Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 94
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Surg Res ; 233: 323-330, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30502266

RESUMO

BACKGROUND: Previously we have shown that volatile anesthetic isoflurane attenuated neutrophil recruitment and phagocytosis in mouse sepsis and skin inflammation models. The objectives of this study were to test ex vivo function of neutrophils in patients who underwent cardiac catheterization under volatile anesthesia versus intravenous anesthesia (IA), and also to assess the effect of anesthesia on surgical site infections (SSIs) using mouse model to understand the clinical relevance of anesthesia-induced immunomodulation. METHODS: Whole blood from patients who underwent cardiac catheterization procedures either by volatile anesthesia or IA was collected and subjected to phagocytosis assay and a lipopolysaccharide-induced tumor necrosis factor-α assay. Mouse SSI with Staphylococcus aureus USA300 was created, and the effect of isoflurane and propofol exposure (short or long exposure) on bacterial loads was tested. RESULTS: Neutrophil phagocytosis was significantly attenuated after the induction of volatile anesthesia in patients, but not by IA. Monocyte phagocytosis was not affected by the anesthesia regimen. Bacterial loads following SSIs were significantly higher in mice receiving long, but not short, isoflurane exposure. Propofol exposure did not affect bacterial loads. DISCUSSION: Neutrophil phagocytosis can be affected by the type of anesthesia, and preclinical model of SSIs showed potential clinical relevance. The effects of anesthesia regimen on SSIs in patients needs to be studied extensively in the future.


Assuntos
Anestésicos Inalatórios/efeitos adversos , Carga Bacteriana/imunologia , Neutrófilos/efeitos dos fármacos , Fagocitose/efeitos dos fármacos , Infecção da Ferida Cirúrgica/imunologia , Adolescente , Adulto , Anestésicos Inalatórios/administração & dosagem , Anestésicos Intravenosos/administração & dosagem , Anestésicos Intravenosos/efeitos adversos , Animais , Carga Bacteriana/efeitos dos fármacos , Cateterismo Cardíaco/efeitos adversos , Criança , Pré-Escolar , Modelos Animais de Doenças , Escherichia coli/imunologia , Feminino , Humanos , Isoflurano/administração & dosagem , Isoflurano/efeitos adversos , Masculino , Camundongos , Neutrófilos/imunologia , Propofol/administração & dosagem , Propofol/efeitos adversos , Staphylococcus aureus/imunologia , Staphylococcus aureus/isolamento & purificação , Infecção da Ferida Cirúrgica/microbiologia , Infecção da Ferida Cirúrgica/prevenção & controle , Adulto Jovem
2.
Clin Microbiol Infect ; 25(4): 516.e1-516.e4, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30583061

RESUMO

OBJECTIVES: Acinetobacter baumannii can cause severe nosocomial and community-acquired pneumonia. To study the pathogenesis of A. baumannii and to develop new treatments, appropriate mouse models are needed. Most reported mouse models of pulmonary A. baumannii infection are non-lethal or require mouse immunosuppression to enhance infection. These models are not suitable for studying host immune responses or evaluating immunotherapies. METHODS: The virulence of 30 clinical isolates was assessed in mice. The most virulent isolate, SJZ24, was selected to develop a pneumonia model in immunocompetent mice. The cytokine mRNA expression in the lung was assessed with real-time PCR. The cell infiltration in bronchoalveolar lavage fluid (BALF) after SJZ24 infection was determined by flow cytometry. Vaccine efficacy was assessed using this model. RESULTS: Intratracheal inoculation of SJZ24 (5 × 107 CFU) resulted in death in 100% of the mice (5/5). SJZ24-infected mice showed high bacterial burdens in blood and organs as well as severe lung-tissue damage. Infection with SJZ24 induced increased inflammatory cytokine expression in the lung and increased neutrophil infiltration in BALF. Immunization with inactivated whole cells of SJZ24 showed 100% protection (5/5) against A. baumanni infection in this model. CONCLUSIONS: We established a lethal pneumonia model in immunocompetent mice with hypervirulent A. baumannii isolate SJZ24. This model can be used to study the immune response to A. baumannii infection and to evaluate vaccine efficacy.


Assuntos
Infecções por Acinetobacter/imunologia , Infecções por Acinetobacter/mortalidade , Acinetobacter baumannii/imunologia , Pneumonia Bacteriana/mortalidade , Pneumonia Bacteriana/patologia , Infecções por Acinetobacter/patologia , Acinetobacter baumannii/isolamento & purificação , Animais , Carga Bacteriana/imunologia , Vacinas Bacterianas/imunologia , Líquido da Lavagem Broncoalveolar/microbiologia , Citocinas/biossíntese , Citocinas/genética , Modelos Animais de Doenças , Citometria de Fluxo , Humanos , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Pneumonia Bacteriana/microbiologia , RNA Mensageiro/biossíntese , Vacinação
3.
Emerg Microbes Infect ; 7(1): 207, 2018 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-30538219

