ’/βˆ’ mice. Vaginal delivery of FimH, but not LPS, completely protected wild type, but not MyD88βˆ’/βˆ’, IFN-Ξ±/Ξ²Rβˆ’/βˆ’, IRF3βˆ’/βˆ’ or TLR4βˆ’/βˆ’ mice from subsequent genital HSV-2 challenge. The FimH-induced innate antiviral immunity correlated with the production of IFN-Ξ², but not IFN-Ξ± or IFN-Ξ³. To examine whether FimH plays a role in innate immune induction in the context of a natural infection, the innate immune responses to wild type uropathogenic E. coli (UPEC) and a FimH null mutant were examined in the urinary tract of C57Bl/6 (B6) mice and TLR4-deficient mice. While UPEC expressing FimH induced a robust polymorphonuclear response in B6, but not TLR4βˆ’/βˆ’ mice, mutant bacteria lacking FimH did not. In addition, the presence of TLR4 was essential for innate control of and protection against UPEC. Our results demonstrate that FimH is a potent inducer of innate antimicrobial responses and signals differently, from that of LPS, via TLR4 at mucosal surfaces. Our studies suggest that FimH can potentially be used as an innate microbicide against mucosal pathogens

    Recombinant human osteopontin expressed in Nicotiana benthamiana stimulates osteogenesis related genes in human periodontal ligament cells.

    Get PDF
    Tissue engineering aims to utilise biologic mediators to facilitate tissue regeneration. Several recombinant proteins have potential to mediate induction of bone production, however, the high production cost of mammalian cell expression impedes patient access to such treatments. The aim of this study is to produce recombinant human osteopontin (hOPN) in plants for inducing dental bone regeneration. The expression host was Nicotiana benthamiana using a geminiviral vector for transient expression. OPN expression was confirmed by Western blot and ELISA, and OPN was purified using Ni affinity chromatography. Structural analysis indicated that plant-produced hOPN had a structure similar to commercial HEK cell-produced hOPN. Biological function of the plant-produced hOPN was also examined. Human periodontal ligament stem cells were seeded on an OPN-coated surface. The results indicated that cells could grow normally on plant-produced hOPN as compared to commercial HEK cell-produced hOPN determined by MTT assay. Interestingly, increased expression of osteogenic differentiation-related genes, including OSX, DMP1, and Wnt3a, was observed by realtime PCR. These results show the potential of plant-produced OPN to induce osteogenic differentiation of stem cells from periodontal ligament in vitro, and suggest a therapeutic strategy for bone regeneration in the future

    The Vanishing of the Primary Emission Region in PKS 1510-089

    Get PDF
    In 2021 July, PKS 1510-089 exhibited a significant flux drop in the high-energy Ξ³-ray (by a factor 10) and optical (by a factor 5) bands and remained in this low state throughout 2022. Similarly, the optical polarization in the source vanished, resulting in the optical spectrum being fully explained through the steady flux of the accretion disk and the broad-line region. Unlike the aforementioned bands, the very-high-energy Ξ³-ray and X-ray fluxes did not exhibit a significant flux drop from year to year. This suggests that the steady-state very-high-energy Ξ³-ray and X-ray fluxes originate from a different emission region than the vanished parts of the high-energy Ξ³-ray and optical jet fluxes. The latter component has disappeared through either a swing of the jet away from the line of sight or a significant drop in the photon production efficiency of the jet close to the black hole. Either change could become visible in high-resolution radio images

    Resveratrol Prevents Endothelial Cells Injury in High-Dose Interleukin-2 Therapy against Melanoma

