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1.
J Infect Dis ; 221(2): 267-275, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31504652

RESUMO

Staphylococcus aureus is a common pathogen causing infections in humans with various degrees of severity, with pneumonia being one of the most severe infections. In as much as staphylococcal pneumonia is a disease driven in large part by α-hemolysin (Hla) and Panton-Valentine leukocidin (PVL), we evaluated whether active immunization with attenuated forms of Hla (HlaH35L/H48L) alone, PVL components (LukS-PVT28F/K97A/S209A and LukF-PVK102A) alone, or combination of all 3 toxoids could prevent lethal challenge in a rabbit model of necrotizing pneumonia caused by the USA300 community-associated methicillin-resistant S. aureus (MRSA). Rabbits vaccinated with Hla toxoid alone or PVL components alone were only partially protected against lethal pneumonia, whereas those vaccinated with all 3 toxoids had 100% protection against lethality. Vaccine-mediated protection correlated with induction of polyclonal antibody response that neutralized not only α-hemolysin and PVL, but also other related toxins, produced by USA300 and other epidemic MRSA clones.


Assuntos
Toxinas Bacterianas/imunologia , Exotoxinas/imunologia , Proteínas Hemolisinas/imunologia , Leucocidinas/imunologia , Pneumonia Necrosante/prevenção & controle , Pneumonia Estafilocócica/prevenção & controle , Animais , Toxinas Bacterianas/administração & dosagem , Modelos Animais de Doenças , Exotoxinas/administração & dosagem , Proteínas Hemolisinas/administração & dosagem , Humanos , Leucocidinas/administração & dosagem , Staphylococcus aureus Resistente à Meticilina , Pneumonia Necrosante/imunologia , Pneumonia Estafilocócica/imunologia , Coelhos , Vacinação
2.
Artigo em Inglês | MEDLINE | ID: mdl-31844012

RESUMO

Staphylococcus aureus is a major human pathogen that causes a wide range of infections by producing an arsenal of cytotoxins. We found that passive immunization with either a monoclonal antibody (MAb) neutralizing alpha-hemolysin or a broadly cross-reactive MAb neutralizing Panton-Valentine leukocidin, leukocidin ED, and gamma-hemolysins HlgAB and HlgCB conferred only partial protection, whereas the combination of those two MAbs conferred significant protection in a rabbit model of necrotizing pneumonia caused by the USA300 methicillin-resistant S. aureus epidemic clone.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Proteínas Hemolisinas/imunologia , Leucocidinas/uso terapêutico , Pneumonia Necrosante/tratamento farmacológico , Pneumonia Necrosante/imunologia , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/microbiologia , Animais , Modelos Animais de Doenças , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/microbiologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/patogenicidade , Coelhos , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/patogenicidade
3.
PLoS Pathog ; 14(9): e1007308, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30248149

RESUMO

Gram-positive bacteria, including Staphylococcus aureus are endemic in the U.S., which cause life-threatening necrotizing pneumonia. Neutrophils are known to be critical for clearance of S. aureus infection from the lungs and extrapulmonary organs. Therefore, we investigated whether the NLRP6 inflammasome regulates neutrophil-dependent host immunity during pulmonary S. aureus infection. Unlike their wild-type (WT) counterparts, NLRP6 knockout (KO) mice were protected against pulmonary S. aureus infection as evidenced by their higher survival rate and lower bacterial burden in the lungs and extrapulmonary organs. In addition, NLRP6 KO mice displayed increased neutrophil recruitment following infection, and when neutrophils were depleted the protective effect was lost. Furthermore, neutrophils from the KO mice demonstrated enhanced intracellular bacterial killing and increased NADPH oxidase-dependent ROS production. Intriguingly, we found higher NK cell-mediated IFN-γ production in KO mouse lungs, and treatment with IFN-γ was found to enhance the bactericidal ability of WT and KO neutrophils. The NLRP6 KO mice also displayed decreased pyroptosis and necroptosis in the lungs following infection. Blocking of pyroptosis and necroptosis in WT mice resulted in increased survival, reduced bacterial burden in the lungs, and attenuated cytokine production. Taken together, these novel findings show that NLRP6 serves as a negative regulator of neutrophil-mediated host defense during Gram-positive bacterial infection in the lungs through regulating both neutrophil influx and function. These results also suggest that blocking NLRP6 to augment neutrophil-associated bacterial clearance should be considered as a potential therapeutic intervention strategy for treatment of S. aureus pneumonia.


