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1.
Nat Microbiol ; 2: 16268, 2017 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-28112722

RESUMO

Host control of infections crucially depends on the capability to kill pathogens with reactive oxygen species (ROS). However, these toxic molecules can also readily damage host components and cause severe immunopathology. Here, we show that neutrophils use their most abundant granule protein, myeloperoxidase, to target ROS specifically to pathogens while minimizing collateral tissue damage. A computational model predicted that myeloperoxidase efficiently scavenges diffusible H2O2 at the surface of phagosomal Salmonella and converts it into highly reactive HOCl (bleach), which rapidly damages biomolecules within a radius of less than 0.1 µm. Myeloperoxidase-deficient neutrophils were predicted to accumulate large quantities of H2O2 that still effectively kill Salmonella, but most H2O2 would leak from the phagosome. Salmonella stimulation of neutrophils from normal and myeloperoxidase-deficient human donors experimentally confirmed an inverse relationship between myeloperoxidase activity and extracellular H2O2 release. Myeloperoxidase-deficient mice infected with Salmonella had elevated hydrogen peroxide tissue levels and exacerbated oxidative damage of host lipids and DNA, despite almost normal Salmonella control. These data show that myeloperoxidase has a major function in mitigating collateral tissue damage during antimicrobial oxidative bursts, by converting diffusible long-lived H2O2 into highly reactive, microbicidal and locally confined HOCl at pathogen surfaces.


Assuntos
Peróxido de Hidrogênio/metabolismo , Neutrófilos/enzimologia , Peroxidase/metabolismo , Fagossomos/microbiologia , Explosão Respiratória , Salmonella/metabolismo , Animais , Simulação por Computador , Humanos , Ácido Hipocloroso/metabolismo , Cinética , Camundongos , Neutrófilos/imunologia , Oxirredução , Estresse Oxidativo , Fagossomos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Salmonella/patogenicidade
2.
Cell ; 158(4): 722-733, 2014 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-25126781

RESUMO

Antibiotic therapy often fails to eliminate a fraction of transiently refractory bacteria, causing relapses and chronic infections. Multiple mechanisms can induce such persisters with high antimicrobial tolerance in vitro, but their in vivo relevance remains unclear. Using a fluorescent growth rate reporter, we detected extensive phenotypic variation of Salmonella in host tissues. This included slow-growing subsets as well as well-nourished fast-growing subsets driving disease progression. Monitoring of Salmonella growth and survival during chemotherapy revealed that antibiotic killing correlated with single-cell division rates. Nondividing Salmonella survived best but were rare, limiting their impact. Instead, most survivors originated from abundant moderately growing, partially tolerant Salmonella. These data demonstrate that host tissues diversify pathogen physiology, with major consequences for disease progression and control.


Assuntos
Antibacterianos/administração & dosagem , Fluoroquinolonas/administração & dosagem , Imagem Óptica/métodos , Salmonella typhimurium/efeitos dos fármacos , Febre Tifoide/tratamento farmacológico , Febre Tifoide/microbiologia , Animais , Proteínas de Bactérias/análise , Enrofloxacina , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos BALB C , Proteoma/análise , Salmonella typhimurium/citologia , Salmonella typhimurium/crescimento & desenvolvimento , Baço/microbiologia , Baço/patologia
3.
Nature ; 509(7500): 366-70, 2014 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-24739961

RESUMO

Lipopolysaccharide from Gram-negative bacteria is sensed in the host cell cytoplasm by a non-canonical inflammasome pathway that ultimately results in caspase-11 activation and cell death. In mouse macrophages, activation of this pathway requires the production of type-I interferons, indicating that interferon-induced genes have a critical role in initiating this pathway. Here we report that a cluster of small interferon-inducible GTPases, the so-called guanylate-binding proteins, is required for the full activity of the non-canonical caspase-11 inflammasome during infections with vacuolar Gram-negative bacteria. We show that guanylate-binding proteins are recruited to intracellular bacterial pathogens and are necessary to induce the lysis of the pathogen-containing vacuole. Lysis of the vacuole releases bacteria into the cytosol, thus allowing the detection of their lipopolysaccharide by a yet unknown lipopolysaccharide sensor. Moreover, recognition of the lysed vacuole by the danger sensor galectin-8 initiates the uptake of bacteria into autophagosomes, which results in a reduction of caspase-11 activation. These results indicate that host-mediated lysis of pathogen-containing vacuoles is an essential immune function and is necessary for efficient recognition of pathogens by inflammasome complexes in the cytosol.


