28 results on '"Piccaro, G"'
Search Results
2. Proficiency testing of first- and second-line anti-tuberculosis drugs in Italy
- Author
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Fattorini, L., Migliori, G. B., Cassone, A., Mustazzolu, A., Piccaro, G., Filippini, P., Cirillo, D. M., and Borroni, E.
- Published
- 2012
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Catalog
3. Drug-resistant tuberculosis among foreign-born persons in Italy
- Author
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Fattorini, L, Mustazzolu, A, Piccaro, G, Pardini, M, Filippini, P, Giannoni, F, Migliori, Gb, Sotgiu, G, Borroni, E, Cirillo, Dm, Piersimoni, C, Lorenzetti, P, Costa, D, Grimaldi, A, Arosio, M, Goglio, A, Mazza, C, Squintani, L, Larcher, C, Frizzera, E, Pinsi, G, Caddeu, R, Farris, Ag, Di Naso, C, Cavalcanti, P, Tomei, G, Mantini, G, Tortoli, E, Simonetti, Mt, di Taranto, A, Senno, E, Nisticò, S, Colonna, C, Buono, L, Mazzola, E, Gesu, G, Cichero, P, Lombardi, A, Fabio, A, Santoro, G, Molinari, Gl, Camaggi, A, Chirillo, Mg, Peracchi, M, Fallico, L, Marone, P, Bono, L, Mazzolla, R, Tiecco, C, Chiaradonna, P, Tronci, M, Altieri, Am, Bordi, E, De Mori, P, Di Caro, A, Libanori, E, De Lorenzo, S, Milano, R, Mondo, A, Barbui, A, Centis, R, D'Ambrosio, L, Spanevello, Antonio, Caola, I, Fabris, C, Screm, Mc, and Scarparo, C. more...
- Subjects
Adult ,Male ,Italy ,Residence Characteristics ,Communicable Disease Control ,Tuberculosis, Multidrug-Resistant ,Prevalence ,Emigrants and Immigrants ,Humans ,Female ,Middle Aged ,Aged - Published
- 2012
4. Proficiency testing of first- and second-line anti-tuberculosis drugs in Italy
- Author
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Fattorini, L, Migliori, Gb, Cassone, A, Mustazzolu, A, Piccaro, G, Filippini, P, Cirillo, Dm, Borroni, E, Piersimoni, C, Costa, D, Grimaldi, A, De Santis, A, Arosio, M, Goglio, A, Mazza, C, Squintani, L, Di Pede, B, Gaspari, G, Marchetti, D, Nanetti, A, Larcher, C, Frizzera, E, Rizza, F, Pinsi, G, Turano, A, Caddeu, R, Farris, Ag, Di Naso, C, Cavalcanti, P, Tomei, G, Mantini, G, Ceruti, T, Ferrari, L, Rossi, Mr, Tortoli, E, Montini, G, Senno, E, Nisticò, S, Colonna, C, Buono, L, Mazzola, E, Gesu, G, Penati, V, Vaccarino, P, Piana, F, Cichero, P, Lombardi, A, Mantovani, G, Fabio, A, Bertoli, G, Rumpianesi, F, Santoro, G, Molinari, Gl, Camaggi, A, Chirillo, Mg, Peracchi, M, Fallico, L, Menozzi, M, Dettori, G, Marone, P, Bono, L, Matteo, S, Mazzolla, R, Sposini, T, Tiecco, C, Barbaro, A, Vecchia, L, Piscina, A, Chiaradonna, P, Tronci, M, Bordi, E, De Mori, P, Diamare, F, Libanori, E, Panaiota, T, Milano, R, Mondo, A, Barbui, A, Fabbro, L, Centis, R, D'Ambrosio, L, Spanevello, Antonio, Caola, I, Mottola, A, Fabris, C, Scagnelli, M, Screm, Mc, and Scarparo, C. more...
- Subjects
Pulmonary and Respiratory Medicine ,Treatment Outcome ,Italy ,Tuberculosis, Multidrug-Resistant ,Antitubercular Agents ,Humans ,Tuberculosis ,Mycobacterium tuberculosis ,Pulmonary ,Multidrug-Resistant ,Tuberculosis, Pulmonary ,Settore MED/36 - DIAGNOSTICA PER IMMAGINI E RADIOTERAPIA - Published
- 2012
5. Activity of drugs against dormant Mycobacterium tuberculosis
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Iacobino, A., Piccaro, G., Giannoni, F., Mustazzolu, A., and Fattorini, L.
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- 2016
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6. Mycobacterium tuberculosis antigen 85B modifies BCG-induced antituberculosis immunity and favors pathogen survival.
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Piccaro G, Aquino G, Gigantino V, Tirelli V, Sanchez M, Iorio E, Matarese G, Cassone A, and Palma C
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- Animals, Mice, CD4-Positive T-Lymphocytes immunology, Cytokines metabolism, Microbial Viability, Acyltransferases immunology, Antigens, Bacterial immunology, Bacterial Proteins immunology, BCG Vaccine immunology, Mice, Inbred C57BL, Mycobacterium tuberculosis immunology, Tuberculosis immunology, Tuberculosis microbiology
- Abstract
Tuberculosis is one of the deadliest infectious diseases worldwide. Mycobacterium tuberculosis has developed strategies not only to evade host immunity but also to manipulate it for its survival. We investigated whether Mycobacterium tuberculosis exploited the immunogenicity of Ag85B, one of its major secretory proteins, to redirect host antituberculosis immunity to its advantage. We found that administration of Ag85B protein to mice vaccinated with Bacillus Calmette-Guérin impaired the protection elicited by vaccination, causing a more severe infection when mice were challenged with Mycobacterium tuberculosis. Ag85B administration reduced Bacillus Calmette-Guérin-induced CD4 T-cell activation and IFN-γ, CCL-4, and IL-22 production in response to Mycobacterium tuberculosis-infected cells. On the other hand, it promoted robust Ag85B-responsive IFN-γ-producing CD4 T cells, expansion of a subset of IFN-γ/IL-10-producing CD4+FOXP3+Treg cells, differential activation of IL-17/IL-22 responses, and activation of regulatory and exhaustion pathways, including programmed death ligand 1 expression on macrophages. All this resulted in impaired intracellular Mycobacterium tuberculosis growth control by systemic immunity, both before and after the Mycobacterium tuberculosis challenge. Interestingly, Mycobacterium tuberculosis infection itself generated Ag85B-reactive inflammatory immune cells incapable of clearing Mycobacterium tuberculosis in both unvaccinated and Bacillus Calmette-Guérin-vaccinated mice. Our data suggest that Mycobacterium tuberculosis can exploit the strong immunogenicity of Ag85B to promote its own survival and spread. Since Ag85B is normally secreted by replicating bacteria and is commonly found in the lungs of the Mycobacterium tuberculosis-infected host, our findings may advance the understanding on the mechanisms of Mycobacterium tuberculosis pathogenesis and immune evasion., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.) more...