Assuntos
Infiltração de Neutrófilos/imunologia , Pneumonia Estafilocócica/imunologia , Receptores de Superfície Celular/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Feminino , Interações Hospedeiro-Patógeno/imunologia , Humanos , Inflamassomos/imunologia , Interferon gama/biossíntese , Células Matadoras Naturais/imunologia , Pulmão/imunologia , Pulmão/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pneumonia Necrosante/imunologia , Pneumonia Necrosante/microbiologia , Pneumonia Estafilocócica/microbiologia , Piroptose/imunologia , Espécies Reativas de Oxigênio/metabolismo , Receptores de Superfície Celular/deficiência , Receptores de Superfície Celular/genética , Staphylococcus aureus/imunologia , Regulação para Cima
5.
Antimicrob Agents Chemother ; 60(10): 6333-40, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27527081

RESUMO

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA), especially the USA300 pulsotype, is a frequent cause of skin and soft tissue infections and severe pneumonia. Despite appropriate antibiotic treatment, complications are common and pneumonia is associated with high mortality. S. aureus strains express multiple cytotoxins, including alpha-hemolysin (Hla) and up to five bicomponent leukocidins that specifically target phagocytic cells for lysis. CA-MRSA USA300 strains carry the genes for all six cytotoxins. Species specificity of the leukocidins greatly contributes to the ambiguity regarding their role in S. aureus pathogenesis. We performed a comparative analysis of the leukocidin susceptibility of human, rabbit, and mouse polymorphonuclear leukocytes (PMNs) to assess the translational value of mouse and rabbit S. aureus models. We found that mouse PMNs were largely resistant to LukSF-PV, HlgAB, and HlgCB and susceptible only to LukED, whereas rabbit and human PMNs were highly sensitive to all these cytotoxins. In the rabbit pneumonia model with a USA300 CA-MRSA strain, passive immunization with a previously identified human monoclonal antibody (MAb), Hla-F#5, which cross-neutralizes Hla, LukSF-PV, HlgAB, HlgCB, and LukED, provided full protection, whereas an Hla-specific MAb was only partially protective. In the mouse USA300 CA-MRSA pneumonia model, both types of antibodies demonstrated full protection, suggesting that Hla, but not leukocidin(s), is the principal virulence determinant in mice. As the rabbit recapitulates the high susceptibility to leukocidins characteristic of humans, this species represents a valuable model for assessing novel, cytotoxin-targeting anti-S. aureus therapeutic approaches.


Assuntos
Anticorpos Neutralizantes/farmacologia , Toxinas Bacterianas/imunologia , Proteínas Hemolisinas/imunologia , Leucocidinas/imunologia , Staphylococcus aureus Resistente à Meticilina/patogenicidade , Pneumonia Necrosante/prevenção & controle , Pneumonia Estafilocócica/prevenção & controle , Animais , Anticorpos Monoclonais/farmacologia , Infecções Comunitárias Adquiridas/microbiologia , Modelos Animais de Doenças , Feminino , Humanos , Leucocidinas/farmacologia , Masculino , Camundongos Endogâmicos BALB C , Neutrófilos/efeitos dos fármacos , Neutrófilos/microbiologia , Pneumonia Necrosante/imunologia , Pneumonia Necrosante/microbiologia , Pneumonia Necrosante/mortalidade , Pneumonia Estafilocócica/imunologia , Coelhos
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