Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.36 (caspase-1)
 6,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Modified vaccinia virus Ankara (MVA) is an attenuated double-stranded DNA poxvirus currently developed as a vaccine vector against HIV/AIDS. Profiling of the innate immune responses induced by MVA is essential for the design of vaccine vectors and for anticipating potential adverse interactions between naturally acquired and vaccine-induced immune responses. Here we report on innate immune sensing of MVA and cytokine responses in human THP-1 cells, primary human macrophages and mouse bone marrow-derived macrophages (BMDMs). The innate immune responses elicited by MVA in human macrophages were characterized by a robust chemokine production and a fairly weak pro-inflammatory cytokine response. Analyses of the cytokine production profile of macrophages isolated from knockout mice deficient in Toll-like receptors (TLRs) or in the adapter molecules MyD88 and TRIF revealed a critical role for TLR2, TLR6 and MyD88 in the production of IFNbeta-independent chemokines. MVA induced a marked up-regulation of the expression of RIG-I like receptors (RLR) and the IPS-1 adapter (also known as Cardif, MAVS or VISA). Reduced expression of RIG-I, MDA-5 and IPS-1 by shRNAs indicated that sensing of MVA by RLR and production of IFNbeta and IFNbeta-dependent chemokines was controlled by the MDA-5 and IPS-1 pathway in the macrophage. Crosstalk between TLR2-MyD88 and the NALP3 inflammasome was essential for expression and processing of IL-1beta. Transcription of the Il1b gene was markedly impaired in TLR2(-/-) and MyD88(-/-) BMDM, whereas mature and secreted IL-1beta was massively reduced in NALP3(-/-) BMDMs or in human THP-1 macrophages with reduced expression of NALP3, ASC or caspase-1 by shRNAs. Innate immune sensing of MVA and production of chemokines, IFNbeta and IL-1beta by macrophages is mediated by the TLR2-TLR6-MyD88, MDA-5-IPS-1 and NALP3 inflammasome pathways. Delineation of the host response induced by MVA is critical for improving our understanding of poxvirus antiviral escape mechanisms and for designing new MVA vaccine vectors with improved immunogenicity.
 ...
PMID:Innate immune sensing of modified vaccinia virus Ankara (MVA) is mediated by TLR2-TLR6, MDA-5 and the NALP3 inflammasome. 1954 80

Epidemiology of infectious endocarditis has changed in last decades, endocarditis associated to hospital practices, sustained by multiresistant pathogens being highly increased. In particular, methicillin-resistant staphylococci (MRSA), almost resistant to a number of other antimicrobial classes, often exhibit a reduced susceptibility to vancomycin (h-VISA) with MICs' values more e than 1 mg/l, leading to suppose a reduced therapeutic efficacy of this drug. Thirty-one percent of MRSA strains in the ICE study, which prospectively collected more than 5000 endocarditis, were h-VISA. Daptomycin shows a rapid bactericidal activity against both methicillin-susceptible staphylococcci (MSSA) and MRSA, included those strains with reduced susceptibility to vancomycin. Daptomycin shows a good therapeutic efficacy in staphylococcal endocarditis: MRSA 71%, MSSA 75%. These data suggest the use of daptomycin as initial therapy for treatment of staphylococcal endocarditis, independently from methcillin susceptibility. Some experimental data showed that daptomycin efficacy can diminish, if it is used as a rescue therapy after vancomycin failure. The thickness of bacterial cell-wall recognized in h-VISA strains can represent a physical and electrical barrier to reach both the vancomycin and daptomycin target site. However, the reduced efficacy of daptomycin following vancomycin exposure is an extremely rare event in the clinical practice. It is preferrable to use daptomycin as first line therapy, at a proper dosage. As far as endocarditis is concerned, recent data proved the excellent daptomycin tolerability, with dosages up to 8-10 mg/kg/die. During the treatment, CPK values must be always monitored. For endocarditis sustained by vancomycin-resistant enterococci, therapeutic choices are based on linezolid or ampicillin-ceftriaxone combination therapy. Daptomycin alone, or in association with gentamycin and rifampin, can represent a promising therapeutic alternative.
 ...
PMID:[Treatment of multiresistant Gram positive endocarditis]. 1983 95