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- 2024
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7. Caloric Restriction Promotes Immunometabolic Reprogramming Leading to Protection from Tuberculosis.
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Palma C, La Rocca C, Gigantino V, Aquino G, Piccaro G, Di Silvestre D, Brambilla F, Rossi R, Bonacina F, Lepore MT, Audano M, Mitro N, Botti G, Bruzzaniti S, Fusco C, Procaccini C, De Rosa V, Galgani M, Alviggi C, Puca A, Grassi F, Rezzonico-Jost T, Norata GD, Mauri P, Netea MG, de Candia P, and Matarese G more...
- Subjects
- Animals, Caloric Restriction, Female, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Mycobacterium tuberculosis immunology, Mycobacterium tuberculosis metabolism, Tuberculosis immunology, Tuberculosis metabolism, Tuberculosis prevention & control
- Abstract
There is a strong relationship between metabolic state and susceptibility to Mycobacterium tuberculosis (MTB) infection, with energy metabolism setting the basis for an exaggerated immuno-inflammatory response, which concurs with MTB pathogenesis. Herein, we show that controlled caloric restriction (CR), not leading to malnutrition, protects susceptible DBA/2 mice against pulmonary MTB infection by reducing bacterial load, lung immunopathology, and generation of foam cells, an MTB reservoir in lung granulomas. Mechanistically, CR induced a metabolic shift toward glycolysis, and decreased both fatty acid oxidation and mTOR activity associated with induction of autophagy in immune cells. An integrated multi-omics approach revealed a specific CR-induced metabolomic, transcriptomic, and proteomic signature leading to reduced lung damage and protective remodeling of lung interstitial tightness able to limit MTB spreading. Our data propose CR as a feasible immunometabolic manipulation to control MTB infection, and this approach offers an unexpected strategy to boost immunity against MTB., Competing Interests: Declaration of Interests Authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.) more...
- Published
- 2021
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8. Moxifloxacin Activates the SOS Response in Mycobacterium tuberculosis in a Dose- and Time-Dependent Manner.
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Iacobino A, Piccaro G, Pardini M, Fattorini L, and Giannoni F
- Abstract
Previous studies on Escherichia coli demonstrated that sub-minimum inhibitory concentration (MIC) of fluoroquinolones induced the SOS response, increasing drug tolerance. We characterized the transcriptional response to moxifloxacin in Mycobacterium tuberculosis . Reference strain H37Rv was treated with moxifloxacin and gene expression studied by qRT-PCR. Five SOS regulon genes, recA , lexA , dnaE2 , Rv3074 and Rv3776, were induced in a dose- and time-dependent manner. A range of moxifloxacin concentrations induced recA , with a peak observed at 2 × MIC (0.25 μg/mL) after 16 h. Another seven SOS responses and three DNA repair genes were significantly induced by moxifloxacin. Induction of recA by moxifloxacin was higher in log-phase than in early- and stationary-phase cells, and absent in dormant bacilli. Furthermore, in an H37Rv fluoroquinolone-resistant mutant carrying the D94G mutation in the gyrA gene, the SOS response was induced at drug concentrations higher than the mutant MIC value. The 2 × MIC of moxifloxacin determined no significant changes in gene expression in a panel of 32 genes, except for up-regulation of the relK toxin and of Rv3290c and Rv2517c , two persistence-related genes. Overall, our data show that activation of the SOS response by moxifloxacin, a likely link to increased mutation rate and persister formation, is time, dose, physiological state and, possibly, MIC dependent. more...
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- 2021
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9. Use of probiotics in medical devices applied to some common pathologies.
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Verrucci M, Iacobino A, Fattorini L, Marcoaldi R, Maggio A, and Piccaro G
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- Administration, Oral, Adolescent, Adult, Child, Child, Preschool, Colic therapy, Dermatitis, Atopic, Diabetes Mellitus, Type 2 therapy, Double-Blind Method, Equipment and Supplies microbiology, Female, Humans, Infant, Infant, Newborn, Lactobacillus, Male, Obesity prevention & control, Obesity therapy, Pharyngitis therapy, Prebiotics administration & dosage, Prebiotics adverse effects, Probiotics adverse effects, Randomized Controlled Trials as Topic, Suppositories, Synbiotics administration & dosage, Synbiotics adverse effects, Tonsillitis therapy, Vaginitis microbiology, Vaginitis therapy, Vaginosis, Bacterial microbiology, Probiotics administration & dosage, Vaginosis, Bacterial therapy
- Abstract
Probiotics, defined as "living microorganisms that, whether ingested in useful amount, may have beneficial effects on human body", are widely used in various products for human use, such as dietary supplements, medical devices and pharmaceutical products. The European Directive on medical devices (MDs) (DDM 93/42), also includes those MDs containing live microorganisms, particularly probiotics, that may have various destinations of use, including that of assisting the therapy of several human pathologies. In this brief note we analyzed the use of probiotics in MDs and how probiotics administration could represent one of the new frontiers of scientific research on the prevention and treatment of various diseases. We'll analyze the literature on probiotics based MDs, to review their major targets in the therapy of some of the most common human pathologies: bacterial vaginosis and vaginitis, atopic dermatitis, infantile colic, obesity, type 2 diabetes, and pharyngotonsillitis. more...