RESUMO

Tuberculosis (TB) has become the most deadly infectious diseases due to epidemics of HIV/AIDS and multidrug-resistant/extensively drug-resistant TB (MDR-/XDR-TB). Although person-to-person transmission contributes to MDR-TB, it remains unknown whether infection with MDR strains resembles infection with drug-sensitive (DS) TB strains, manipulating limited or broad immune responses. To address these questions, macaques were infected with MDR strain V791 and a drug-sensitive Erdman strain of TB. MDR bacilli burdens in the airway were significantly higher than those of the Erdman control after pulmonary exposure. This productive MDR strain infection upregulated the expression of caspase 3 in macrophages/monocytes and induced appreciable innate-like effector responses of CD3-negative lymphocytes and Ag-specific γδ T-cell subsets. Concurrently, MDR strain infection induced broad immune responses of T-cell subpopulations producing Th1, Th17, Th22, and CTL cytokines. Furthermore, MDR bacilli, like the Erdman strain, were capable of inducing typical TB disease characterized by weight loss, lymphocytopenia, and severe TB lesions. For the first time, our results suggest that MDR-TB infection acts like DS to induce high bacterial burdens in the airway (transmission advantage), innate/adaptive immune responses, and disease processes. Because nonhuman primates are biologically closer to humans than other species, our data may provide useful information for predicting the effects of primary MDR strain infection after person-to-person transmission. The findings also support the hypothesis that a vaccine or host-directed adjunctive modality that is effective for drug-sensitive TB is likely to also impact MDR-TB.


Assuntos
Imunidade Adaptativa , Carga Bacteriana/imunologia , Imunidade Inata , Pulmão/imunologia , Tuberculose Resistente a Múltiplos Medicamentos/imunologia , Animais , Caspase 3 , Citocinas/imunologia , Farmacorresistência Bacteriana Múltipla , Pulmão/microbiologia , Macaca , Macrófagos/imunologia , Macrófagos/microbiologia , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia , Tuberculose Pulmonar/imunologia
4.
PLoS Pathog ; 14(8): e1007244, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30102746

RESUMO

The early events that shape the innate immune response to restrain pathogens during skin infections remain elusive. Methicillin-resistant Staphylococcus aureus (MRSA) infection engages phagocyte chemotaxis, abscess formation, and microbial clearance. Upon infection, neutrophils and monocytes find a gradient of chemoattractants that influence both phagocyte direction and microbial clearance. The bioactive lipid leukotriene B4 (LTB4) is quickly (seconds to minutes) produced by 5-lipoxygenase (5-LO) and signals through the G protein-coupled receptors LTB4R1 (BLT1) or BLT2 in phagocytes and structural cells. Although it is known that LTB4 enhances antimicrobial effector functions in vitro, whether prompt LTB4 production is required for bacterial clearance and development of an inflammatory milieu necessary for abscess formation to restrain pathogen dissemination is unknown. We found that LTB4 is produced in areas near the abscess and BLT1 deficient mice are unable to form an abscess, elicit neutrophil chemotaxis, generation of neutrophil and monocyte chemokines, as well as reactive oxygen species-dependent bacterial clearance. We also found that an ointment containing LTB4 synergizes with antibiotics to eliminate MRSA potently. Here, we uncovered a heretofore unknown role of macrophage-derived LTB4 in orchestrating the chemoattractant gradient required for abscess formation, while amplifying antimicrobial effector functions.


Assuntos
Abscesso/imunologia , Carga Bacteriana/imunologia , Leucotrieno B4/fisiologia , Macrófagos/metabolismo , Staphylococcus aureus Resistente à Meticilina , Infecções Cutâneas Estafilocócicas/imunologia , Abscesso/genética , Abscesso/microbiologia , Abscesso/patologia , Animais , Araquidonato 5-Lipoxigenase/genética , Carga Bacteriana/genética , Células Cultivadas , Feminino , Leucotrieno B4/metabolismo , Macrófagos/imunologia , Masculino , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Staphylococcus aureus Resistente à Meticilina/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores do Leucotrieno B4/genética , Infecções Cutâneas Estafilocócicas/genética , Infecções Cutâneas Estafilocócicas/patologia
5.
Microb Pathog ; 123: 115-119, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29959043

RESUMO

Streptococcus pneumoniae is a major respiratory tract pathogen causing high levels of mortality and morbidity in infants and the elderly. In spite of the multitude of capsular polysaccharide vaccines used to guard against pneumococcal disease, fatal pneumococcal disease remains epidemic. Immunization with pneumococcal surface protein A (PspA), a highly immunogenic surface protein present in all strains of S. pneumoniae, can elicit protection against deadly pneumococcal infection. We have previously evaluated PspA in systemic vaccination. However, the mucosal immune system, as a first line of defense against respiratory infection, plays the most important role against the invasion of S. pneumoniae. In this study, we employed bacterium-like particles (BLPs) as an adjuvant for a PspA mucosal vaccine. The BLPs served as a carrier for PspA proteins bound to their surface. Mice were immunized intranasally with the PspA-BLP pneumococcal vaccine consisting of PspA3 from pneumococcal family 2. Not only did the immunized mice show a high level of serum IgG antibodies but also a high level of SIgA antibodies in the respiratory tract. After immunization with the PspA3-BLP vaccine, the mice were broadly protected against fatal intranasal challenge with homologous and heterogenous pneumococcal strains of different PspA families regardless of serotype, and the colony count was notably decreased in the lungs. Therefore, the PspA3-BLP pneumococcal vaccine has the potential to serve as a novel mucosal vaccine to enhance both systemic and mucosal immune responses to this disease.