    Get PDF
    Immunotherapy with high-dose interleukin-2 (HDIL-2) is an effective treatment for patients with metastatic melanoma and renal cell carcinoma. However, it is accompanied by severe toxicity involving endothelial cell injury and induction of vascular leak syndrome (VLS). In this study, we found that resveratrol, a plant polyphenol with anti-inflammatory and anti-cancer properties, was able to prevent the endothelial cell injury and inhibit the development of VLS while improving the efficacy of HDIL-2 therapy in the killing of metastasized melanoma. Specifically, C57BL/6 mice were injected with B16F10 cells followed by resveratrol by gavage the next day and continued treatment with resveratrol once a day. On day 9, mice received HDIL-2. On day 12, mice were evaluated for VLS and tumor metastasis. We found that resveratrol significantly inhibited the development of VLS in lung and liver by protecting endothelial cell integrity and preventing endothelial cells from undergoing apoptosis. The metastasis and growth of the tumor in lung were significantly inhibited by HDIL-2 and HDIL-2 + resveratrol treatment. Notably, HDIL-2 + resveratrol co-treatment was more effective in inhibiting tumor metastasis and growth than HDIL-2 treatment alone. We also analyzed the immune status of Gr-1+CD11b+ myeloid-derived suppressor cells (MDSC) and FoxP3+CD4+ regulatory T cells (Treg). We found that resveratrol induced expansion and suppressive function of MDSC which inhibited the development of VLS after adoptive transfer. However, resveratrol suppressed the HDIL-2-induced expansion of Treg cells. We also found that resveratrol enhanced the susceptibility of melanoma to the cytotoxicity of IL-2-activated killer cells, and induced the expression of the tumor suppressor gene FoxO1. Our results suggested the potential use of resveratrol in HDIL-2 treatment against melanoma. We also demonstrated, for the first time, that MDSC is the dominant suppressor cell than regulatory T cell in the development of VLS

    Search for dark matter annihilation signals in the H.E.S.S. Inner galaxy survey

    Get PDF
    The central region of the MilkyΒ Way is one of the foremost locations to look for dark matter (DM) signatures. We report the first results on a search for DM particle annihilation signals using new observations from an unprecedented Ξ³-ray survey of the Galactic Center (GC) region, i.e., the Inner Galaxy Survey, at very high energies (≳100  GeV) performed with the H.E.S.S. array of five ground-based Cherenkov telescopes. No significant Ξ³-ray excess is found in the search region of the 2014-2020 dataset and a profile likelihood ratio analysis is carried out to set exclusion limits on the annihilation cross section βŸ¨Οƒv⟩. Assuming Einasto and Navarro-Frenk-White (NFW) DM density profiles at the GC, these constraints are the strongest obtained so far in the TeV DM mass range. For the Einasto profile, the constraints reachΒ βŸ¨Οƒv⟩ values of 3.7Γ—10^{-26}  cm^{3} s^{-1} for 1.5Β TeV DM mass in the W^{+}W^{-} annihilation channel, and 1.2Γ—10^{-26}  cm^{3} s^{-1} for 0.7Β TeV DM mass in the Ο„^{+}Ο„^{-} annihilation channel. With the H.E.S.S. Inner Galaxy Survey, ground-based Ξ³-ray observations thus probe βŸ¨Οƒv⟩ values expected from thermal-relic annihilating TeV DM particles

    Searching for TeV gamma-ray emission from SGR 1935+2154 during its 2020 X-ray and radio bursting phase

    Get PDF
    Magnetar hyperflares are the most plausible explanation for fast radio bursts (FRBs)β€”enigmatic powerful radio pulses with durations of several milliseconds and high brightness temperatures. The first observational evidence for this scenario was obtained in 2020 April when an FRB was detected from the direction of the Galactic magnetar and soft gamma-ray repeater SGR 1935+2154. The FRB was preceded by two gamma-ray outburst alerts by the BAT instrument aboard the Swift satellite, which triggered follow-up observations by the High Energy Stereoscopic System (H.E.S.S.). H.E.S.S. observed SGR 1935+2154 for 2 hr on 2020 April 28. The observations are coincident with X-ray bursts from the magnetar detected by INTEGRAL and Fermi-GBM, thus providing the first very high energy gamma-ray observations of a magnetar in a flaring state. High-quality data acquired during these follow-up observations allow us to perform a search for short-time transients. No significant signal at energies E > 0.6 TeV is found, and upper limits on the persistent and transient emission are derived. We here present the analysis of these observations and discuss the obtained results and prospects of the H.E.S.S. follow-up program for soft gamma-ray repeaters.H. Abdalla … S. Einecke … K. Feijen … G. Rowell … P. deWilt … et al. (The H.E.S.S. Collaboration

    H.E.S.S. and MAGIC observations of a sudden cessation of a very-high-energy Ξ³-ray flare in PKS 1510-089 in May 2016

