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1.
Int J Mol Sci ; 24(4)2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-36835297

RESUMO

Legionella pneumophila is an intracellular pathogen that can cause severe pneumonia after the inhalation of contaminated aerosols and replication in alveolar macrophages. Several pattern recognition receptors (PRRs) have been identified that contribute to the recognition of L. pneumophila by the innate immune system. However, the function of the C-type lectin receptors (CLRs), which are mainly expressed by macrophages and other myeloid cells, remains largely unexplored. Here, we used a library of CLR-Fc fusion proteins to search for CLRs that can bind the bacterium and identified the specific binding of CLEC12A to L. pneumophila. Subsequent infection experiments in human and murine macrophages, however, did not provide evidence for a substantial role of CLEC12A in controlling innate immune responses to the bacterium. Consistently, antibacterial and inflammatory responses to Legionella lung infection were not significantly influenced by CLEC12A deficiency. Collectively, CLEC12A is able to bind to L. pneumophila-derived ligands but does not appear to play a major role in the innate defense against L. pneumophila.


Assuntos
Interações Hospedeiro-Patógeno , Imunidade Inata , Lectinas Tipo C , Legionella pneumophila , Doença dos Legionários , Receptores Mitogênicos , Animais , Humanos , Camundongos , Lectinas Tipo C/metabolismo , Legionella pneumophila/imunologia , Doença dos Legionários/imunologia , Doença dos Legionários/microbiologia , Macrófagos/metabolismo , Macrófagos Alveolares/metabolismo , Receptores Mitogênicos/imunologia
2.
Int J Mol Sci ; 23(23)2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36498843

RESUMO

Staphylococcus aureus implant-associated infections are difficult to treat because of the ability of bacteria to form biofilm on medical devices. Here, the efficacy of Sb-1 to control or prevent S. aureus colonization on medical foreign bodies was investigated in a Galleria mellonella larval infection model. For colonization control assays, sterile K-wires were implanted into larva prolegs. After 2 days, larvae were infected with methicillin-resistant S. aureus ATCC 43300 and incubated at 37 °C for a further 2 days, when treatments with either daptomycin (4 mg/kg), Sb-1 (107 PFUs) or a combination of them (3 x/day) were started. For biofilm prevention assays, larvae were pre-treated with either vancomycin (10 mg/kg) or Sb-1 (107 PFUs) before the S. aureus infection. In both experimental settings, K-wires were explanted for colony counting two days after treatment. In comparison to the untreated control, more than a 4 log10 CFU and 1 log10 CFU reduction was observed on K-wires recovered from larvae treated with the Sb-1/daptomycin combination and with their singular administration, respectively. Moreover, pre-infection treatment with Sb-1 was found to prevent K-wire colonization, similarly to vancomycin. Taken together, the obtained results demonstrated the strong potential of the Sb-1 antibiotic combinatory administration or the Sb-1 pretreatment to control or prevent S. aureus-associated implant infections.


Assuntos
Bacteriófagos , Staphylococcus aureus Resistente à Meticilina , Mariposas , Infecções Estafilocócicas , Animais , Staphylococcus aureus , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Vancomicina/farmacologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Biofilmes , Mariposas/microbiologia , Larva/microbiologia , Testes de Sensibilidade Microbiana
3.
Nat Commun ; 15(1): 2788, 2024 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-38555356

RESUMO

Hospital-acquired pneumonia (HAP) is associated with high mortality and costs, and frequently caused by multidrug-resistant (MDR) bacteria. Although prior antimicrobial therapy is a major risk factor for HAP, the underlying mechanism remains incompletely understood. Here, we demonstrate that antibiotic therapy in hospitalized patients is associated with decreased diversity of the gut microbiome and depletion of short-chain fatty acid (SCFA) producers. Infection experiments with mice transplanted with patient fecal material reveal that these antibiotic-induced microbiota perturbations impair pulmonary defense against MDR Klebsiella pneumoniae. This is dependent on inflammatory monocytes (IMs), whose fatty acid receptor (FFAR)2/3-controlled and phagolysosome-dependent antibacterial activity is compromized in mice transplanted with antibiotic-associated patient microbiota. Collectively, we characterize how clinically relevant antibiotics affect antimicrobial defense in the context of human microbiota, and reveal a critical impairment of IM´s antimicrobial activity. Our study provides additional arguments for the rational use of antibiotics and offers mechanistic insights for the development of novel prophylactic strategies to protect high-risk patients from HAP.