Assuntos
Anticorpos Antibacterianos/sangue , Proteínas de Bactérias/imunologia , Vacinas Pneumocócicas/imunologia , Pneumonia Pneumocócica/imunologia , Pneumonia Pneumocócica/prevenção & controle , Streptococcus pneumoniae/imunologia , Adjuvantes Imunológicos/administração & dosagem , Administração Intranasal , Animais , Carga Bacteriana/imunologia , Proteínas de Bactérias/administração & dosagem , Proteção Cruzada/imunologia , Imunização/métodos , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Camundongos , Camundongos Endogâmicos BALB C , Vacinas Pneumocócicas/administração & dosagem , Pneumonia Pneumocócica/microbiologia , Sistema Respiratório/imunologia
6.
Crit Care ; 22(1): 105, 2018 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-29679983

RESUMO

BACKGROUND: Rapid and accurate diagnosis of neonatal sepsis is highly warranted because of high associated morbidity and mortality. The aim of this study was to evaluate the performance of a novel multiplex PCR assay for diagnosis of late-onset sepsis and to investigate the value of bacterial DNA load (BDL) determination as a measure of infection severity. METHODS: This cross-sectional study was conducted in a neonatal intensive care unit. Preterm and/or very low birth weight infants suspected for late-onset sepsis were included. Upon suspicion of sepsis, a whole blood sample was drawn for multiplex PCR to detect the eight most common bacteria causing neonatal sepsis, as well as for blood culture. BDL was determined in episodes with a positive multiplex PCR. RESULTS: In total, 91 episodes of suspected sepsis were investigated, and PCR was positive in 53 (58%) and blood culture in 60 (66%) episodes, yielding no significant difference in detection rate (p = 0.17). Multiplex PCR showed a sensitivity of 77%, specificity of 81%, positive predictive value of 87%, and negative predictive value of 68% compared with blood culture. Episodes with discordant results of PCR and blood culture included mainly detection of coagulase-negative staphylococci (CoNS). C-reactive protein (CRP) level and immature to total neutrophil (I/T) ratio were lower in these episodes, indicating less severe disease or even contamination. Median BDL was high (4.1 log10 cfu Eq/ml) with a wide range, and was it higher in episodes with a positive blood culture than in those with a negative blood culture (4.5 versus 2.5 log10 cfu Eq/ml; p < 0.0001). For CoNS infection episodes BDL and CRP were positively associated (p = 0.004), and for Staphylococcus aureus infection episodes there was a positive association between BDL and I/T ratio (p = 0.049). CONCLUSIONS: Multiplex PCR provides a powerful assay to enhance rapid identification of the causative pathogen in late-onset sepsis. BDL measurement may be a useful indicator of severity of infection.


Assuntos
DNA Bacteriano/análise , Sepse/diagnóstico , Carga Bacteriana/imunologia , Carga Bacteriana/métodos , Hemocultura/métodos , Estudos Transversais , DNA Bacteriano/genética , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Recém-Nascido Prematuro/sangue , Recém-Nascido Prematuro/fisiologia , Unidades de Terapia Intensiva Neonatal/organização & administração , Tempo de Internação/estatística & dados numéricos , Masculino , Países Baixos , Reação em Cadeia da Polimerase em Tempo Real/métodos
7.
J Theor Biol ; 447: 25-31, 2018 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-29555432

RESUMO

Predators may be limited in their ability to kill prey (i.e., have type II or III functional responses), an insight that has had far-reaching consequences in the ecological literature. With few exceptions, however, this possibility has not been extended to the behaviour of immune cells, which kill pathogens much as predators kill their prey. Rather, models of the within-host environment have tended to tacitly assume that immune cells have an unlimited ability to target and kill pathogens (i.e., a type I functional response). Here we explore the effects of changing this assumption on infection outcomes (i.e., pathogen loads). We incorporate immune cell handling time into an ecological model of the within-host environment that considers both the predatory nature of the pathogen-immune cell interaction as well as competition between immune cells and pathogens for host resources. Unless pathogens can preempt immune cells for host resources, adding an immune cell handling time increases equilibrium pathogen load. We find that the shape of the relationship between energy intake and pathogen load can change: with a type I functional response, pathogen load is maximised at intermediate inputs, while for a type II or III functional response, pathogen load is solely increasing. With a type II functional response, pathogen load can fluctuate rather than settling to an equilibrium, a phenomenon unobserved with type I or III functional responses. Our work adds to a growing literature highlighting the role of resource availability in host-parasite interactions. Implications of our results for adaptive anorexia are discussed.


