Leishmania guyanensis parasites block the activation of the inflammasome by inhibiting maturation of IL-1β.

The various symptomatic outcomes of cutaneous leishmaniasis relates to the type and potency of its underlying inflammatory responses. Presence of the cytoplasmic javax.xml.bind.JAXBElement@52daeaa2 RNA virus-1 (LRV1) within javax.xml.bind.JAXBElement@be11ae5 , worsens lesional inflammation and parasite burden, as the viral dsRNA genome acts as a potent innate immunogen stimulating Toll-Like-Receptor-3 (TLR3). Here we investigated other innate pattern recognition receptors capable of reacting to dsRNA and potentially contributing to LRV1-mediated inflammatory pathology. We included the cytoplasmic dsRNA sensors, namely, the RIG-like receptors (RLRs) and the inflammasome-dependent and -independent Nod-like-receptors (NLRs). Our study found no role for RLRs or inflammasome-dependent NLRs in the pathology of javax.xml.bind.JAXBElement@3dfe8dc4 infection irrespective of its LRV1-status. Further, neither LRV1-bearing javax.xml.bind.JAXBElement@6e03fdb4 ( javax.xml.bind.JAXBElement@6b89952c +) nor LRV1-negative javax.xml.bind.JAXBElement@68bc8c8a ( javax.xml.bind.JAXBElement@2165acf4 ) activated the inflammasome javax.xml.bind.JAXBElement@507a0b31 . Interestingly, similarly to javax.xml.bind.JAXBElement@77fdd4e7 , javax.xml.bind.JAXBElement@7b29ce4e infection induced the up-regulation of the A20 protein, known to be involved in the evasion of inflammasome activation. Moreover, we observed that javax.xml.bind.JAXBElement@77a7dfd3 + promoted the transcription of inflammasome-independent NLRC2 (also called NOD2) and NLRC5. However, only NLRC2 showed some contribution to LRV1-dependent pathology. These data confirmed that the endosomal TLR3 pathway is the dominant route of LRV1-dependent signalling, thus excluding the cytosolic and inflammasome pathways. We postulate that avoidance of the inflammasome pathways is likely an important mechanism of virulence in javax.xml.bind.JAXBElement@77047195 infection irrespective of the LRV1-status

Type I interferons induced by endogenous or exogenous viral infections promote metastasis and relapse of leishmaniasis.

The presence of the endogenous <i>Leishmania</i> RNA virus 1 (LRV1) replicating stably within some parasite species has been associated with the development of more severe forms of leishmaniasis and relapses after drug treatment in humans. Here, we show that the disease-exacerbatory role of LRV1 relies on type I IFN (type I IFNs) production by macrophages and signaling in vivo. Moreover, infecting mice with the LRV1-cured <i>Leishmania guyanensis</i> ( <i>LgyLRV1</i> <sup> <i>-</i> </sup> ) strain of parasites followed by type I IFN treatment increased lesion size and parasite burden, quantitatively reproducing the LRV1-bearing ( <i>LgyLRV1</i> <sup> <i>+</i> </sup> ) infection phenotype. This finding suggested the possibility that exogenous viral infections could likewise increase pathogenicity, which was tested by coinfecting mice with <i>L. guyanensis</i> and lymphocytic choriomeningitis virus (LCMV), or the sand fly-transmitted arbovirus Toscana virus (TOSV). The type I IFN antiviral response increased the pathology of <i>L. guyanensis</i> infection, accompanied by down-regulation of the IFN-γ receptor normally required for antileishmanial control. Further, LCMV coinfection of IFN-γ-deficient mice promoted parasite dissemination to secondary sites, reproducing the <i>LgyLRV1</i> <sup> <i>+</i> </sup> metastatic phenotype. Remarkably, LCMV coinfection of mice that had healed from <i>L. guyanensis</i> infection induced reactivation of disease pathology, overriding the protective adaptive immune response. Our findings establish that type I IFN-dependent responses, arising from endogenous viral elements (dsRNA/LRV1), or exogenous coinfection with IFN-inducing viruses, are able to synergize with New World <i>Leishmania</i> parasites in both primary and relapse infections. Thus, viral infections likely represent a significant risk factor along with parasite and host factors, thereby contributing to the pathological spectrum of human leishmaniasis

