1,721,045 research outputs found
Endothelial cells are major players in SARS-CoV-2-related acute respiratory distress syndrome
No full textHIV-1 infection, microenvironment and endothelial cell dysfunction.
No full textHIV-1 promotes a generalized immune activation that involves the main targets of HIV-1 infection but also cells that are not sensitive to viral infection. ECs display major dysfunctions in HIV+ patients during long-standing viral infection that persist even in the current cART era, in which new-generation drugs have reduced dysmetabolic side effects and successfully impeded viral replication. In vivo studies have failed to demonstrate the presence of replicating virus in ECs suggesting that a direct role of the virus is unlikely, and implying that the mechanism accounting for vascular dysfunction may rely on the indirect action of molecules released in the microenvironment by HIV-1-infected cells. This article reviews the current understanding of how HIV-1 infection can contribute to vascular dysfunction. In particular, we discuss the emerging role played by different HIV-1 proteins in driving inflammation and EC dysregulation, and highlight the need to target them for therapeutic benefit
HIV-1 matrix protein p17 and its receptors.
No full textThe HIV-1 matrix protein p17 (p17) plays a crucial role in the virus life cycle. It is released in the extracellular space from HIV-1-infected cells and accumulates in the tissues of patients, even in those successfully treated with highly active antiretroviral therapy. Extracellular p17 deregulates the biological activity of many different cells that are directly or indirectly involved in AIDS pathogenesis. All p17 actions depend on interaction between its functional epitope (AT20) located at the protein N-terminal region and different receptors expressed on target cells. This finding corroborates the importance of impeding p17/p17 receptors interaction as a contribution to block AIDS. In this article we review the interaction of p17 with heparan sulfate proteoglycans (HSPGs) and with the chemokine (C-X-C motif) receptor 1 (CXCR1) and 2 (CXCR2). We provide details on how p17 interacts with its receptors and how these interactions are central to the p17 biological activities. Moreover, we highlight the presence of a p17 variant, named S75X, that displays opposite effects on B-cell proliferation, as compared to p17. A two-site model for p17 interaction with G-coupled receptors provides a possible explanation on how mutations naturally occurring within the primary amino acid structure can lead S75X to activate the Akt signaling pathway and promote B-cell growth and transformation. Identifying p17 interaction with HSPGs, CXCR1 and CXCR2 as fundamental events in supporting its activity could help us to find new treatment approaches aimed at blocking all p17/p17 receptors interaction and, consequently, all p17 detrimental activities
Detection of SARS-CoV-2 Alpha variant in a severely immunocompromised HIV-1-infected patient in the omicron era
No full text: Persistence of detectable viral RNA does not depend on the symptomatic status of the patients. Here we describe the case of a strongly immunocompromised patient living with a prolonged SARSCoV-2 Alpha variant infection without showing any symptoms. The importance of our findings is that the persistent infection with an old SARS-CoV-2 strain, in an immunocompromised host, may allow recombination events generating new viral variants whose pathogenicity cannot be predicted. Our observation calls for the urgent need for continuous monitoring of SARS-CoV-2 genomic evolution in immunocompromised patients
Emergence of S gene-based quasispecies explains an optimal adaptation of Omicron BA.5 subvariant in the immunocompetent vaccinated human host
No full textEmergence of carbapenem-resistant Klebsiella Pneumoniae strains producing KPC-3 in Brescia Hospital, Italy.
No full textCarbapenem-resistant K. pneumoniae has recently been reported as a new multidrug-resistant nosocomial pathogen. This study reports the emergence of carbapenem-resistant K. pneumoniae strains in Brescia Civic Hospital, Italy. Different samples, collected from April 2012 to February 2013, showed that 29 patients presented infections from multidrug-resistant K. pneumoniae and three of these patients were intestinal carriers. In total, 40 carbapenem-resistant K. pneumoniae strains were isolated from multiple specimens of these patients. In 39 out of 40 samples, we identified the bla(KPC-3) carbapenemase gene variant responsible for bacterial carbapenem resistance. The DiversiLab analysis showed four different genetic patterns within multidrug-resistant K. pneumoniae isolates, with pattern 1 and 2 including 95% of the bacterial strains. Carbapenem-resistant K. pneumoniae strains belonging to patterns 1 and 2 were also detected in the intestinal tract of the three asymptomatic carriers. Moreover, isolation of the same strains in other body sites of the same patients and in bronchial fluid of a non-colonized patient in the same ward indicates an initial dissemination of this pathogen. Our results highlight the emergence of carbapenemase-producing K. pneumoniae strains in different hospital wards and the urgent need for infection control, antibiotic stewardship programmes and utilization of a surveillance and prevention system
The immunomodulatory molecule pidotimod induces the expression of the nod-like receptor nlrp12 and attenuates tlr-induced inflammation.
