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1.
Front Immunol ; 13: 1038349, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36341418

RESUMO

Helicobacter pylori is a major human pathogen that colonizes the gastric mucosa and plays a causative role in development of peptic ulcers and gastric cancer. Neutrophils are heavily infected with this organism in vivo and play a prominent role in tissue destruction and disease. Recently, we demonstrated that H. pylori exploits neutrophil plasticity as part of its virulence strategy eliciting N1-like subtype differentiation that is notable for profound nuclear hypersegmentation. We undertook this study to test the hypothesis that hypersegmentation may enhance neutrophil migratory capacity. However, EZ-TAXIScan™ video imaging revealed a previously unappreciated and progressive chemotaxis defect that was apparent prior to hypersegmentation onset. Cell speed and directionality were significantly impaired to fMLF as well as C5a and IL-8. Infected cells oriented normally in chemotactic gradients, but speed and direction were impaired because of a uropod retraction defect that led to cell elongation, nuclear lobe trapping in the contracted rear and progressive narrowing of the leading edge. In contrast, chemotactic receptor abundance, adhesion, phagocytosis and other aspects of cell function were unchanged. At the molecular level, H. pylori phenocopied the effects of Blebbistatin as indicated by aberrant accumulation of F-actin and actin spikes at the uropod together with enhanced ROCKII-mediated phosphorylation of myosin IIA regulatory light chains at S19. At the same time, RhoA and ROCKII disappeared from the cell rear and accumulated at the leading edge whereas myosin IIA was enriched at both cell poles. These data suggest that H. pylori inhibits the dynamic changes in myosin IIA contractility and front-to-back polarity that are essential for chemotaxis. Taken together, our data advance understanding of PMN plasticity and H. pylori pathogenesis.


Assuntos
Helicobacter pylori , Transtornos Leucocíticos , Miosina não Muscular Tipo IIA , Humanos , Quimiotaxia , Neutrófilos/metabolismo , Helicobacter pylori/metabolismo , Miosina não Muscular Tipo IIA/metabolismo , Transtornos Leucocíticos/metabolismo , Actinas/metabolismo , Cadeias Leves de Miosina/metabolismo
2.
Sci Transl Med ; 10(460)2018 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-30257953

RESUMO

The lack of new antibiotics is among the most critical challenges facing medicine. The problem is particularly acute for Gram-negative bacteria. An unconventional antibiotic strategy is to target bacterial nutrition and metabolism. The metal gallium can disrupt bacterial iron metabolism because it substitutes for iron when taken up by bacteria. We investigated the antibiotic activity of gallium ex vivo, in a mouse model of airway infection, and in a phase 1 clinical trial in individuals with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa airway infections. Our results show that micromolar concentrations of gallium inhibited P. aeruginosa growth in sputum samples from patients with CF. Ex vivo experiments indicated that gallium inhibited key iron-dependent bacterial enzymes and increased bacterial sensitivity to oxidants. Furthermore, gallium resistance developed slowly, its activity was synergistic with certain antibiotics, and gallium did not diminish the antibacterial activity of host macrophages. Systemic gallium treatment showed antibiotic activity in murine lung infections. In addition, systemic gallium treatment improved lung function in people with CF and chronic P. aeruginosa lung infection in a preliminary phase 1 clinical trial. These findings raise the possibility that human infections could be treated by targeting iron metabolism or other nutritional vulnerabilities of bacterial pathogens.


Assuntos
Gálio/uso terapêutico , Ferro/metabolismo , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/metabolismo , Infecções Respiratórias/microbiologia , Adolescente , Adulto , Animais , Antibacterianos/farmacologia , Proteínas de Bactérias/metabolismo , Fibrose Cística/microbiologia , Fibrose Cística/fisiopatologia , Elementos de DNA Transponíveis/genética , Farmacorresistência Bacteriana/efeitos dos fármacos , Sinergismo Farmacológico , Gálio/farmacocinética , Gálio/farmacologia , Genes Bacterianos , Humanos , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Pulmão/fisiopatologia , Macrófagos/efeitos dos fármacos , Macrófagos/microbiologia , Camundongos Endogâmicos C57BL , Viabilidade Microbiana/efeitos dos fármacos , Pessoa de Meia-Idade , Mutagênese , Mutação/genética , Oxidantes/toxicidade , Infecções por Pseudomonas/fisiopatologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/crescimento & desenvolvimento , Infecções Respiratórias/fisiopatologia , Escarro/microbiologia , Adulto Jovem
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