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- 2019
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10. Caveolin-1 Endows Order in Cholesterol-Rich Detergent Resistant Membranes.
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Raggi C, Diociaiuti M, Caracciolo G, Fratini F, Fantozzi L, Piccaro G, Fecchi K, Pizzi E, Marano G, Ciaffoni F, Bravo E, Fiani ML, and Sargiacomo M
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- Animals, Caveolae metabolism, Humans, X-Ray Diffraction, Caveolin 1 metabolism, Cholesterol metabolism, Proteomics methods
- Abstract
Cholesterol-enriched functional portions of plasma membranes, such as caveolae and rafts, were isolated from lungs of wild-type (WT) and caveolin-1 knockout (Cav-1 KO) mice within detergent resistant membranes (DRMs). To gain insight into their molecular composition we performed proteomic and lipid analysis on WT and Cav-1 KO-DRMs that showed predicted variations of proteomic profiles and negligible differences in lipid composition, while Langmuir monolayer technique and small and wide-angle X-ray scattering (SAXS-WAXS) were here originally introduced to study DRMs biophysical association state. Langmuir analysis of Cav-1 containing DRMs displayed an isotherm with a clear-cut feature, suggesting the coexistence of the liquid-ordered ( L
o ) phase typical of the raft structure, namely "cholesterol-rich Lo phase," with a phase fully missing in Cav-1 KO that we named "caveolin-induced Lo phase." Furthermore, while the sole lipid component of both WT and KO-DRMs showed qualitatively similar isotherm configuration, the reinsertion of recombinant Cav-1 into WT-DRMs lipids restored the WT-DRM pattern. X-ray diffraction results confirmed that Cav-1 causes the formation of a "caveolin-induced Lo phase," as suggested by Langmuir experiments, allowing us to speculate about a possible structural model. These results show that the unique molecular link between Cav-1 and cholesterol can spur functional order in a lipid bilayer strictly derived from biological sources., Competing Interests: The authors declare no conflicts of interest. more...- Published
- 2019
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11. The Combination Rifampin-Nitazoxanide, but Not Rifampin-Isoniazid-Pyrazinamide-Ethambutol, Kills Dormant Mycobacterium tuberculosis in Hypoxia at Neutral pH.
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Iacobino A, Giannoni F, Pardini M, Piccaro G, and Fattorini L
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- Drug Combinations, Drug Therapy, Combination, Ethambutol pharmacology, Humans, Hydrogen-Ion Concentration, Hypoxia, Microbial Sensitivity Tests, Nitroimidazoles pharmacology, Oxazolidinones pharmacology, Tuberculosis microbiology, Antitubercular Agents pharmacology, Isoniazid pharmacology, Mycobacterium tuberculosis drug effects, Pyrazinamide pharmacology, Rifampin pharmacology
- Abstract
The activities of rifampin, nitazoxanide, PA-824, and sutezolid were tested against dormant Mycobacterium tuberculosis under conditions mimicking caseous granulomas (hypoxia at pH 7.3) in comparison with those of the combination rifampin-isoniazid-pyrazinamide-ethambutol (R-I-Z-E), which is used for human therapy. Mycobacterial viability was monitored by CFU and regrowth in MGIT 960. As shown by lack of regrowth in MGIT, rifampin-nitazoxanide-containing combinations, but not R-I-Z-E, killed dormant cells in 28 to 35 days. These observations might be important in designing new tuberculosis therapies., (Copyright © 2019 American Society for Microbiology.) more...
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- 2019
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12. Parenteral Vaccination With a Tuberculosis Subunit Vaccine in Presence of Retinoic Acid Provides Early but Transient Protection to M. Tuberculosis Infection.
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Riccomi A, Piccaro G, Christensen D, Palma C, Andersen P, and Vendetti S
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- Allergens immunology, Animals, Antibodies, Bacterial immunology, Antibody-Producing Cells immunology, CD4-Positive T-Lymphocytes immunology, Cytokines immunology, Female, Immunoglobulin A immunology, Immunoglobulin G immunology, Lung immunology, Lymphocytes immunology, Mice, Mycobacterium tuberculosis growth & development, Mycobacterium tuberculosis immunology, Ovalbumin immunology, Tuberculosis, Pulmonary immunology, Vaccination, Immunity, Mucosal, Tretinoin administration & dosage, Tuberculosis Vaccines administration & dosage, Tuberculosis, Pulmonary prevention & control, Vaccines, Subunit administration & dosage
- Abstract
Most microbes invading through mucosal surfaces cause disease and therefore strategies to induce mucosal immune responses are strongly needed. Vitamin A metabolites, such as retinoic acid (RA), play crucial roles in programming T and B cells to home to mucosal compartments, therefore we evaluated the capacity of RA to elicit mucosal immune responses against tuberculosis (TB) after parenteral vaccination. We found that mice immunized through subcutaneous injections with the TB subunit vaccine (CAF01+H56) in presence of RA show enhanced mucosal H56-specific IgA responses and enhanced Ag-specific CD4
+ T lymphocytes homing to the lung as compared with control mice. Immunization with CAF01+H56 in presence of RA resulted in lower bacterial loads in the lungs of mice 14 days after challenge with virulent Mycobacterium tuberculosis (Mtb) as compared to mice immunized in the absence of RA or vaccinated with BCG. Higher amounts of IFNγ and IL-17 pro-inflammatory cytokines were found in lung homogenates of mice immunized with CAF01+H56 and RA 24 h after Mtb infection. However, 6 weeks after infection the protection was comparable in vaccinated mice with or without RA even though treatment with RA during immunization is able to better contain the inflammatory response by the host. Furthermore, at later stage of the infection a higher percentage of Mtb specific CD4+ PD1+ T lymphocytes were found in the lungs of mice immunized with CAF01+H56 and RA. These data show that an enhanced mucosal immune response is generated during parenteral vaccination in presence of RA. Furthermore, RA treatment contained the bacterial growth at an early stage of the infection and limited the inflammatory response in the lung at later time points. more...- Published
- 2019
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13. Fighting tuberculosis by drugs targeting nonreplicating Mycobacterium tuberculosis bacilli.