Assuntos
Interações Hospedeiro-Patógeno/imunologia , Sistema Imunitário/citologia , Modelos Biológicos , Modelos Teóricos , Animais , Anorexia , Carga Bacteriana/imunologia , Humanos , Sistema Imunitário/fisiologia , Fatores de Tempo , Carga Viral/imunologia
8.
JCI Insight ; 3(3)2018 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-29415887

RESUMO

Neutrophils dominate the early immune response in pathogen-induced acute lung injury, but efforts to harness their responses have not led to therapeutic advancements. Neutrophil extracellular traps (NETs) have been proposed as an innate defense mechanism responsible for pathogen clearance, but there are concerns that NETs may induce collateral damage to host tissues. Here, we detected NETs in abundance in mouse models of severe bacterial pneumonia/acute lung injury and in human subjects with acute respiratory distress syndrome (ARDS) from pneumonia or sepsis. Decreasing NETs reduced lung injury and improved survival after DNase I treatment or with partial protein arginine deiminase 4 deficiency (PAD4+/-). Complete PAD4 deficiency (PAD4-/-) reduced NETs and lung injury but was counterbalanced by increased bacterial load and inflammation. Importantly, we discovered that the lipoxin pathway could be a potent modulator of NET formation, and that mice deficient in the lipoxin receptor (Fpr2-/-) produced excess NETs leading to increased lung injury and mortality. Lastly, we observed in humans that increased plasma NETs were associated with ARDS severity and mortality, and lower plasma DNase I levels were associated with the development of sepsis-induced ARDS. We conclude that a critical balance of NETs is necessary to prevent lung injury and to maintain microbial control, which has important therapeutic implications.


Assuntos
Armadilhas Extracelulares/imunologia , Lesão Pulmonar/imunologia , Pneumonia Bacteriana/imunologia , Síndrome do Desconforto Respiratório do Adulto/imunologia , Sepse/imunologia , Animais , Bactérias/imunologia , Carga Bacteriana/efeitos dos fármacos , Carga Bacteriana/imunologia , Desoxirribonuclease I/administração & dosagem , Modelos Animais de Doenças , Armadilhas Extracelulares/efeitos dos fármacos , Armadilhas Extracelulares/metabolismo , Humanos , Hidrolases/genética , Hidrolases/metabolismo , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/microbiologia , Lesão Pulmonar/mortalidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Pneumonia Bacteriana/microbiologia , Receptores de Formil Peptídeo/genética , Receptores de Formil Peptídeo/imunologia , Receptores de Formil Peptídeo/metabolismo , Síndrome do Desconforto Respiratório do Adulto/microbiologia , Sepse/microbiologia
9.
Eur J Immunol ; 48(3): 454-463, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29168180

RESUMO

Staphylococcus aureus is the main pathogen associated with septic arthritis. Upon infection, neutrophils are quickly recruited to the joint by different chemoattractants, especially CXCR1/2 binding chemokines. Although their excessive accumulation is associated with intense pain and permanent articular damage, neutrophils have an important function in controlling bacterial burden. This work aimed to study the role of CXCR2 in the control of infection, hypernociception and tissue damage in S. aureus-induced septic arthritis in mice. The kinetics of neutrophil recruitment correlated with the bacterial load recovered from inflamed joint after intra-articular injection of S. aureus. Treatment of mice from the start of infection with the non-competitive antagonist of CXCR1/2, DF2156A, reduced neutrophil accumulation, cytokine production in the tissue, joint hypernociception and articular damage. However, early DF2156A treatment increased the bacterial load locally. CXCR2 was important for neutrophil activation and clearance of bacteria in vitro and in vivo. Start of treatment with DF2156A 3 days after infection prevented increase in bacterial load and reduced the hypernociception in the following days, but did not improve tissue damage. In conclusion, treatment with DF2156A seems be effective in controlling tissue inflammation and dysfunction but its effects are highly dependent on the timing of the treatment start.


Assuntos
Artrite Experimental/etiologia , Artrite Experimental/imunologia , Artrite Infecciosa/etiologia , Artrite Infecciosa/imunologia , Receptores de Interleucina-8B/imunologia , Infecções Estafilocócicas/complicações , Infecções Estafilocócicas/imunologia , Animais , Artrite Experimental/patologia , Artrite Infecciosa/patologia , Carga Bacteriana/efeitos dos fármacos , Carga Bacteriana/imunologia , Articulações/efeitos dos fármacos , Articulações/patologia , Articulações/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ativação de Neutrófilo/efeitos dos fármacos , Dor/tratamento farmacológico , Dor/imunologia , Dor/fisiopatologia , Receptores de Interleucina-8A/antagonistas & inibidores , Receptores de Interleucina-8A/imunologia , Receptores de Interleucina-8B/antagonistas & inibidores , Infecções Estafilocócicas/patologia , Staphylococcus aureus/imunologia , Staphylococcus aureus/patogenicidade , Sulfonamidas/farmacologia
10.
Nat Commun ; 8(1): 1576, 2017 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-29146903