Assuntos
Caspases/metabolismo , GTP Fosfo-Hidrolases/metabolismo , Bactérias Gram-Negativas/imunologia , Inflamassomos/metabolismo , Interferon Tipo I/imunologia , Vacúolos/microbiologia , Animais , Autofagia/imunologia , Caspases Iniciadoras , Citosol/microbiologia , Ativação Enzimática , Galectinas/imunologia , Bactérias Gram-Negativas/crescimento & desenvolvimento , Bactérias Gram-Negativas/patogenicidade , Imunidade Inata/imunologia , Inflamassomos/imunologia , Lipopolissacarídeos/imunologia , Camundongos , Fagossomos/imunologia , Fagossomos/microbiologia , Salmonella typhimurium/crescimento & desenvolvimento , Salmonella typhimurium/imunologia
4.
Cell Host Microbe ; 15(1): 72-83, 2014 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-24439899

RESUMO

Reactive oxygen and nitrogen species function in host defense via mechanisms that remain controversial. Pathogens might encounter varying levels of these species, but bulk measurements cannot resolve such heterogeneity. We used single-cell approaches to determine the impact of oxidative and nitrosative stresses on individual Salmonella during early infection in mouse spleen. Salmonella encounter and respond to both stresses, but the levels and impact vary widely. Neutrophils and inflammatory monocytes kill Salmonella by generating overwhelming oxidative stress through NADPH oxidase and myeloperoxidase. This controls Salmonella within inflammatory lesions but does not prevent their spread to more permissive resident red pulp macrophages, which generate only sublethal oxidative bursts. Regional host expression of inducible nitric oxide synthase exposes some Salmonella to nitrosative stress, triggering effective local Salmonella detoxification through nitric oxide denitrosylase. Thus, reactive oxygen and nitrogen species influence dramatically different outcomes of disparate Salmonella-host cell encounters, which together determine overall disease progression.


Assuntos
Monócitos/imunologia , Neutrófilos/imunologia , Infecções por Salmonella/imunologia , Infecções por Salmonella/metabolismo , Salmonella typhimurium/fisiologia , Baço/imunologia , Animais , Feminino , Expressão Gênica , Interações Hospedeiro-Patógeno , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Camundongos , Monócitos/metabolismo , Monócitos/microbiologia , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Neutrófilos/metabolismo , Neutrófilos/microbiologia , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Oxigenases/genética , Oxigenases/metabolismo , Peroxidase/genética , Peroxidase/metabolismo , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Explosão Respiratória/imunologia , Infecções por Salmonella/microbiologia , Infecções por Salmonella/patologia , Salmonella typhimurium/patogenicidade , Análise de Célula Única , Baço/microbiologia , Baço/patologia
5.
Am J Hum Genet ; 85(5): 593-605, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19836010

RESUMO

We report recessive mutations in the gene for the latent transforming growth factor-beta binding protein 4 (LTBP4) in four unrelated patients with a human syndrome disrupting pulmonary, gastrointestinal, urinary, musculoskeletal, craniofacial, and dermal development. All patients had severe respiratory distress, with cystic and atelectatic changes in the lungs complicated by tracheomalacia and diaphragmatic hernia. Three of the four patients died of respiratory failure. Cardiovascular lesions were mild, limited to pulmonary artery stenosis and patent foramen ovale. Gastrointestinal malformations included diverticulosis, enlargement, tortuosity, and stenosis at various levels of the intestinal tract. The urinary tract was affected by diverticulosis and hydronephrosis. Joint laxity and low muscle tone contributed to musculoskeletal problems compounded by postnatal growth delay. Craniofacial features included microretrognathia, flat midface, receding forehead, and wide fontanelles. All patients had cutis laxa. Four of the five identified LTBP4 mutations led to premature termination of translation and destabilization of the LTBP4 mRNA. Impaired synthesis and lack of deposition of LTBP4 into the extracellular matrix (ECM) caused increased transforming growth factor-beta (TGF-beta) activity in cultured fibroblasts and defective elastic fiber assembly in all tissues affected by the disease. These molecular defects were associated with blocked alveolarization and airway collapse in the lung. Our results show that coupling of TGF-beta signaling and ECM assembly is essential for proper development and is achieved in multiple human organ systems by multifunctional proteins such as LTBP4.


Assuntos
Derme/anormalidades , Intestinos/anormalidades , Proteínas de Ligação a TGF-beta Latente/genética , Pulmão/anormalidades , Mutação , Sistema Urinário/anormalidades , Células Cultivadas , Criança , Pré-Escolar , Técnicas de Cocultura , Meios de Cultivo Condicionados/química , DNA/genética , DNA/isolamento & purificação , Derme/metabolismo , Derme/ultraestrutura , Feminino , Fibroblastos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Heterozigoto , Homozigoto , Humanos , Imuno-Histoquímica , Lactente , Mucosa Intestinal/metabolismo , Proteínas de Ligação a TGF-beta Latente/química , Pulmão/metabolismo , Masculino , Sistema Musculoesquelético , Estrutura Terciária de Proteína , RNA Mensageiro/metabolismo , Análise de Sequência de DNA , Pele/citologia , Síndrome , Sistema Urinário/metabolismo
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