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Iacobino A, Piccaro G, Giannoni F, Mustazzolu A, and Fattorini L
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- Animals, Antitubercular Agents pharmacology, Colony Count, Microbial, Humans, Isoniazid therapeutic use, Latent Tuberculosis microbiology, Mice, Mycobacterium tuberculosis physiology, Pyrazinamide therapeutic use, Rifampin analogs & derivatives, Rifampin therapeutic use, Tuberculosis, Pulmonary drug therapy, Tuberculosis, Pulmonary microbiology, Antitubercular Agents therapeutic use, Latent Tuberculosis drug therapy, Mycobacterium tuberculosis drug effects, Tuberculosis drug therapy, Tuberculosis microbiology
- Abstract
Current tuberculosis (TB) treatment requires 6 months of combination therapy with isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol for active TB and 9 months of INH or 3 months of rifapentine (RFP) + INH for latent TB. The lungs of patients with active and latent TB contain heterogeneous mixtures of cellular and caseous granulomas harboring Mycobacterium tuberculosis bacilli ranging from actively replicating (AR) to nonreplicating (NR), phenotypically drug-resistant stages. Several in vitro models to obtain NR cells were reported, including exposure to hypoxia, nutrient starvation, acid + nitric oxide, and stationary phase. Overall, these models showed that RIF, RFP, PA-824 (PA), metronidazole (MZ), bedaquiline (BQ), and fluoroquinolones were the most active drugs against NR M. tuberculosis. In hypoxia at pH 5.8, some combinations killed AR plus NR cells, as shown by lack of regrowth in liquid media, whereas in hypoxia at pH 7.3 (the pH of the caseum), only RIF and RFP efficiently killed NR bacilli while several other drugs showed little effect. In conventional mouse models, combinations containing RFP, BQ, PA, PZA, moxifloxacin, sutezolid, linezolid, and clofazimine sterilized animals in ≤2 months, as shown by lack of viable bacilli in lung homogenates after 3 months without therapy. Drugs were less effective in C3HeB/FeJ mice forming caseous granulomas. Overall, in vitro observations and in vivo studies suggest that the search for new TB drugs could be addressed to low lipophilic molecules (e.g., new rpoB inhibitors with clogP < 3) killing NR M. tuberculosis in hypoxia at neutral pH and reaching high rates of unbound drug in the caseum. more...
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- 2017
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14. Mycobacterium tuberculosis Is Selectively Killed by Rifampin and Rifapentine in Hypoxia at Neutral pH.
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Iacobino A, Piccaro G, Giannoni F, Mustazzolu A, and Fattorini L
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- Anaerobiosis, Hydrogen-Ion Concentration, Isonicotinic Acids pharmacology, Microbial Sensitivity Tests, Mycobacterium tuberculosis growth & development, Nitroimidazoles pharmacology, Phenazines pharmacology, Quinolines pharmacology, Thiazoles pharmacology, Antitubercular Agents pharmacology, Mycobacterium tuberculosis drug effects, Rifampin analogs & derivatives, Rifampin pharmacology
- Abstract
The activities of rifampin, rifapentine, bedaquiline, PA-824, clofazimine, nitazoxanide, isoniazid, amikacin, moxifloxacin, niclosamide, thioridazine, and pyrazinamide were tested against nonreplicating (dormant) Mycobacterium tuberculosis H37Rv under conditions of hypoxia at pHs 5.8 and 7.3, mimicking environments of cellular granulomas and caseous granulomas, respectively. At pH 5.8, several drugs killed dormant bacilli, with the best being rifampin and rifapentine. At pH 7.3, only rifampin and rifapentine efficiently killed dormant bacilli, while all other drugs showed little activity., (Copyright © 2017 American Society for Microbiology.) more...
- Published
- 2017
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15. HIV-1 Tat protein vaccination in mice infected with Mycobacterium tuberculosis is safe, immunogenic and reduces bacterial lung pathology.