RESUMO

Dysregulation of autophagy and inflammasome activity contributes to the development of auto-inflammatory diseases. Emerging evidence highlights the importance of the actin cytoskeleton in modulating inflammatory responses. Here we show that deficiency of Wiskott-Aldrich syndrome protein (WASp), which signals to the actin cytoskeleton, modulates autophagy and inflammasome function. In a model of sterile inflammation utilizing TLR4 ligation followed by ATP or nigericin treatment, inflammasome activation is enhanced in monocytes from WAS patients and in WAS-knockout mouse dendritic cells. In ex vivo models of enteropathogenic Escherichia coli and Shigella flexneri infection, WASp deficiency causes defective bacterial clearance, excessive inflammasome activation and host cell death that are associated with dysregulated septin cage-like formation, impaired autophagic p62/LC3 recruitment and defective formation of canonical autophagosomes. Taken together, we propose that dysregulation of autophagy and inflammasome activities contribute to the autoinflammatory manifestations of WAS, thereby identifying potential targets for therapeutic intervention.


Assuntos
Citoesqueleto de Actina/metabolismo , Autofagia/imunologia , Inflamassomos/imunologia , Proteína da Síndrome de Wiskott-Aldrich/genética , Proteína da Síndrome de Wiskott-Aldrich/metabolismo , Síndrome de Wiskott-Aldrich/imunologia , Animais , Autofagia/genética , Carga Bacteriana/imunologia , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Escherichia coli Enteropatogênica/imunologia , Humanos , Imunidade Inata/imunologia , Interferon Tipo I/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Nigericina/farmacologia , Septinas/metabolismo , Shigella flexneri/imunologia , Células THP-1 , Receptor 4 Toll-Like/imunologia , Síndrome de Wiskott-Aldrich/metabolismo
11.
Microbiol Immunol ; 61(9): 371-379, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28752940

RESUMO

Bordetella pertussis causes whooping cough, a severe and prolonged respiratory disease that results inhas high morbidity and mortality rates, particularly in developing countries. The number incidence of whooping cough cases is increasing in many countries despite high vaccine coverage. Causes for the re-emergence of the disease include the limited duration of protection conferred by the acellular pertussis vaccines (aP)s and pathogenic adaptations that involve antigenic divergence from vaccine strains. Therefore, current vaccines therefore need to be improved. In the present study, we focused on five autotransporters: namely SphB1, BatB, SphB2, Phg, and Vag8, which were previously found to be expressed by B. bronchiseptica during the course of infection in rats and examined their protective efficiencies as vaccine antigens. The passenger domains of these proteins were produced in recombinant forms and used as antigens. An intranasal murine challenge assay showed that immunization with a mixture of SphB1 and Vag8 (SV) significantly reduced bacterial load in the lower respiratory tract and a combination of aP and SV acts synergistically in effects of conferring protection against B. pertussis infection, implying that these antigens have potential as components to for improvinge th the currently available acellular pertussis vaccine.


Assuntos
Antígenos de Bactérias/imunologia , Bordetella pertussis/imunologia , Vacina contra Coqueluche/imunologia , Sistemas de Secreção Tipo V/imunologia , Coqueluche/prevenção & controle , Animais , Anticorpos Antibacterianos/imunologia , Variação Antigênica/imunologia , Carga Bacteriana/imunologia , Proteínas de Bactérias/imunologia , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Sistema Respiratório/imunologia , Sistema Respiratório/microbiologia , Serina Endopeptidases/imunologia , Vacinação , Coqueluche/imunologia , Coqueluche/microbiologia
12.
Sci Rep ; 7: 41240, 2017 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-28128217

RESUMO

The protective effects of mycobacterial infections on lung allergy are well documented. However, the inverse relationship between tuberculosis and type 2 immunity is still elusive. Although type 1 immunity is essential to protection against Mycobacterium tuberculosis it might be also detrimental to the host due to the induction of extensive tissue damage. Here, we determined whether lung type 2 immunity induced by allergen sensitization and challenge could affect the outcome of M. tuberculosis infection. We used two different protocols in which sensitization and allergen challenge were performed before or after M. tuberculosis infection. We found an increased resistance to M. tuberculosis only when allergen exposure was given after, but not before infection. Infected mice exposed to allergen exhibited lower bacterial load and cellular infiltrates in the lungs. Enhanced resistance to infection after allergen challenge was associated with increased gene expression of alternatively activated macrophages (M2 macrophages) and IL-33 levels. Accordingly, either adoptive transfer of M2 macrophages or systemic IL-33 treatment was effective in attenuating M. tuberculosis infection. Notably, the enhanced resistance induced by allergen exposure was dependent on IL-33 receptor ST2. Our work indicates that IL-33 might be an alternative therapeutic treatment for severe tuberculosis.