Facile Synthesis of Three-Dimensional Pt-TiO2Nano-networks: A Highly Active Catalyst for the Hydrolytic Dehydrogenation of Ammonia–Borane

Three-dimensional (3D) porous metal and metal oxide nanostructures have received considerable interest because organization of inorganic materials into 3D nanomaterials holds extraordinary properties such as low density, high porosity, and high surface area. Supramolecular self-assembled peptide nanostructures were exploited as an organic template for catalytic 3D Pt-TiO2nano-network fabrication. A 3D peptide nanofiber aerogel was conformally coated with TiO2by atomic layer deposition (ALD) with angstrom-level thickness precision. The 3D peptide-TiO2nano-network was further decorated with highly monodisperse Pt nanoparticles by using ozone-assisted ALD. The 3D TiO2nano-network decorated with Pt nanoparticles shows superior catalytic activity in hydrolysis of ammonia–borane, generating three equivalents of H2. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinhei

Mammalian Innate Immune Response to a Leishmania-Resident RNA Virus Increases Macrophage Survival to Promote Parasite Persistence.

Some strains of the protozoan parasite Leishmania guyanensis (L.g) harbor a viral endosymbiont called Leishmania RNA virus 1 (LRV1). LRV1 recognition by TLR-3 increases parasite burden and lesion swelling in vivo. However, the mechanisms by which anti-viral innate immune responses affect parasitic infection are largely unknown. Upon investigating the mammalian host's response to LRV1, we found that miR-155 was singularly and strongly upregulated in macrophages infected with LRV1+ L.g when compared to LRV1- L.g. LRV1-driven miR-155 expression was dependent on TLR-3/TRIF signaling. Furthermore, LRV1-induced TLR-3 activation promoted parasite persistence by enhancing macrophage survival through Akt activation in a manner partially dependent on miR-155. Pharmacological inhibition of Akt resulted in a decrease in LRV1-mediated macrophage survival and consequently decreased parasite persistence. Consistent with these data, miR-155-deficient mice showed a drastic decrease in LRV1-induced disease severity, and lesional macrophages from these mice displayed reduced levels of Akt phosphorylation

Exacerbated Leishmaniasis Caused by a Viral Endosymbiont can be Prevented by Immunization with Its Viral Capsid.

Recent studies have shown that a cytoplasmic virus called Leishmaniavirus (LRV) is present in some Leishmania species and acts as a potent innate immunogen, aggravating lesional inflammation and development in mice. In humans, the presence of LRV in Leishmania guyanensis and in L. braziliensis was significantly correlated with poor treatment response and symptomatic relapse. So far, no clinical effort has used LRV for prophylactic purposes. In this context, we designed an original vaccine strategy that targeted LRV nested in Leishmania parasites to prevent virus-related complications. To this end, C57BL/6 mice were immunized with a recombinant LRV1 Leishmania guyanensis viral capsid polypeptide formulated with a T helper 1-polarizing adjuvant. LRV1-vaccinated mice had significant reduction in lesion size and parasite load when subsequently challenged with LRV1+ Leishmania guyanensis parasites. The protection conferred by this immunization could be reproduced in naïve mice via T-cell transfer from vaccinated mice but not by serum transfer. The induction of LRV1 specific T cells secreting IFN-γ was confirmed in vaccinated mice and provided strong evidence that LRV1-specific protection arose via a cell mediated immune response against the LRV1 capsid. Our studies suggest that immunization with LRV1 capsid could be of a preventive benefit in mitigating the elevated pathology associated with LRV1 bearing Leishmania infections and possibly avoiding symptomatic relapses after an initial treatment. This novel anti-endosymbiotic vaccine strategy could be exploited to control other infectious diseases, as similar viral infections are largely prevalent across pathogenic pathogens and could consequently open new vaccine opportunities

Measurements of differential production cross sections for a Z boson in association with jets in pp collisions at root s=8 TeV

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Search for leptophobic Z ' bosons decaying into four-lepton final states in proton-proton collisions at root s=8 TeV

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Search for black holes and other new phenomena in high-multiplicity final states in proton-proton collisions at root s=13 TeV

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Search for high-mass diphoton resonances in proton-proton collisions at 13 TeV and combination with 8 TeV search

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Search for heavy resonances decaying into a vector boson and a Higgs boson in final states with charged leptons, neutrinos, and b quarks

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