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Cafaro A, Piccaro G, Altavilla G, Gigantino V, Matarese G, Olivieri E, Ferrantelli F, Ensoli B, and Palma C
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- Animals, BCG Vaccine immunology, Bacterial Load, Cells, Cultured, Chemokine CCL4 metabolism, Enzyme-Linked Immunosorbent Assay, Female, HIV Antibodies blood, HIV-1 immunology, Interferon-gamma metabolism, Interleukin-17 metabolism, Interleukin-1beta metabolism, Lung microbiology, Lung pathology, Mice, Mice, Inbred C57BL, Recombinant Proteins biosynthesis, Recombinant Proteins immunology, Recombinant Proteins isolation & purification, Spleen cytology, Spleen metabolism, Spleen microbiology, Vaccination, tat Gene Products, Human Immunodeficiency Virus genetics, tat Gene Products, Human Immunodeficiency Virus metabolism, HIV-1 metabolism, Mycobacterium tuberculosis pathogenicity, tat Gene Products, Human Immunodeficiency Virus immunology
- Abstract
Background: The therapeutic HIV-1 Tat protein vaccine is in advanced clinical development. Tuberculosis, the main AIDS co-infection, is highly endemic in areas where AIDS prevention through vaccination is needed. However, safety and immunogenicity of Tat vaccination in the course of Mycobacterium tuberculosis (Mtb) infection is still unknown and it prevents the possibility to administer the vaccine to Mtb-infected individuals. We addressed the interplay and effects of Tat vaccination on Mtb infection in immunocompetent mice., Methods: C57BL/6 mice were vaccinated or not with Bacillus Calmette-Guerin (BCG), the current tuberculosis vaccine, and after 5 weeks were infected with Mtb by intravenous route. The Tat protein was injected intradermally at 1, 2 and 4 weeks after Mtb challenge. Eight weeks after Mtb infection, all mice were sacrificed, and both the degree of pathology and immune responses to Mtb and Tat were evaluated. As additional control, some mice were either vaccinated or not with BCG, were not challenged with Mtb, but received the Tat protein. Statistical significances were evaluated by one-way or two-way ANOVA and Tukey's multiple comparisons post-test., Results: In the lungs of Mtb-infected mice, Tat-vaccine did not favour Mtb replication and indeed reduced both area of cellular infiltration and protein levels of Interferon-γ, Chemokine (C-C motif) ligand-4 and Interleukin-1β, pathological events triggered by Mtb-infection. Moreover, the protection against Mtb infection conferred by BCG remained good after Tat protein treatment. In spleen cells of Mtb-infected mice, Tat vaccination enhanced Mtb-specific Interferon-γ and Interleukin-17 responses, which may have a protective role. Of note, Mtb infection reduced, but did not suppress, the development of anti-Tat antibodies, required for Tat vaccine efficacy and the titer of anti-Tat IgG was potentiated by BCG vaccination in Mtb-free mice. In general, Tat treatment was well tolerated in both Mtb-infected and Mtb-free mice., Conclusions: Tat protein vaccine, administered in Mtb-infected mice with a protocol resembling that used in the clinical trials, was safe, immunogenic, limited the lung Mtb-associated immunopathology and did not abrogate the protective efficacy of BCG. These data provide preliminary evidence for a safe use of Tat vaccine in people vaccinated with BCG and/or suffering from tuberculosis. more...
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- 2016
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16. Mycobacterium tuberculosis gene expression at different stages of hypoxia-induced dormancy and upon resuscitation.
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Iona E, Pardini M, Mustazzolu A, Piccaro G, Nisini R, Fattorini L, and Giannoni F
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- Anaerobiosis, Bacterial Proteins genetics, Bacterial Proteins metabolism, Gene Expression Regulation, Bacterial, Gene Expression Regulation, Developmental, Mycobacterium tuberculosis metabolism, Regulon, Mycobacterium tuberculosis genetics, Mycobacterium tuberculosis growth & development, Oxygen metabolism
- Abstract
The physiology of dormant Mycobacterium tuberculosis was studied in detail by examining the gene expression of 51 genes using quantitative Reverse-Transcription Polymerase Chain Reaction. A forty-day period of dormancy in the Wayne culture model depicted four major transcription patterns. Some sigma factors and many metabolic genes were constant, whereas genes belonging to the dormancy regulon were activated on day 9. In particular, alpha-crystallin mRNA showed more than a 1,000-fold increase compared to replicating bacilli. Genes belonging to the enduring hypoxic response were up-regulated at day 16, notably, transcription factors sigma B and E. Early genes typical of log-phase bacilli, esat-6 and fbpB, were uniformly down-regulated during dormancy. Late stages of dormancy showed a drop in gene expression likely due to a lack of substrates in anaerobic respiration as demonstrated by the transcriptional activation observed following nitrates addition. Among genes involved in nitrate metabolism, narG was strongly up-regulated by nitrates addition. Dormant bacilli responded very rapidly when exposed to oxygen and fresh medium, showing a transcriptional activation of many genes, including resuscitation-promoting factors, within one hour. Our observations extend the current knowledge on dormant M. tuberculosis gene expression and its response to nutrients and to aerobic and anaerobic respiration. more...
- Published
- 2016
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17. Gender differences in pain and its relief.
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Pieretti S, Di Giannuario A, Di Giovannandrea R, Marzoli F, Piccaro G, Minosi P, and Aloisi AM
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- Female, Humans, Male, Pain Threshold, Prevalence, Pain epidemiology, Pain Management statistics & numerical data, Sex Characteristics, Sex Factors
- Abstract
There is much evidence to suggest that gender is an important factor in the modulation of pain. Literature data strongly suggest that men and women differ in their responses to pain: they are more variable in women than men, with increased pain sensitivity and many more painful diseases commonly reported among women. Gender differences in pharmacological therapy and non-pharmacological pain interventions have also been reported, but these effects appear to depend on the treatment type and characteristics. It is becoming very evident that gender differences in pain and its relief arise from an interaction of genetic, anatomical, physiological, neuronal, hormonal, psychological and social factors which modulate pain differently in the sexes. Experimental data indicate that both a different modulation of the endogenous opioid system and sex hormones are factors influencing pain sensitivity in males and females. This brief review will examine the literature on sex differences in experimental and clinical pain, focusing on several biological mechanisms implicated in the observed gender-related differences. more...
- Published
- 2016
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18. Tuberculosis in migrants from 106 countries to Italy, 2008-2014.
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Fattorini L, Mustazzolu A, Borroni E, Piccaro G, Giannoni F, and Cirillo DM
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- Africa, Antitubercular Agents therapeutic use, Europe, Extensively Drug-Resistant Tuberculosis epidemiology, Geography, Humans, Italy epidemiology, Microbial Sensitivity Tests, Mycobacterium tuberculosis, Russia, Tuberculosis, Multidrug-Resistant epidemiology, World Health Organization, Transients and Migrants, Tuberculosis epidemiology
- Published
- 2016
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19. Activity of lipophilic and hydrophilic drugs against dormant and replicating Mycobacterium tuberculosis.