Assuntos
Interleucina-33/imunologia , Pulmão/imunologia , Tuberculose Pulmonar/imunologia , Tuberculose/imunologia , Alérgenos/imunologia , Alérgenos/toxicidade , Animais , Carga Bacteriana/imunologia , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1/imunologia , Interleucina-33/genética , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/patogenicidade , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Tuberculose/genética , Tuberculose/microbiologia , Tuberculose/patologia , Tuberculose Pulmonar/genética , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologia
13.
Tuberculosis (Edinb) ; 102: 34-46, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-28061951

RESUMO

Despite international control programmes, the global burden of tuberculosis remains enormous. Efforts to discover novel drugs have largely focused on targeting the bacterium directly. Alternatively, manipulating the host immune response may represent a valuable approach to enhance immunological clearance of the bacilli, but necessitates a deeper understanding of the immune mechanisms associated with protection against Mycobacterium tuberculosis infection. Here, we examined the various dendritic cells (DC) subsets present in the lung and draining lymph nodes (LN) from mice intra-tracheally infected with M. tuberculosis. We showed that although limited in number, pulmonary CD103+ DCs appeared to be involved in the initial transport of mycobacteria to the draining mediastinal LN and subsequent activation of T cells. Using CLEC9A-DTR transgenic mice enabling the inducible depletion of CD103+ DCs, we established that this DC subset contributes to the control of mycobacterial burden and plays a role in the early activation of T cells, in particular CD8+ T cells. Our findings thus support a previously unidentified role for pulmonary CD103+ DCs in the rapid mobilization of mycobacteria from the lungs to the draining LN soon after exposure to M. tuberculosis, which is a critical step for the development of the host adaptive immune response.


Assuntos
Antígenos CD/imunologia , Células Dendríticas/imunologia , Cadeias alfa de Integrinas/imunologia , Pulmão/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Animais , Carga Bacteriana/imunologia , Linfócitos T CD8-Positivos/imunologia , Citocinas/biossíntese , Pulmão/microbiologia , Linfonodos/imunologia , Linfonodos/microbiologia , Ativação Linfocitária/imunologia , Mediastino , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Mycobacterium tuberculosis/isolamento & purificação , Células Th1/imunologia
14.
Vaccine ; 35(6): 945-950, 2017 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-28087146

RESUMO

BACKGROUND: In addition to reducing vaccine-type nasopharyngeal carriage rates, pneumococcal conjugate vaccines (PCVs) may decrease carriage density in vaccinated individuals still carrying vaccine serotypes. However, reduction of carriage density has not been systematically studied. This study compared the effect of PCV13 versus PCV7 on carriage density of the serotypes in PCV13 that are not included in PCV7. METHODS: This randomized, double-blind study was conducted in southern Israel and included Jewish and Bedouin subjects. Per protocol, 881 and 873 infants received PCV13 and PCV7, respectively, at ages 2, 4, 6, and 12months. Nasopharyngeal cultures at ages 7, 12, 13, 18, and 24months were plated using the 4-quadrant semiquantitative method and graded 0 (negative) to 4 (growth in all plate quadrants). In this post hoc analysis, the least squares means of cumulative colonization densities per serotype and serotype combination of the total population and each ethnic subpopulation in each vaccine group were calculated, and differences between vaccine groups derived from a linear model. RESULTS: PCV13-vaccinated children still carrying the 6 additional PCV13 serotypes unique to PCV13 showed no significant differences in carriage density compared with the PCV7-vaccinated control group. No differences in carriage density were shown between Jewish and Bedouin subpopulations despite higher carriage rates among Bedouin subjects. CONCLUSIONS: Although PCV13 vaccination reduces vaccine-type carriage compared with PCV7 vaccination by reducing nasopharyngeal acquisition of the additional PCV13 serotypes as previously reported, the current study lacks evidence of a decrease in carriage density of these serotypes when acquired in vaccinated children. Despite the lack of effect on carriage density observed, surveillance data suggest a dramatic decrease in disease rates after PCV implementation. Thus, the current analysis suggests that PCV's impact on carriage density has minimal or no impact on vaccine success. (www.ClinicalTrials.gov: NCT00508742).


Assuntos
Portador Sadio/imunologia , Vacina Pneumocócica Conjugada Heptavalente/administração & dosagem , Vacinas Pneumocócicas/administração & dosagem , Pneumonia Pneumocócica/prevenção & controle , Streptococcus pneumoniae/efeitos dos fármacos , Árabes , Carga Bacteriana/imunologia , Portador Sadio/microbiologia , Pré-Escolar , Método Duplo-Cego , Feminino , Humanos , Lactente , Judeus , Masculino , Nasofaringe/imunologia , Nasofaringe/microbiologia , Pneumonia Pneumocócica/etnologia , Pneumonia Pneumocócica/imunologia , Pneumonia Pneumocócica/microbiologia , Sorogrupo , Streptococcus pneumoniae/classificação , Streptococcus pneumoniae/crescimento & desenvolvimento , Streptococcus pneumoniae/imunologia , Vacinas Conjugadas
15.
Trends Immunol ; 37(12): 815-818, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27773684

RESUMO

Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) and provided original proof that an infectious agent can cause human disease. However, key steps in TB pathogenesis remain poorly understood. We propose that autoimmunity is a critical and overlooked process driving pathology in TB, and present clinical and experimental observations supporting this hypothesis.