No full textPidotimod (3-L-pyroglutamyl-L-thiaziolidine-4-carboxylic acid) (PDT) is a synthetic dipeptide with in vitro and in vivo immunomodulatory properties that is largely used for treatment and prevention of infections in paediatric and disease-prone patients. However, the effects of PDT on cellular immune responses are still poorly characterized and there is little information on the mechanism of action of this compound. It has been speculated that PDT action may be exerted through the interaction with a Pattern Recognition Receptor (PRR). Therefore, to gain a further understanding of the immune pathways involved by PDT, we first decided to investigate whether PDT could modify the immune response triggered by TLR ligands. Monocytic cells were exposed to PDT then stimulated with a panel of TLR agonists. Under these experimental conditions, we observed a significant decrease in the synthesis of key proinflammatory mediators in comparison to the production observed in TLR-stimulated cells that were not treated with PDT. Using RT2 Profiler PCR Array we have observed that PDT specifically up-regulates the expression of the NOD-like receptor NLRP12 mRNA in the absence of any further costimulation. Increase of NLRP12 in cells treated with PDT was confirmed using specifically designed real-time quantitative PCR and western blotting assays where a clear increase in the amount of NLRP12 protein was detected. Furthermore, in myeloid/monocytic cells we demonstrated that PDT treatment counteracts the NLRP12 reduction induced by TLR agonists. Finally, the results obtained using NLRP12 silenced cells showed that down-regulation of the proinflammatory function occurring in PDT-treated cells upon interaction with TLRs is associated with the increased levels of NLRP12 induced by PDT. To our knowledge this is the first evidence of an immunomodulatory peptide that upregulates NLRP12 and, through this molecule, antagonizes the TLR-induced inflammatory response. These results pave the way for the development of innovative therapeutic approaches aimed at controlling different pathological settings such as tumorigenesis, systemic inflammatory processes and autoimmunity, where NLRP12 plays a crucial role
Long-lasting humoral immune response induced in HIV-1-infected patients by a synthetic peptide (AT20) derived from the HIV-1 matrix protein p17 functional epitope.
No full textOBJECTIVE:
A therapeutic vaccination based on a synthetic peptide (AT20) representative of the HIV-1 matrix protein p17 (p17) functional region, coupled to keyhole limpet hemocyanin (KLH) AT20-KLH was capable of inducing the production of high-avidity antibodies (Abs) toward a previous untargeted p17 hotspot of functional activity in highly active antiretroviral therapy (HAART)-treated HIV-1-infected patients. Since avidity of Abs after immunization and the retention of antigens are important in sustaining the long-lasting production of specific humoral responses, we asked whether AT20-KLH vaccination would result in development of a long-lived immune response.
METHODS:
The long-term duration of Ab response to AT20-KLH has been evaluated in 10 patients previously enrolled for the AT20-KLH vaccination trial at day 898 post-immunization. Ab titer and their avidity was assessed using specifically designed ELISA assays, whereas their neutralizing capacity was estimated in vitro using a 'wound sealing assay'.
RESULTS:
Data obtained show that high titers of specific anti-AT20 Abs were maintained at more than 2 years after the last immunization. Furthermore, these Abs were capable to neutralize exogenous p17, as assessed by ability of sera derived from AT20-KLH-immunized patients to block the ability of p17 to promote cell migration in vitro.
CONCLUSION:
This finding attests for a successful AT20-KLH vaccine molecule formulation and for an effective HAART-dependent Ab persistenc
In vitro activity of solithromycin against erythromycin-resistant Streptococcus agalactiae.
No full textThe in vitro antibacterial activity of solithromycin (CEM-101) against macrolide-resistant isolates (n=62) of Streptococcus agalactiae (group B streptococcus [GBS]) was determined. Phenotypic characterization of macrolide-resistant strains was performed by double-disc diffusion testing. A multiplex PCR was used to identify the erm(B), erm(TR), and mef(A/E) genes, capsular genotypes, and alpha-like (Alp) protein genes from the GBS strains. Determination of MIC was carried out using the microdilution broth method. The Etest method was used for penicillin, azithromycin, clarithromycin, and erythromycin. Solithromycin had a MIC50 of ≤0.008 μg/ml and a MIC90 of 0.015 μg/ml against macrolide-susceptible S. agalactiae. These MICs were lower than those displayed by penicillin (MIC50 of 0.032 μg/ml and MIC90 of 0.047 μg/ml), the antibiotic agent of choice for prophylaxis and treatment of GBS infections. Against macrolide-resistant S. agalactiae, solithromycin had a MIC50 of 0.03 μg/ml and a MIC90 of 0.125 μg/ml. Against erm(B) strains, solithromycin had a MIC50 of 0.03 μg/ml and a MIC90 of 0.06 μg/ml, while against mef(A) strains, it had a MIC50 of 0.03 μg/ml and a MIC90 of 0.125 μg/ml. Most erythromycin-resistant GBS strains were of serotype V (64.5%) and associated significantly with alp2-3. Moreover, a statistically significant association was observed between the constitutive macrolide-lincosamide-streptogramin B resistance (cMLSB) phenotype and the erm(B) gene-carrying strains, the alp2-3 gene and the M phenotype, and the mef(A/E) gene and epsilon. Overall, our results show that solithromycin had lower or similar MICs than penicillin and potent activity against macrolide-resistant strains independent of their genotype or phenotype, representing a valid therapeutic alternative where β-lactams cannot be use
Analysis of mutations in DNA gyrase and topoisomerase IV of Ureaplasma urealyticum and Ureaplasma parvum serovars resistant to fluoroquinolones
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