    Get PDF
    The flat spectrum radio quasar (FSRQ) PKS 1510-089 is known for its complex multiwavelength behaviour and it is one of only a few FSRQs detected in very-high-energy (VHE, E> 100 GeV) γ rays. The VHE γ-ray observations with H.E.S.S. and MAGIC in late May and early June 2016 resulted in the detection of an unprecedented flare, which revealed, for the first time, VHE γ-ray intranight variability for this source. While a common variability timescale of 1.5 h has been found, there is a significant deviation near the end of the flare, with a timescale of ∼20 min marking the cessation of the event. The peak flux is nearly two orders of magnitude above the low-level emission. For the first time, a curvature was detected in the VHE γ-ray spectrum of PKS 1510-089, which can be fully explained by the absorption on the part of the extragalactic background light. Optical R-band observations with ATOM revealed a counterpart of the γ-ray flare, even though the detailed flux evolution differs from the VHE γ-ray light curve. Interestingly, a steep flux decrease was observed at the same time as the cessation of the VHE γ-ray flare. In the high-energy (HE, E> 100 MeV) γ-ray band, only a moderate flux increase was observed with Fermi-LAT, while the HE γ-ray spectrum significantly hardens up to a photon index of 1.6. A search for broad-line region (BLR) absorption features in the γ-ray spectrum indicates that the emission region is located outside of the BLR. Radio very-long-baseline interferometry observations reveal a fast-moving knot interacting with a standing jet feature around the time of the flare. As the standing feature is located ∼50 pc from the black hole, the emission region of the flare may have been located at a significant distance from the black hole. If this is indeed a true correlation, the VHE γ rays must have been produced far down in the jet, where turbulent plasma crosses a standing shock

    Interleukin-15 Treatment Induces Weight Loss Independent of Lymphocytes

    Get PDF
    Obesity is a chronic inflammatory condition characterized by activation and infiltration of proinflammatory immune cells and a dysregulated production of proinflammatory cytokines. While known as a key regulator of immune natural killer (NK) cell function and development, we have recently demonstrated that reduced expression of the cytokine Interleukin-15 (IL-15) is closely linked with increased body weight and adiposity in mice and humans. Previously, we and others have shown that obese individuals have lower circulating levels of IL-15 and NK cells. Lean IL-15 overexpressing (IL-15 tg) mice had an accumulation in adipose NK cells compared to wildtype and NK cell deficient obese IL-15βˆ’/βˆ’ mice. Since IL-15 induces weight loss in IL-15βˆ’/βˆ’ and diet induced obese mice and has effects on various lymphocytes, the aim of this paper was to determine if lymphocytes, particularly NK cells, play a role in IL-15 mediated weight loss. Acute IL-15 treatment resulted in an increased accumulation of NK, NKT, and CD3+ T cells in adipose tissue of B6 mice. Mice depleted of NK and NKT cells had similar weight loss comparable to controls treated with IL-15. Finally, IL-15 treatment induces significant weight loss in lymphocyte deficient RAG2βˆ’/βˆ’Ξ³cβˆ’/βˆ’ mice independent of food intake. Fat pad cross-sections show decreased pad size with cytokine treatment is due to adipocyte shrinkage. These results clearly suggest that IL-15 mediates weight loss independent of lymphocytes

    Keratinocytes Determine Th1 Immunity during Early Experimental Leishmaniasis

    Get PDF
    Experimental leishmaniasis is an excellent model system for analyzing Th1/Th2 differentiation. Resistance to Leishmania (L.) major depends on the development of a L. major specific Th1 response, while Th2 differentiation results in susceptibility. There is growing evidence that the microenvironment of the early affected tissue delivers the initial triggers for Th-cell differentiation. To analyze this we studied differential gene expression in infected skin of resistant and susceptible mice 16h after parasite inoculation. Employing microarray technology, bioinformatics, laser-microdissection and in-situ-hybridization we found that the epidermis was the major source of immunomodulatory mediators. This epidermal gene induction was significantly stronger in resistant mice especially for several genes known to promote Th1 differentiation (IL-12, IL-1Ξ², osteopontin, IL-4) and for IL-6. Expression of these cytokines was temporally restricted to the crucial time of Th1/2 differentiation. Moreover, we revealed a stronger epidermal up-regulation of IL-6 in the epidermis of resistant mice. Accordingly, early local neutralization of IL-4 in resistant mice resulted in a Th2 switch and mice with a selective IL-6 deficiency in non-hematopoietic cells showed a Th2 switch and dramatic deterioration of disease. Thus, our data indicate for the first time that epidermal cytokine expression is a decisive factor in the generation of protective Th1 immunity and contributes to the outcome of infection with this important human pathogen
    • …
    corecore