Assuntos
Doenças Autoimunes/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Animais , Autoimunidade , Carga Bacteriana/imunologia , Humanos , Hospedeiro Imunocomprometido , Controle de Infecções , Camundongos , Tuberculose/transmissão
16.
Genet Mol Res ; 15(3)2016 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-27706786

RESUMO

Nontuberculous mycobacteria are ubiquitous in outside environment and animals. As for nontuberculous mycobacteria infection, there is only limited information in humans regarding infection and the subsequent immune response, especially for Mycobacterium neoaurum. Here, haematoxylin-eosin and Ziehl-Neelsen staining were used to observe pathological changes and detect acid-fast bacilli in organ samples in mouse model. Flow cytometry and quantitative real-time polymerase chain reaction were performed to analyze the contribution of Th1, Th17 and Tregs to the host immune response. M. neoaurum caused chronic infection in mice, resulting in infiltrates with large aggregates of inflammatory cells, especially macrophages, in lung tissues. Our results indicated that 72% of CD4+ T cells appeared in the early days of infection, which was followed by a decrease to 47% by day 32, and then a rise to 76% by day 56. Moreover, we found higher frequency of IFN-g-producing CD4+ T cells and elevated mRNA expression of the transcription factor T-bet in the lungs; however, we observed lower mRNA expression of the transcription factor RORgt and lower frequency of IL-17-producing CD4+ T cells. A transient relative decrease in the number of Treg cells was observed in the lungs; however, the number of Tregs did not change significantly between the first and last day following infection. Thus, M. neoaurum causes chronic infection in C57BL/6 mice, with Th1, Th17, and Tregs playing a prominent role in the host response. The present study may lay the basis for further studies on the mechanisms underlying infection with nontuberculous mycobacteria.


Assuntos
Interações Hospedeiro-Patógeno/imunologia , Infecções por Mycobacterium/imunologia , Infecções por Mycobacterium/microbiologia , Mycobacterium/imunologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th17/imunologia , Imunidade Adaptativa , Animais , Carga Bacteriana/imunologia , Contagem de Colônia Microbiana , Feminino , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Pulmão/metabolismo , Pulmão/microbiologia , Pulmão/patologia , Subpopulações de Linfócitos/imunologia , Camundongos Endogâmicos C57BL , Mycobacterium/crescimento & desenvolvimento , Infecções por Mycobacterium/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
17.
PLoS One ; 11(6): e0158020, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27322540

RESUMO

BACKGROUND: Human Campylobacter jejuni infections are progressively rising worldwide. Information about the molecular mechanisms underlying campylobacteriosis, however, are limited. In the present study we investigated whether cytokines such as IL-23, IL-22 and IL-18, which share pivotal functions in host immunity, were involved in mediating intestinal and systemic immunopathological responses upon C. jejuni infection. METHODOLOGY/PRINCIPAL FINDINGS: To assure stable infection, gnotobiotic (i.e. secondary abiotic) IL-23p19-/-, IL-22-/- and IL-18-/- mice were generated by broad-spectrum antibiotic treatment. Following peroral C. jejuni strain 81-176 infection, mice of all genotypes harbored comparably high pathogenic loads in their intestines. As compared to wildtype controls, however, IL-18-/- mice displayed less distinct C. jejuni induced sequelae as indicated by less pronounced large intestinal shrinkage and lower numbers of apoptotic cells in the colonic epithelial layer at day 8 postinfection (p.i.). Furthermore, lower colonic numbers of adaptive immune cells including regulatory T cells and B lymphocytes were accompanied by less distinct secretion of pro-inflammatory cytokines such as TNF and IFN-γ and lower IL-17A mRNA expression levels in colonic ex vivo biopsies of infected IL-18-/- as compared to wildtype mice. Upon C. jejuni infection, colonic IL-23p19 expression was up-regulated in IL-18-/- mice only, whereas IL-22 mRNA levels were lower in uninfected and infected IL-23p19-/- as well as infected IL-18-/- as compared to respective wildtype control mice. Remarkably, not only intestinal, but also systemic infection-induced immune responses were less pronounced in IL-18-/- mice as indicated by lower TNF, IFN-γ and IL-6 serum levels as compared to wildtype mice. CONCLUSION/SIGNIFICANCE: We here show for the first time that IL-18 is essentially involved in mediating C. jejuni infection in the gnotobiotic mouse model. Future studies need to further unravel the underlying regulatory mechanisms orchestrating pathogen-host interaction.