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Piccaro G, Poce G, Biava M, Giannoni F, and Fattorini L
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- Microbial Sensitivity Tests, Antitubercular Agents pharmacology, Mycobacterium tuberculosis drug effects
- Published
- 2015
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20. Rifampin induces hydroxyl radical formation in Mycobacterium tuberculosis.
- Author
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Piccaro G, Pietraforte D, Giannoni F, Mustazzolu A, and Fattorini L
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- Antitubercular Agents metabolism, Bacterial Proteins chemistry, Catalase chemistry, Cyclic N-Oxides, DNA-Directed RNA Polymerases, Electron Spin Resonance Spectroscopy, Hydroxyl Radical chemistry, Mycobacterium tuberculosis chemistry, Mycobacterium tuberculosis metabolism, Oxidative Stress, Pentetic Acid chemistry, Protein Binding, Rifampin metabolism, Spin Labels, Superoxide Dismutase chemistry, Superoxides chemistry, Thiourea chemistry, Antitubercular Agents pharmacology, Bacterial Proteins metabolism, Hydroxyl Radical metabolism, Mycobacterium tuberculosis drug effects, Rifampin pharmacology, Superoxides metabolism
- Abstract
The antituberculosis (anti-TB) drug rifampin (RIF) binds to the beta subunit of the RNA polymerase (RpoB) of Mycobacterium tuberculosis, but the bactericidal responses triggered after target interaction are not known. To evaluate whether RIF induced an oxidative burst, lysates of RIF-treated M. tuberculosis were tested for determination of reactive oxygen species (ROS) by the electron paramagnetic resonance (EPR) technique using 1-hydroxy-3-carboxy-pyrrolidine (CPH) and 5,5-dimethyl-1-pyrrolidine-N-oxide (DMPO) as spin traps. M. tuberculosis killing by RIF stimulated an increase in the rate of formation of the CPH radical (CP·). Lysate pretreatment with the O2·(-) and ·OH scavengers superoxide dismutase (SOD) and thiourea (THIO), respectively, or with the metal chelator diethylene triamine pentaacetic acid (DTPA) inhibited CP· formation, arguing in favor of a metal-catalyzed ROS response. Formation of CP· did not increase following treatment of RIF-resistant strains with RIF, indicating that the ROS were induced after RpoB binding. To identify the ROS formed, lysates of RIF-treated bacilli were incubated with DMPO, a spin trap specific for ·OH and O2·(-), with or without pretreatment with SOD, catalase, THIO, or DTPA. Superoxide dismutase, catalase, and THIO decreased formation of the DMPO-OH adduct, and SOD plus DTPA completely suppressed it, suggesting that RIF activated metal-dependent O2·(-)-mediated mechanisms producing ·OH inside tubercle bacilli. The finding that the metal chelator DTPA reduced the bactericidal activity of RIF supported the possibility that ·OH was generated through these mechanisms and that it participated at least in part in M. tuberculosis killing by the drug., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.) more...
- Published
- 2014
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21. Gender-dependent resiliency to stressful and metabolic challenges following prenatal exposure to high-fat diet in the p66(Shc-/-) mouse.
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Bellisario V, Berry A, Capoccia S, Raggi C, Panetta P, Branchi I, Piccaro G, Giorgio M, Pelicci PG, and Cirulli F
- Abstract
Metabolic stressful challenges during susceptible time windows, such as fetal life, can have important implications for health throughout life. Deletion of the p66(Shc) gene in mice leads to reduced oxidative stress (OS), resulting in a healthy and lean phenotype characterized by increased metabolic rate, resistance to high-fat diet (HFD)-induced obesity and reduced emotionality at adulthood. Here we hypothesize that p66(Shc-/-) (KO) adult offspring might be protected from the detrimental effects induced by maternal HFD administered before and during pregnancy. To test such hypothesis, we fed p66(Shc+/+) (WT) and KO females with HFD for 13 weeks starting on 5 weeks of age until delivery and tested adult male and female offspring for their metabolic, neuroendocrine, and emotional profile. Prenatal diet affected stress responses and metabolic features in a gender-dependent fashion. In particular, prenatal HFD increased plasma leptin levels and decreased anxiety-like behavior in females, while increasing body weight, particularly in KO subjects. KO mice were overall characterized by metabolic resiliency, showing a blunted change in glycemia levels in response to glucose or insulin challenges. However, in p66(Shc-/-) mice, prenatal HFD affected glucose tolerance response in an opposite manner in the two genders, overriding the resilience in males and exacerbating it in females. Finally, KO females were protected from the disrupting effect of prenatal HFD on neuroendocrine response. These findings indicate that prenatal HFD alters the emotional profile and metabolic functionality of the adult individual in a gender-dependent fashion and suggest that exposure to high-caloric food during fetal life is a stressful condition interfering with the developmental programming of the adult phenotype. Deletion of the p66(Shc) gene attenuates such effects, acting as a protective factor. more...
- Published
- 2014
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22. Targeting dormant bacilli to fight tuberculosis.
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Fattorini L, Piccaro G, Mustazzolu A, and Giannoni F
- Abstract
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb), which kills about 2 million people annually. Furthermore, 2 billion people worldwide are latently infected with this organism, with 10% of them reactivating to active TB due to re-growth of nonreplicating (dormant) Mtb residing in their tissues. Because of the huge reservoir of latent TB it is important to find novel drugs/drug combinations killing dormant bacilli (microaerophiles, anaerobes and drug-tolerant persisters) surviving for decades in a wide spectrum of granulomatous lesions in the lungs of TB patients. Antibiotic treatment of drug-susceptible TB requires administration of isoniazid, rifampin, pyrazinamide, ethambutol for 2 months, followed by isoniazid and rifampin for 4 months. To avoid reactivation of dormant Mtb to active pulmonary TB, up to 9 months of treatment with isoniazid is required. Therefore, a strategy to eliminate dormant bacilli needs to be developed to shorten therapy of active and latent TB and reduce the reservoir of people with latent TB. Finding drugs with high rate of penetration into the caseous granulomas and understanding the biology of dormant bacilli and in particular of persister cells, phenotypically resistant to antibiotics, will be essential to eradicate Mtb from humans. In recent years unprecedented efforts have been done in TB drug discovery, aimed at identifying novel drugs and drug combinations killing both actively replicating and nonreplicating Mtb in vitro, in animal models and in clinical trials in humans. more...
- Published
- 2013
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23. Mycobacterium tuberculosis PstS1 amplifies IFN-γ and induces IL-17/IL-22 responses by unrelated memory CD4+ T cells via dendritic cell activation.
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Palma C, Schiavoni G, Abalsamo L, Mattei F, Piccaro G, Sanchez M, Fernandez C, Singh M, and Gabriele L
- Subjects
- Acyltransferases immunology, Animals, Antigens, Bacterial immunology, Bacterial Proteins immunology, CD4-Positive T-Lymphocytes metabolism, CD8 Antigens metabolism, CD8-Positive T-Lymphocytes immunology, Cell Proliferation, Dendritic Cells immunology, Immunologic Memory, Interferon-gamma biosynthesis, Interleukin-17 biosynthesis, Interleukin-1beta metabolism, Interleukin-23 metabolism, Interleukin-6 metabolism, Interleukins biosynthesis, Lymphocyte Activation immunology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Mycobacterium tuberculosis immunology, Toll-Like Receptor 2 deficiency, Toll-Like Receptor 2 genetics, Tuberculosis immunology, Interleukin-22, ATP-Binding Cassette Transporters metabolism, Bacterial Proteins metabolism, CD4-Positive T-Lymphocytes immunology, Interferon-gamma metabolism, Interleukin-17 metabolism, Interleukins metabolism
- Abstract
The immunological mechanisms that modulate protection during Mycobacterium tuberculosis (Mtb) infection or vaccination are not fully understood. Secretion of IFN-γ and, to a lesser extent, of IL-17 by CD4(+) T cells plays a major role both in protection and immunopathology. Few Mtb Ags interacting with DCs affect priming, activation, and regulation of Ag-unrelated CD4(+) T-cell responses. Here we demonstrate that PstS1, a 38 kDa-lipoprotein of Mtb, promotes Ag-independent activation of memory T lymphocytes specific for Ag85B or Ag85A, two immunodominant protective Ags of Mtb. PstS1 expands CD4(+) and CD8(+) memory T cells, amplifies secretion of IFN-γ and IL-22 and induces IL-17 production by effector memory cells in an Ag-unrelated manner in vitro and in vivo. These effects were mediated through the stimulation of DCs, particularly of the CD8α(-) subtype, which respond to PstS1 by undergoing phenotypic maturation and by secreting IL-6, IL-1β and, to a lower extent, IL-23. IL-6 secretion by PstS1-stimulated DCs was required for IFN-γ, and to a lesser extent for IL-22 responses by Ag85B-specific memory T cells. These results may open new perspectives for immunotherapeutic strategies to control Th1/Th17 immune responses in Mtb infections and in vaccinations against tuberculosis., (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.) more...
- Published
- 2013
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24. Activities of drug combinations against Mycobacterium tuberculosis grown in aerobic and hypoxic acidic conditions.
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Piccaro G, Giannoni F, Filippini P, Mustazzolu A, and Fattorini L
- Subjects
- Aerobiosis physiology, Anaerobiosis physiology, Colony Count, Microbial, Culture Media, Hydrogen-Ion Concentration, Microbial Sensitivity Tests, Microbial Viability drug effects, Mycobacterium tuberculosis growth & development, Aerobiosis drug effects, Anaerobiosis drug effects, Antitubercular Agents pharmacology, Drug Combinations, Mycobacterium tuberculosis drug effects
- Abstract
Mycobacterium tuberculosis is exposed to hypoxia and acidity within granulomatous lesions. In this study, an acidic culture model of M. tuberculosis was used to test drug activity against aerobic 5-day-old (A5) and hypoxic 5-, 12-, and 19-day-old (H5, H12, and H19, respectively) bacilli after 7, 14, and 21 days of exposure. In A cultures, CFU and pH rapidly increased, while in H cultures growth stopped and pH increased slightly. Ten drugs were tested: rifampin (R), isoniazid (I), pyrazinamide (Z), ethambutol (E), moxifloxacin (MX), amikacin (AK), metronidazole (MZ), nitazoxanide (NZ), niclosamide (NC), and PA-824 (PA). Rifampin was the most active against A5, H5, H12, and H19 bacilli. Moxifloxacin and AK efficiently killed A5 and H5 cells, I was active mostly against A5 cells, Z was most active against H12 and H19 cells, and E showed low activity. Among nitrocompounds, NZ, NC, and PA were effective against A5, H5, H12, and H19 cells, while MZ was active against H12 and H19 cells. To kill all A and H cells, A5- and H5-active agents R, MX, and AK were used in combination with MZ, NZ, NC, or PA, in comparison with R-I-Z-E, currently used for human therapy. Mycobacterial viability was determined by CFU and a sensitive test in broth (day to positivity, MGIT 960 system). As shown by lack of regrowth in MGIT, the most potent combination was R-MX-AK-PA, which killed all A5, H5, H12, and H19 cells in 14 days. These observations demonstrate the sterilizing effect of drug combinations against cells of different M. tuberculosis stages grown in aerobic and hypoxic acidic conditions. more...
- Published
- 2013
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25. Human melanoma cells express FGFR/Src/Rho signaling that entails an adhesion-independent caveolin-1 membrane association.
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Fecchi K, Travaglione S, Spadaro F, Quattrini A, Parolini I, Piccaro G, Raggi C, Fabbri A, Felicetti F, Carè A, Fiorentini C, and Sargiacomo M
- Subjects
- Actins metabolism, Caveolin 1 genetics, Cell Count, Cell Line, Tumor, Cell Membrane genetics, Cell Membrane metabolism, Cell Movement physiology, Cytoskeleton genetics, Cytoskeleton metabolism, Humans, MAP Kinase Signaling System, Melanoma genetics, Melanoma pathology, Phosphorylation, Receptors, Fibroblast Growth Factor genetics, Signal Transduction, rho GTP-Binding Proteins genetics, src-Family Kinases genetics, Caveolin 1 metabolism, Melanoma metabolism, Receptors, Fibroblast Growth Factor metabolism, rho GTP-Binding Proteins metabolism, src-Family Kinases metabolism
- Abstract
Caveolae have been indicated as a center of cytoskeleton regulation for Src kinase/Rho GTPase signaling. In addition, Src recruitment on intact cortical actin cytoskeleton appears to be required for bFGF/FGFR signal activation. Recently, we established a relationship between caveolin-1 (Cav-1) expression and cell migration in human malignant melanoma, constitutively activated by a bFGF autoregulatory loop. This work intends to investigate whether caveolae's asset, through bFGF/FGFR/c-Src/Rho signaling, could be related to melanoma cell anchorage. Accordingly, we revealed the existence of a FGFR/Src kinase pathway in Cav-1 enriched detergent-resistant membranes (DRMs) of Me665/1 metastatic melanoma cells, as confirmed by FGFR silencing. Moreover, we determined the expression and phosphorylation levels of Cav-1/Src/Erk signal pathway as a function of FGFR activation and cell density. A sucrose density gradient ultracentrifugation was employed to monitor Cav-1 membrane association and buoyancy in Me665/1 cells treated for actin fragmentation or for altered phosphorylation signals. As a result, melanoma cells show remarkable resistance to Cav-1 disassembly, together with persisting cell signal activity, being Src and Cav-1 crucial modulators of Rho GTPases. In conclusion, our study primarily highlights, in a metastatic melanoma cell line expressing caveolin, the circumstances whereby caveola structural and functional endurance enables the FGFR/Src/Rho GTPases pathway to keep on cell progression., (Copyright © 2011 UICC.) more...
- Published
- 2012
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26. Activity of drugs against dormant Mycobacterium tuberculosis.
- Author
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Piccaro G, Filippini P, Giannoni F, Scipione L, Tortorella S, De Vita D, Mellini P, and Fattorini L
- Subjects
- Microbial Sensitivity Tests, Antitubercular Agents pharmacology, Mycobacterium tuberculosis drug effects
- Published
- 2011
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27. The M. tuberculosis phosphate-binding lipoproteins PstS1 and PstS3 induce Th1 and Th17 responses that are not associated with protection against M. tuberculosis infection.
- Author
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Palma C, Spallek R, Piccaro G, Pardini M, Jonas F, Oehlmann W, Singh M, and Cassone A
- Subjects
- Acyltransferases immunology, Animals, Antigens, Bacterial immunology, BCG Vaccine immunology, Bacterial Load immunology, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Epitopes, Female, Immunization, Immunologic Memory immunology, Interferon-gamma biosynthesis, Interleukin-17 biosynthesis, Interleukin-17 immunology, Mice, Mice, Inbred C57BL, Tuberculosis Vaccines immunology, Bacterial Proteins immunology, Mycobacterium tuberculosis immunology, Th1 Cells immunology, Th17 Cells immunology, Tuberculosis immunology, Tuberculosis prevention & control
- Abstract
The M. tuberculosis phosphate-binding transporter lipoproteins PstS1 and PstS3 were good immunogens inducing CD8(+) T-cell activation and both Th1 and Th17 immunity in mice. However, this antigen-specific immunity, even when amplified by administration of the protein with the adjuvant LTK63 or by the DNA priming/protein boosting regimen, was not able to contain M. tuberculosis replication in the lungs of infected mice. The lack of protection might be ascribed with the scarce/absent capacity of PstS1/PstS3 antigens to modulate the IFN-γ response elicited by M. tuberculosis infection during which, however, PstS1-specific IL-17 secreting cells were generated in both unvaccinated and BCG-vaccinated mice. In spite of a lack of protection by PstS1/PstS3 immunizations, our results do show that PstS1 is able to induce IL-17 response upon M. tuberculosis infection which is of interest in the study of anti-M. tuberculosis immunity and as potential immunomodulator in combined vaccines. more...
- Published
- 2011
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28. Activity of drug combinations against dormant Mycobacterium tuberculosis.
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Filippini P, Iona E, Piccaro G, Peyron P, Neyrolles O, and Fattorini L
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- 3T3 Cells, Adipocytes drug effects, Adipocytes microbiology, Amikacin administration & dosage, Animals, Aza Compounds administration & dosage, Capreomycin administration & dosage, Colony Count, Microbial, Drug Combinations, Drug Resistance, Bacterial, Fluoroquinolones, Humans, In Vitro Techniques, Metronidazole administration & dosage, Mice, Microbial Sensitivity Tests, Models, Biological, Moxifloxacin, Quinolines administration & dosage, Rifampin administration & dosage, Antitubercular Agents administration & dosage, Latent Tuberculosis drug therapy, Latent Tuberculosis microbiology, Mycobacterium tuberculosis drug effects, Mycobacterium tuberculosis growth & development
- Abstract
Aerobic (5-day-old cultures) and nonreplicating (dormant) Mycobacterium tuberculosis (5-, 12-, and 19-day-old cultures) bacteria were treated with rifampin (R), moxifloxacin (MX), metronidazole (MZ), amikacin (AK), or capreomycin (CP) for 7, 14, and 21 days. R-MX-MZ-AK and R-MX-MZ-CP killed both aerobic and dormant bacilli in 21 days, as shown by lack of regrowth in solid and liquid media. R-MX-MZ-AK and R-MX-MZ-CP also caused a strong decrease of nonreplicating bacilli in 7 days in a cell-based dormancy model. more...
- Published
- 2010
- Full Text
- View/download PDF
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