Assuntos
Antibacterianos , Anti-Infecciosos , Humanos , Camundongos , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Monócitos , Anti-Infecciosos/farmacologia , Klebsiella pneumoniae , Pulmão
4.
Nat Commun ; 12(1): 7165, 2021 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-34887398

RESUMO

Legionella pneumophila is the most common cause of the severe respiratory infection known as Legionnaires' disease. However, the microorganism is typically a symbiont of free-living amoeba, and our understanding of the bacterial factors that determine human pathogenicity is limited. Here we carried out a population genomic study of 902 L. pneumophila isolates from human clinical and environmental samples to examine their genetic diversity, global distribution and the basis for human pathogenicity. We find that the capacity for human disease is representative of the breadth of species diversity although some clones are more commonly associated with clinical infections. We identified a single gene (lag-1) to be most strongly associated with clinical isolates. lag-1, which encodes an O-acetyltransferase for lipopolysaccharide modification, has been distributed horizontally across all major phylogenetic clades of L. pneumophila by frequent recent recombination events. The gene confers resistance to complement-mediated killing in human serum by inhibiting deposition of classical pathway molecules on the bacterial surface. Furthermore, acquisition of lag-1 inhibits complement-dependent phagocytosis by human neutrophils, and promoted survival in a mouse model of pulmonary legionellosis. Thus, our results reveal L. pneumophila genetic traits linked to disease and provide a molecular basis for resistance to complement-mediated killing.


Assuntos
Proteínas do Sistema Complemento/imunologia , Legionella pneumophila/genética , Doença dos Legionários/imunologia , Doença dos Legionários/microbiologia , Acetiltransferases/genética , Acetiltransferases/imunologia , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/imunologia , Feminino , Genoma Bacteriano , Humanos , Legionella pneumophila/classificação , Legionella pneumophila/imunologia , Legionella pneumophila/isolamento & purificação , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Filogenia
5.
Int J Antimicrob Agents ; 52(6): 842-853, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30236955

RESUMO

Most antibiotics have limited or no activity against bacterial biofilms, whereas bacteriophages can eradicate biofilms. We evaluated whether Staphylococcus aureus-specific bacteriophage Sb-1 could eradicate biofilm, both alone and in combination with different classes of antibiotics, degrade the extracellular matrix and target persister cells. Biofilm of methicillin-resistant S. aureus (MRSA) ATCC 43300 was treated with Sb-1 alone or in (simultaneous or staggered) combination with fosfomycin, rifampin, vancomycin, daptomycin or ciprofloxacin. The matrix was visualized by confocal fluorescent microscopy. Persister cells were treated with 104 and 107 plaque-forming units (PFU)/mL Sb-1 for 3 h in phosphate-buffered saline (PBS), followed by colony-forming units (CFU) counting. Alternatively, bacteria were washed and incubated in fresh brain heart infusion (BHI) medium and bacterial growth assessed after a further 24 h. Pretreatment with Sb-1 followed by the administration of subinhibitory concentrations of antibiotic caused a synergistic effect in eradicating MRSA biofilm. Sb-1 determined a dose-dependent reduction of matrix exopolysaccharide. Sb-1 at 107 PFU/mL showed direct killing activity on ≈ 5 × 105 CFU/mL persisters. However, even a lower titer had lytic activity when phage-treated persister cells were inoculated in fresh medium, reverting to a normal-growing phenotype. This study provides valuable data on the enhancing effect of Sb-1 on antibiotic efficacy, exhibiting specific antibiofilm features. Sb-1 can degrade the MRSA polysaccharide matrix and target persister cells and is therefore suitable for treatment of biofilm-associated infections.


Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Matriz Extracelular/metabolismo , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/virologia , Fagos de Staphylococcus/crescimento & desenvolvimento , Bacteriólise , Contagem de Colônia Microbiana , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Viabilidade Microbiana/efeitos dos fármacos , Microscopia Confocal , Microscopia de Fluorescência , Polissacarídeos Bacterianos/metabolismo
6.
Res Microbiol ; 169(9): 515-521, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29886257

RESUMO

Bacterial biofilms, highly resistant to the conventional antimicrobial therapy, remain an unresolved challenge pressing the medical community to investigate new and alternative strategies to fight chronic implant-associated infections. Recently, strictly lytic bacteriophages have been revalued as powerful agents to kill antibiotic-resistant bacteria even in biofilm. Here, the interaction of T3 bacteriophage and planktonic and biofilm Escherichia coli TG1, respectively, was evaluated using isothermal microcalorimetry. Microcalorimetry is a non-invasive and highly sensitive technique measuring growth-related heat production of microorganisms in real-time. Planktonic and biofilm E. coli TG1 were exposed to different titers of T3 bacteriophage, ranging from 102 to 107 PFU/ml. The incubation of T3 with E. coli TG1 showed a strong inhibition of heat production both in planktonic and biofilm already at lower bacteriophage titers (103 PFU/ml). This method could be used to screen and evaluate the antimicrobial potential of different bacteriophages, alone and in combination with antibiotics in order to improve the treatment success of biofilm-associated infections.


Assuntos
Antibacterianos/farmacologia , Bacteriófago T3/fisiologia , Biofilmes/crescimento & desenvolvimento , Escherichia coli/fisiologia , Escherichia coli/virologia , Bacteriófago T3/patogenicidade , Calorimetria/métodos , Sistemas Computacionais , Testes de Sensibilidade Microbiana
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