Assuntos
Infecções por Campylobacter/imunologia , Campylobacter jejuni/imunologia , Vida Livre de Germes/imunologia , Interleucina-18/metabolismo , Animais , Apoptose , Carga Bacteriana/imunologia , Translocação Bacteriana , Biópsia , Infecções por Campylobacter/genética , Infecções por Campylobacter/patologia , Campylobacter jejuni/crescimento & desenvolvimento , Proliferação de Células , Contagem de Colônia Microbiana , Feminino , Regulação da Expressão Gênica , Mediadores da Inflamação/metabolismo , Interleucina-17/genética , Interleucina-17/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Subunidade p19 da Interleucina-23/metabolismo , Interleucinas/metabolismo , Mucosa Intestinal/patologia , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
18.
Microbiologyopen ; 5(3): 436-52, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26919641

RESUMO

Mitogen-activated protein kinases (MAPK) are critical mediators of cellular responses to pathogens and are activated in response to infection, but investigation is difficult in multi-cell hosts due to developmental lethality of mutations. Mycobacterium marinum (Mm) is an established model for tuberculosis, a disease afflicting nearly one-third of the world's population. We found that Mm-infected Caenorhabditis elegans display >80% mortality, but nonpathogenic M. smegmatis cause <15% mortality. C. elegans display pathological changes when infected with Mm, whereas Mm mutants produce lower mortality, suggesting that C. elegans is a promising virulence model for detailed genetic analysis. C. elegans MAPK mutants are hypersusceptible to mycobacterial infection; however, the C. elegans TOL-like, TGF-ß and insulin-like pathway genes do not play important roles in susceptibility. We show that pathogenic mycobacteria inhibit MAPK-mediated protection through the MAPK phosphatase gene and demonstrate that C. elegans provide a genetically tractable pathogenicity model of both the host and pathogen.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/imunologia , Caenorhabditis elegans/microbiologia , Fosfatases de Especificidade Dupla/genética , Proteínas Quinases Ativadas por Mitógeno/genética , Mycobacterium marinum/patogenicidade , Mycobacterium smegmatis/patogenicidade , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Animais , Carga Bacteriana/imunologia , Caenorhabditis elegans/genética , Proteínas de Ligação a DNA/genética , Fatores de Transcrição Forkhead/genética , Intestinos/imunologia , Intestinos/microbiologia , Mycobacterium marinum/imunologia , Mycobacterium smegmatis/imunologia , Proteínas do Tecido Nervoso/genética , Neuropeptídeos/genética , Interferência de RNA , RNA Interferente Pequeno/genética , Fatores de Transcrição/genética , Fator de Crescimento Transformador beta/genética
19.
Artigo em Inglês | MEDLINE | ID: mdl-26858942

RESUMO

Mycobacterium bovis bacillus Calmette-Guérin (BCG) is currently the only vaccine available for preventing tuberculosis (TB), however, BCG has varying success in preventing pulmonary TB. In this study, a recombinant BCG (rBCG::Ag85A) strain overexpressing the immunodominant Ag85A antigen was constructed, and its immunogenicity and protective efficacy were evaluated. Our results indicated that the Ag85A protein was successfully overexpressed in rBCG::Ag85A, and the Ag85A peptide-MHC complexes on draining lymph node dendritic cells of C57BL/6 mice infected with rBCG::Ag85A were detectable 4 h post-infection. The C57BL/6 mice infected with this strain had stronger antigen-specific interferon-gamma (IFN-γ) responses and higher antibody titers than those immunized with BCG, and the protective experiments showed that rBCG::Ag85A can enhance protection against Mycobacterium tuberculosis (M. tuberculosis) H37Rv infection compared to the BCG vaccine alone. Our results demonstrate the potential of rBCG::Ag85A as a candidate vaccine against TB.


Assuntos
Aciltransferases/imunologia , Anticorpos Antibacterianos/imunologia , Antígenos de Bactérias/imunologia , Vacina BCG/imunologia , Mycobacterium bovis/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Aciltransferases/genética , Animais , Antígenos de Bactérias/genética , Carga Bacteriana/imunologia , Células Dendríticas/imunologia , Feminino , Interferon gama/imunologia , Pulmão/microbiologia , Linfonodos/citologia , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Recombinantes/imunologia , Baço/microbiologia , Células Th1/imunologia , Tuberculose/prevenção & controle , Vacinação , Vacinas Sintéticas/imunologia
20.
Pathog Dis ; 74(3)2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26903072

RESUMO

Necrotizing granulomas, exacerbating pathogenesis and neutrophil influx at the site of infection are hallmarks of active pulmonary tuberculosis (TB) in humans. The role of polymorphonuclear neutrophils (PMN) in host defence and TB pathogenesis has recently attracted broader interest. Association of infiltrating PMN, enhanced mycobacterial load and disease exacerbation in both, mice susceptible to experimental TB as well as in TB patients, link PMN to exacerbated pathology. Targeting PMN resulted in smaller lung lesions and reduced mycobacterial burden. Therefore, PMN-associated molecules represent interesting biomarkers to determine TB severity and treatment success. More importantly, PMN are putative targets for host-directed therapies (HDT) in TB. Due to the rise of multi- and extensively drug-resistant Mycobacterium tuberculosis isolates, HDT represent adjunct measures to support antibiotic treatment by ameliorating pathology and local host defences.


Assuntos
Mycobacterium tuberculosis/imunologia , Neutrófilos/imunologia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/terapia , Animais , Carga Bacteriana/imunologia , Citocinas/imunologia , Humanos , Inflamação/imunologia , Inflamação/microbiologia , Camundongos , Tuberculose Pulmonar/microbiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA