Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.155
Filtrar
1.
J Leukoc Biol ; 112(3): 499-512, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35435271

RESUMO

Clearance of airway intruders by immune cells is required to resolve infectious pneumonia. However, the molecular mechanisms underlying this process remain elusive. Here, we demonstrated that alveolar macrophage (AM)-derived neuropilin 2 (NRP2) plays an essential role in controlling severe pneumonia by enhancing microbial clearance. Mice with conditional deletion of the NRP2 gene in AM had persistent bacteria, uncontrolled neutrophil influx, and decreased survival during Escherichia coli-induced pneumonia. In vitro assays demonstrated that NRP2 could bind to CD11b+ Ly6Glo/+ neutrophils and promote their capacities in phagocytosis and killing of bacteria, which is partially contributed to the increased expression of TLR4 and TNF-a. These findings collectively revealed that AM-derived NRP2 protects the lungs from unwanted injury by promoting the clearance of invading pathogens. This study might provide a promising diagnostic biomarker and therapeutic target for severe pneumonia.


Assuntos
Infecções por Escherichia coli , Macrófagos Alveolares , Neuropilina-2 , Pneumonia Bacteriana , Animais , Infecções por Escherichia coli/imunologia , Pulmão , Lesão Pulmonar , Macrófagos Alveolares/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Neuropilina-2/metabolismo , Neutrófilos , Fagocitose , Pneumonia Bacteriana/imunologia
2.
Viruses ; 14(2)2022 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-35215805

RESUMO

The increased plasma levels of von Willebrand factor (VWF) in patients with COVID-19 was reported in many studies, and its correlation with disease severity and mortality suggest its important role in the pathogenesis of thrombosis in COVID-19. We performed histological and immunohistochemical studies of the lungs of 29 patients who died from COVID-19. We found a significant increase in the intensity of immunohistochemical reaction for VWF in the pulmonary vascular endothelium when the disease duration was more than 10 days. In the patients who had thrombotic complications, the VWF immunostaining in the pulmonary vascular endothelium was significantly more intense than in nonsurvivors without thrombotic complications. Duration of disease and thrombotic complications were found to be independent predictors of increased VWF immunostaining in the endothelium of pulmonary vessels. We also revealed that bacterial pneumonia was associated with increased VWF staining intensity in pulmonary arterial, arteriolar, and venular endothelium, while lung ventilation was an independent predictor of increased VWF immunostaining in arterial endothelium. The results of the study demonstrated an important role of endothelial VWF in the pathogenesis of thrombus formation in COVID-19.


Assuntos
COVID-19/complicações , Pulmão/irrigação sanguínea , Trombose Venosa/etiologia , Trombose Venosa/patologia , Fator de von Willebrand/análise , Adulto , Autopsia , COVID-19/sangue , Endotélio Vascular/imunologia , Feminino , Humanos , Imuno-Histoquímica/métodos , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Pneumonia Bacteriana/imunologia , Embolia Pulmonar , Índice de Gravidade de Doença , Trombose Venosa/classificação
3.
PLoS One ; 17(1): e0261750, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34986178

RESUMO

BACKGROUND: In the nation-wide double-blind cluster-randomised Finnish Invasive Pneumococcal disease trial (FinIP, ClinicalTrials.gov NCT00861380, NCT00839254), we assessed the indirect impact of the 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) against five pneumococcal disease syndromes. METHODS: Children 6 weeks to 18 months received PHiD-CV10 in 48 clusters or hepatitis B/A-vaccine as control in 24 clusters according to infant 3+1/2+1 or catch-up schedules in years 2009-2011. Outcome data were collected from national health registers and included laboratory-confirmed and clinically suspected invasive pneumococcal disease (IPD), hospital-diagnosed pneumonia, tympanostomy tube placements (TTP) and outpatient antimicrobial prescriptions. Incidence rates in the unvaccinated population in years 2010-2015 were compared between PHiD-CV10 and control clusters in age groups <5 and ≥5 years (5-7 years for TTP and outpatient antimicrobial prescriptions), and in infants <3 months. PHiD-CV10 was introduced into the Finnish National Vaccination Programme (PCV-NVP) for 3-month-old infants without catch-up in 9/2010. RESULTS: From 2/2009 to 10/2010, 45398 children were enrolled. Vaccination coverage varied from 29 to 61% in PHiD-CV10 clusters. We detected no clear differences in the incidence rates between the unvaccinated cohorts of the treatment arms, except in single years. For example, the rates of vaccine-type IPD, non-laboratory-confirmed IPD and empyema were lower in PHiD-CV10 clusters compared to control clusters in 2012, 2015 and 2011, respectively, in the age-group ≥5 years. CONCLUSIONS: This is the first report from a clinical trial evaluating the indirect impact of a PCV against clinical outcomes in an unvaccinated population. We did not observe consistent indirect effects in the PHiD-CV10 clusters compared to the control clusters. We consider that the sub-optimal trial vaccination coverage did not allow the development of detectable indirect effects and that the supervening PCV-NVP significantly diminished the differences in PHiD-CV10 vaccination coverage between the treatment arms.


Assuntos
Proteínas de Bactérias/administração & dosagem , Proteínas de Transporte/administração & dosagem , Infecções por Haemophilus/prevenção & controle , Vacinas Anti-Haemophilus/administração & dosagem , Haemophilus influenzae/imunologia , Imunoglobulina D/administração & dosagem , Lipoproteínas/administração & dosagem , Vacinas Pneumocócicas/administração & dosagem , Pneumonia Bacteriana/prevenção & controle , Proteínas de Bactérias/efeitos adversos , Proteínas de Bactérias/imunologia , Proteínas de Transporte/efeitos adversos , Proteínas de Transporte/imunologia , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Infecções por Haemophilus/imunologia , Vacinas Anti-Haemophilus/efeitos adversos , Vacinas Anti-Haemophilus/imunologia , Humanos , Imunoglobulina D/efeitos adversos , Imunoglobulina D/imunologia , Lactente , Lipoproteínas/efeitos adversos , Lipoproteínas/imunologia , Masculino , Vacinas Pneumocócicas/efeitos adversos , Vacinas Pneumocócicas/imunologia , Pneumonia Bacteriana/imunologia , Vacinas Conjugadas/administração & dosagem , Vacinas Conjugadas/efeitos adversos , Vacinas Conjugadas/imunologia
4.
Nat Med ; 28(1): 201-211, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34782790

RESUMO

Although critical for host defense, innate immune cells are also pathologic drivers of acute respiratory distress syndrome (ARDS). Innate immune dynamics during Coronavirus Disease 2019 (COVID-19) ARDS, compared to ARDS from other respiratory pathogens, is unclear. Moreover, mechanisms underlying the beneficial effects of dexamethasone during severe COVID-19 remain elusive. Using single-cell RNA sequencing and plasma proteomics, we discovered that, compared to bacterial ARDS, COVID-19 was associated with expansion of distinct neutrophil states characterized by interferon (IFN) and prostaglandin signaling. Dexamethasone during severe COVID-19 affected circulating neutrophils, altered IFNactive neutrophils, downregulated interferon-stimulated genes and activated IL-1R2+ neutrophils. Dexamethasone also expanded immunosuppressive immature neutrophils and remodeled cellular interactions by changing neutrophils from information receivers into information providers. Male patients had higher proportions of IFNactive neutrophils and preferential steroid-induced immature neutrophil expansion, potentially affecting outcomes. Our single-cell atlas (see 'Data availability' section) defines COVID-19-enriched neutrophil states and molecular mechanisms of dexamethasone action to develop targeted immunotherapies for severe COVID-19.


Assuntos
COVID-19/imunologia , Citocinas/imunologia , Dexametasona/uso terapêutico , Glucocorticoides/uso terapêutico , Neutrófilos/imunologia , Pneumonia Bacteriana/imunologia , Síndrome do Desconforto Respiratório/imunologia , Adulto , Idoso , COVID-19/complicações , COVID-19/genética , Comunicação Celular , Cromatografia Líquida , Regulação para Baixo , Feminino , Redes Reguladoras de Genes , Humanos , Imunidade Inata/imunologia , Interferons/imunologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Pneumonia Bacteriana/complicações , Pneumonia Bacteriana/tratamento farmacológico , Pneumonia Bacteriana/genética , Prostaglandinas/imunologia , Proteômica , RNA-Seq , Síndrome do Desconforto Respiratório/tratamento farmacológico , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/genética , SARS-CoV-2 , Índice de Gravidade de Doença , Fatores Sexuais , Análise de Célula Única , Espectrometria de Massas em Tandem
5.
JCI Insight ; 7(2)2022 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-34908534

RESUMO

Acute respiratory distress syndrome (ARDS) is a life-threatening syndrome, constituted by respiratory failure and diffuse alveolar damage that results from dysregulated local and systemic immune activation, causing pulmonary vascular, parenchymal, and alveolar damage. SARS-CoV-2 infection has become the dominant cause of ARDS worldwide, and emerging evidence implicates neutrophils and their cytotoxic arsenal of effector functions as central drivers of immune-mediated lung injury in COVID-19 ARDS. However, key outstanding questions are whether COVID-19 drives a unique program of neutrophil activation or effector functions that contribute to the severe pathogenesis of this pandemic illness and whether this unique neutrophil response can be targeted to attenuate disease. Using a combination of high-dimensional single-cell analysis and ex vivo functional assays of neutrophils from patients with COVID-19 ARDS, compared with those with non-COVID ARDS (caused by bacterial pneumonia), we identified a functionally distinct landscape of neutrophil activation in COVID-19 ARDS that was intrinsically programmed during SARS-CoV-2 infection. Furthermore, neutrophils in COVID-19 ARDS were functionally primed to produce high amounts of neutrophil extracellular traps. Surprisingly, this unique pathological program of neutrophil priming escaped conventional therapy with dexamethasone, thereby revealing a promising target for adjunctive immunotherapy in severe COVID-19.


Assuntos
COVID-19/imunologia , Armadilhas Extracelulares/imunologia , Ativação de Neutrófilo , Neutrófilos/imunologia , Síndrome do Desconforto Respiratório/imunologia , SARS-CoV-2/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neutrófilos/patologia , Pneumonia Bacteriana/imunologia , Pneumonia Bacteriana/patologia , Síndrome do Desconforto Respiratório/patologia , Índice de Gravidade de Doença
6.
Elife ; 102021 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-34544549

RESUMO

Vaccination strategies for rapid protection against multidrug-resistant bacterial infection are very important, especially for hospitalized patients who have high risk of exposure to these bacteria. However, few such vaccination strategies exist due to a shortage of knowledge supporting their rapid effect. Here, we demonstrated that a single intranasal immunization of inactivated whole cell of Acinetobacter baumannii elicits rapid protection against broad A. baumannii-infected pneumonia via training of innate immune response in Rag1-/- mice. Immunization-trained alveolar macrophages (AMs) showed enhanced TNF-α production upon restimulation. Adoptive transfer of immunization-trained AMs into naive mice mediated rapid protection against infection. Elevated TLR4 expression on vaccination-trained AMs contributed to rapid protection. Moreover, immunization-induced rapid protection was also seen in Pseudomonas aeruginosa and Klebsiella pneumoniae pneumonia models, but not in Staphylococcus aureus and Streptococcus pneumoniae model. Our data reveal that a single intranasal immunization induces rapid and efficient protection against certain Gram-negative bacterial pneumonia via training AMs response, which highlights the importance and the possibility of harnessing trained immunity of AMs to design rapid-effecting vaccine.


Assuntos
Infecções por Acinetobacter/prevenção & controle , Acinetobacter baumannii/imunologia , Vacinas Bacterianas/administração & dosagem , Infecções por Klebsiella/prevenção & controle , Klebsiella pneumoniae/imunologia , Macrófagos Alveolares/efeitos dos fármacos , Pneumonia Bacteriana/prevenção & controle , Infecções por Pseudomonas/prevenção & controle , Pseudomonas aeruginosa/imunologia , Infecções por Acinetobacter/imunologia , Infecções por Acinetobacter/microbiologia , Administração Intranasal , Transferência Adotiva , Animais , Células Cultivadas , Modelos Animais de Doenças , Feminino , Proteínas de Homeodomínio/genética , Imunidade Inata/efeitos dos fármacos , Infecções por Klebsiella/imunologia , Infecções por Klebsiella/microbiologia , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/microbiologia , Macrófagos Alveolares/transplante , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pneumonia Bacteriana/imunologia , Pneumonia Bacteriana/microbiologia , Infecções por Pseudomonas/imunologia , Infecções por Pseudomonas/microbiologia , Fatores de Tempo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Vacinação , Vacinas de Produtos Inativados/administração & dosagem
7.
Viruses ; 13(12)2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34960788

RESUMO

Influenza A viruses (IAVs) are important respiratory pathogens of horses and humans. Infected individuals develop typical respiratory disorders associated with the death of airway epithelial cells (AECs) in infected areas. Virulence and risk of secondary bacterial infections vary among IAV strains. The IAV non-structural proteins, NS1, PB1-F2, and PA-X are important virulence factors controlling AEC death and host immune responses to viral and bacterial infection. Polymorphism in these proteins impacts their function. Evidence from human and mouse studies indicates that upon IAV infection, the manner of AEC death impacts disease severity. Indeed, while apoptosis is considered anti-inflammatory, necrosis is thought to cause pulmonary damage with the release of damage-associated molecular patterns (DAMPs), such as interleukin-33 (IL-33). IL-33 is a potent inflammatory mediator released by necrotic cells, playing a crucial role in anti-viral and anti-bacterial immunity. Here, we discuss studies in human and murine models which investigate how viral determinants and host immune responses control AEC death and subsequent lung IL-33 release, impacting IAV disease severity. Confirming such data in horses and improving our understanding of early immunologic responses initiated by AEC death during IAV infection will better inform the development of novel therapeutic or vaccine strategies designed to protect life-long lung health in horses and humans, following a One Health approach.


Assuntos
Vírus da Influenza A/imunologia , Interleucina-33/imunologia , Infecções por Orthomyxoviridae/imunologia , Animais , Apoptose , Asma , Morte Celular , Células Epiteliais , Cavalos , Humanos , Influenza Humana/virologia , Pulmão/imunologia , Pulmão/virologia , Camundongos , Infecções por Orthomyxoviridae/virologia , Pneumonia Bacteriana/imunologia , Virulência , Fatores de Virulência/metabolismo
8.
Front Immunol ; 12: 761317, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34777376

RESUMO

Pneumonia is a global cause of mortality, and this provides a strong incentive to improve the mechanistic understanding of innate immune responses in the lungs. Here, we characterized the involvement of the cytokine interleukin (IL)-26 in bacterial lung infection. We observed markedly increased concentrations of IL-26 in lower airway samples from patients with bacterial pneumonia and these correlated with blood neutrophil concentrations. Moreover, pathogen-associated molecular patterns (PAMPs) from both Gram-negative and -positive bacteria increased extracellular IL-26 concentrations in conditioned media from human models of alveolar epithelial cells, macrophages, and neutrophils in vitro. Stimulation with IL-26 inhibited the inherent release of neutrophil elastase and myeloperoxidase in unexposed neutrophils. This stimulation also inhibited the expression of activity makers in neutrophils exposed to Klebsiella pneumoniae. In addition, priming of human lung tissue ex vivo with exogenous IL-26 potentiated the endotoxin-induced increase in mRNA for other cytokines involved in the innate immune response, including the master Th17-regulator IL-23 and the archetype inhibitory cytokine IL-10. Finally, neutralization of endogenous IL-26 clearly increased the growth of Klebsiella pneumoniae in the macrophage culture. These findings suggest that IL-26 is involved in bacterial lung infection in a complex manner, by modulating critical aspects of innate immune responses locally and systemically in a seemingly purposeful manner and by contributing to the killing of bacteria in a way that resembles an antimicrobial peptide. Thus, IL-26 displays both diagnostic and therapeutic potential in pneumonia and deserves to be further evaluated in these respects.


Assuntos
Citocinas/imunologia , Pneumonia Bacteriana/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Células Cultivadas , Feminino , Humanos , Klebsiella pneumoniae , Elastase de Leucócito/imunologia , Pulmão/citologia , Pulmão/imunologia , Macrófagos Alveolares/imunologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Peroxidase/imunologia , Adulto Jovem
9.
Iran J Allergy Asthma Immunol ; 20(5): 537-549, 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34664813

RESUMO

Nosocomial infections caused by Acinetobacter baumannii (A. baumannii) nosocomial infections caused by Acinetobacter baumannii (A. baumannii) are considered as a global serious problem in hospitalized patients because of emerging antibiotic resistance. Immunotherapy approaches are promising to prevent such infections. In our previous study, five antigenic epitopes of outer membrane protein A (OmpA), as the most dangerous virulence molecule in A. baumanii, were predicted in silico. In this study, the investigators evaluated some immunological aspects of the peptides. Five peptides were separately injected into C5BL/6 mice; then the cytokine production (interleukin-4 and interferon-gamma) of splenocytes and opsonophagocytic activity of immunized serum were assessed. To identify the protective function of the peptides, animal models of sepsis and pneumonia infections were actively and passively immunized with selected peptides and pooled sera of immunized mice, respectively. Then, survival rates of them were compared with the non-infected controls. Based on the results, activated spleen cells in P127 peptide-immunized mice exhibited an increase level of IFN-γ compared with the other experimental groups, but not about the IL-4 concentration. The results of opsonophagocytic assay revealed an appropriate killing activity of produced antibodies against A. baumannii in a dose-dependent manner. Further, the survival rates of the mice under passive immunization with the immunized sera or active immunization with P127 peptide were significantly more than those in the control group. Moreover, the survival rate of the P127 peptide immunized group was considerably higher than that among the other peptide-immunized group. In conclusion, findings indicated that peptides derived from outer membrane protein-A can be used as a promising tool for designing the epitope-based vaccines against infections caused by A. baumannii.


Assuntos
Infecções por Acinetobacter/prevenção & controle , Acinetobacter baumannii/imunologia , Proteínas da Membrana Bacteriana Externa/imunologia , Vacinas Bacterianas/imunologia , Epitopos/imunologia , Pneumonia Bacteriana/prevenção & controle , Sepse/prevenção & controle , Infecções por Acinetobacter/imunologia , Infecções por Acinetobacter/mortalidade , Animais , Antígenos de Bactérias/imunologia , Vacinas Bacterianas/administração & dosagem , Citocinas/metabolismo , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno/imunologia , Imunização , Camundongos , Pneumonia Bacteriana/imunologia , Pneumonia Bacteriana/mortalidade , Prognóstico , Sepse/imunologia , Sepse/mortalidade , Resultado do Tratamento
10.
PLoS One ; 16(8): e0256166, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34383849

RESUMO

As electronic cigarette (E-cig) use, also known as "vaping", has rapidly increased in popularity, data regarding potential pathologic effects are recently emerging. Recent associations between vaping and lung pathology have led to an increased need to scrutinize E-cigs for adverse health impacts. Our previous work (and others) has associated vaping with Ca2+-dependent cytotoxicity in cultured human airway epithelial cells. Herein, we develop a vaped e-liquid pulmonary exposure mouse model to evaluate vaping effects in vivo. Using this model, we demonstrate lung pathology through the use of preclinical measures, that is, the lung wet: dry ratio and lung histology/H&E staining. Further, we demonstrate that acute vaping increases macrophage chemotaxis, which was ascertained using flow cytometry-based techniques, and inflammatory cytokine production, via Luminex analysis, through a Ca2+-dependent mechanism. This increase in macrophage activation appears to exacerbate pulmonary pathology resulting from microbial infection. Importantly, modulating Ca2+ signaling may present a therapeutic direction for treatment against vaping-associated pulmonary inflammation.


Assuntos
Cálcio/metabolismo , Misturas Complexas/efeitos adversos , Infecções por Klebsiella/etiologia , Klebsiella pneumoniae/patogenicidade , Pneumonia Bacteriana/etiologia , Vaping/efeitos adversos , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/imunologia , Quimiotaxia/imunologia , Sistemas Eletrônicos de Liberação de Nicotina , Expressão Gênica , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Infecções por Klebsiella/imunologia , Infecções por Klebsiella/microbiologia , Infecções por Klebsiella/patologia , Klebsiella pneumoniae/fisiologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Pneumonia Bacteriana/imunologia , Pneumonia Bacteriana/microbiologia , Pneumonia Bacteriana/patologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
11.
PLoS One ; 16(8): e0250133, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34437551

RESUMO

The efficacy of transfusion with hyperimmune plasma (HIP) for preventing pneumonia caused by Rhodococcus equi remains ill-defined. Quarter Horse foals at 2 large breeding farms were randomly assigned to be transfused with 2 L of HIP from adult donors hyperimmunized either with R. equi (RE HIP) or a conjugate vaccine eliciting antibody to the surface polysaccharide ß-1→6-poly-N-acetyl glucosamine (PNAG HIP) within 24 hours of birth. Antibody activities against PNAG and the rhodococcal virulence-associated protein A (VapA), and to deposition of complement component 1q (C՛1q) onto PNAG were determined by ELISA, and then associated with either clinical pneumonia at Farm A (n = 119) or subclinical pneumonia at Farm B (n = 114). Data were analyzed using multivariable logistic regression. Among RE HIP-transfused foals, the odds of pneumonia were approximately 6-fold higher (P = 0.0005) among foals with VapA antibody activity ≤ the population median. Among PNAG HIP-transfused foals, the odds of pneumonia were approximately 3-fold (P = 0.0347) and 11-fold (P = 0.0034) higher for foals with antibody activities ≤ the population median for PNAG or C՛1q deposition, respectively. Results indicated that levels of activity of antibodies against R. equi antigens are correlates of protection against both subclinical and clinical R. equi pneumonia in field settings. Among PNAG HIP-transfused foals, activity of antibodies with C՛1q deposition (an indicator of functional antibodies) were a stronger predictor of protection than was PNAG antibody activity alone. Collectively, these findings suggest that the amount and activity of antibodies in HIP (i.e., plasma volume and/or antibody activity) is positively associated with protection against R. equi pneumonia in foals.


Assuntos
Acetilglucosamina/imunologia , Infecções por Actinomycetales/veterinária , Anticorpos Antibacterianos/uso terapêutico , Proteínas de Bactérias/imunologia , Doenças dos Cavalos/prevenção & controle , Imunização Passiva/veterinária , Pneumonia Bacteriana/veterinária , Rhodococcus equi/imunologia , Infecções por Actinomycetales/imunologia , Infecções por Actinomycetales/microbiologia , Infecções por Actinomycetales/prevenção & controle , Animais , Animais Recém-Nascidos/imunologia , Animais Recém-Nascidos/microbiologia , Anticorpos Antibacterianos/imunologia , Feminino , Doenças dos Cavalos/imunologia , Doenças dos Cavalos/microbiologia , Cavalos/imunologia , Cavalos/microbiologia , Imunização Passiva/métodos , Masculino , Pneumonia Bacteriana/imunologia , Pneumonia Bacteriana/microbiologia , Pneumonia Bacteriana/prevenção & controle
12.
Br J Anaesth ; 127(3): 405-414, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34229832

RESUMO

BACKGROUND: Allogeneic red blood cell (RBC) transfusion can induce immunosuppression, which can then increase the susceptibility to postoperative infection. However, studies in different types of surgery show conflicting results regarding this effect. METHODS: In this retrospective cohort study conducted in a tertiary referral centre, we included adult patients undergoing clean-contaminated surgery from 2014 to 2018. Patients who received allogeneic RBC transfusion from preoperative Day 30 to postoperative Day 30 were included into the transfusion group. The control group was matched for the type of surgery in a 1:1 ratio. The primary outcome was infection within 30 days after surgery, which was defined by healthcare-associated infection, and identified mainly based on antibiotic regimens, microbiology tests, and medical notes. RESULTS: Among the 8098 included patients, 1525 (18.8%) developed 1904 episodes of postoperative infection. Perioperative RBC transfusion was associated with an increased risk of postoperative infection after controlling for 27 confounders by multivariable regression analysis (odds ratio [OR]: 1.60; 95% confidence interval [CI]: 1.39-1.84; P<0.001) and propensity score weighing (OR: 1.64; 95% CI: 1.45-1.85; P<0.001) and matching (OR: 1.70; 95% CI: 1.43-2.01; P<0.001), and a dose-response relationship was observed. The transfusion group also showed higher risks of surgical site infection, pneumonia, bloodstream infection, multiple infections, intensive care admission, unplanned reoperation, prolonged postoperative length of hospital stay, and all-cause death. CONCLUSIONS: Perioperative allogeneic RBC transfusion is associated with an increased risk of infection after clean-contaminated surgery in a dose-response manner. Close monitoring of infections and enhanced prophylactic strategies should be considered after transfusion.


Assuntos
Infecções Bacterianas/microbiologia , Transfusão de Eritrócitos/efeitos adversos , Hospedeiro Imunocomprometido , Assistência Perioperatória/efeitos adversos , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Antibacterianos/uso terapêutico , Bacteriemia/imunologia , Bacteriemia/microbiologia , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/imunologia , Infecções Bacterianas/mortalidade , Cuidados Críticos , Transfusão de Eritrócitos/mortalidade , Humanos , Tempo de Internação , Readmissão do Paciente , Assistência Perioperatória/mortalidade , Pneumonia Bacteriana/imunologia , Pneumonia Bacteriana/microbiologia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Procedimentos Cirúrgicos Operatórios/mortalidade , Infecção da Ferida Cirúrgica/imunologia , Infecção da Ferida Cirúrgica/microbiologia , Fatores de Tempo , Transplante Homólogo/efeitos adversos , Resultado do Tratamento
13.
Life Sci ; 281: 119764, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34186045

RESUMO

AIMS: Although intrauterine growth restriction (IUGR) impairs immune system homeostasis and lung development, its relationship with the susceptibility to pulmonary infections remains unclear. Thus, this study aimed to investigate the impact of IUGR on acute lung inflammatory response induced by bacterial stimulus. MATERIALS AND METHODS: Pregnant female Wistar rats were subjected to 50% caloric-protein food restriction during gestation. To mimic bacterial lung infection, adult male offspring (12 weeks old) were challenged with a single lipopolysaccharide (LPS) intranasal instillation, and 6 h later, we assessed the acute inflammatory response. Normal birth weight (NBW) animals represent the control group. KEY FINDINGS: LPS instillation increased the protein levels in the airways of both the NBW and low birth weight (LBW) groups, indicating vascular leakage. LBW animals exhibited a lower number of neutrophils, reduced production of interleukin-6 and macrophage-inflammatory protein-2 and decreased upregulation of intercellular adhesion molecule-1 gene expression in lung tissues. Further analysis revealed that the LBW group produced lower levels of prostaglandin-E2 and failed to secrete leukotriene-B4 upon LPS stimulation, which correlated with impaired cyclooxygenase-2 and 5-lipoxygenase expression. These results were probably associated with their inability to upregulate the expression of Toll-like receptor-4 and downstream signaling proteins, such as nuclear factor kappa-B, in the lungs. The LBW group also exhibited abnormal airway thickening and high corticosterone levels under basal conditions. SIGNIFICANCE: This study suggests that IUGR-induced foetal programming in LBW offspring threatens HPA axis physiology and corticosterone biodisponibility, and impairs the innate response to bacterial antigens, increasing future susceptibility to pulmonary infection.


Assuntos
Corticosterona/biossíntese , Suscetibilidade a Doenças , Retardo do Crescimento Fetal , Pneumonia Bacteriana/imunologia , Efeitos Tardios da Exposição Pré-Natal , Animais , Ácido Araquidônico/metabolismo , Feminino , Sistema Hipotálamo-Hipofisário/metabolismo , Lipopolissacarídeos/administração & dosagem , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , NF-kappa B/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Gravidez , Ratos , Ratos Wistar , Receptor 4 Toll-Like/metabolismo
14.
J Surg Res ; 265: 212-222, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33951586

RESUMO

BACKGROUND: Sepsis induces gut barrier dysfunction characterized by increased gut epithelial apoptosis and increased intestinal permeability. The cytokine IL-22 has been demonstrated to regulate gut barrier function. Type-3 innate lymphoid cells (ILC3) are the predominate source of IL-22 in the GI tract. We hypothesized that sepsis may cause changes to the gut ILC3/IL-22 axis. MATERIALS AND METHODS: Sepsis was induced in WT and IL-22 KO mice by Pseudomonas aeruginosa pneumonia. Changes in gut-associated leukocyte populations were determined by flow-cytometry and ILC-associated transcripts were measured by RT-PCR. The effect of sepsis on gut permeability, pulmonary microbial burden, gut epithelial apoptosis, and survival was compared between WT and IL-22-/- mice. RESULTS: Sepsis resulted in a significant decrease in the number of ILC3 in the gut, with a reciprocal increase in type-1 ILC (ILC1). Consistent with prior reports, sepsis was associated with increased gut permeability; however there was no difference in gut permeability, gut epithelial apoptosis, pulmonary microbial burden, or survival between WT and IL-22-/- mice. CONCLUSIONS: Septic pneumonia causes a decrease in gut-associated ILC3 and an associated reciprocal increase in ILC1. This may reflect inflammation-induced conversion of ILC3 to ILC1. Constitutive systemic IL-22 deficiency does not alter sepsis-induced gut barrier dysfunction.


Assuntos
Mucosa Intestinal/imunologia , Linfócitos , Pneumonia Bacteriana/imunologia , Infecções por Pseudomonas/imunologia , Sepse/imunologia , Animais , Masculino , Camundongos Endogâmicos C57BL , Pneumonia Bacteriana/complicações , Infecções por Pseudomonas/complicações
15.
Front Immunol ; 12: 629281, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33968022

RESUMO

Alveolar macrophages (AMs) are pivotal for maintaining lung immune homeostasis. We demonstrated that deletion of liver kinase b1 (Lkb1) in CD11c+ cells led to greatly reduced AM abundance in the lung due to the impaired self-renewal of AMs but not the impeded pre-AM differentiation. Mice with Lkb1-deficient AMs exhibited deteriorated diseases during airway Staphylococcus aureus (S. aureus) infection and allergic inflammation, with excessive accumulation of neutrophils and more severe lung pathology. Drug-mediated AM depletion experiments in wild type mice indicated a cause for AM reduction in aggravated diseases in Lkb1 conditional knockout mice. Transcriptomic sequencing also revealed that Lkb1 inhibited proinflammatory pathways, including IL-17 signaling and neutrophil migration, which might also contribute to the protective function of Lkb1 in AMs. We thus identified Lkb1 as a pivotal regulator that maintains the self-renewal and immune function of AMs.


Assuntos
Asma/enzimologia , Autorrenovação Celular , Pulmão/enzimologia , Macrófagos Alveolares/enzimologia , Pneumonia Bacteriana/enzimologia , Proteínas Serina-Treonina Quinases/metabolismo , Infecções Estafilocócicas/enzimologia , Proteínas Quinases Ativadas por AMP , Animais , Asma/genética , Asma/imunologia , Antígenos CD11/genética , Antígenos CD11/metabolismo , Modelos Animais de Doenças , Homeostase , Interleucina-17/genética , Interleucina-17/metabolismo , Pulmão/imunologia , Pulmão/microbiologia , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/microbiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infiltração de Neutrófilos , Pneumonia Bacteriana/genética , Pneumonia Bacteriana/imunologia , Pneumonia Bacteriana/microbiologia , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais , Infecções Estafilocócicas/genética , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Transcriptoma
16.
Front Immunol ; 12: 672523, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33968082

RESUMO

Lower respiratory infections are among the leading causes of morbidity and mortality worldwide. These potentially deadly infections are further exacerbated due to the growing incidence of antimicrobial resistance. To combat these infections there is a need to better understand immune mechanisms that promote microbial clearance. This need in the context of lung infections has been further heightened with the emergence of SARS-CoV-2. Group 3 innate lymphoid cells (ILC3s) are a recently discovered tissue resident innate immune cell found at mucosal sites that respond rapidly in the event of an infection. ILC3s have clear roles in regulating mucosal immunity and tissue homeostasis in the intestine, though the immunological functions in lungs remain unclear. It has been demonstrated in both viral and bacterial pneumonia that stimulated ILC3s secrete the cytokines IL-17 and IL-22 to promote both microbial clearance as well as tissue repair. In this review, we will evaluate regulation of ILC3s during inflammation and discuss recent studies that examine ILC3 function in the context of both bacterial and viral pulmonary infections.


Assuntos
COVID-19/imunologia , Imunidade nas Mucosas/imunologia , Linfócitos/imunologia , Pneumonia Bacteriana/imunologia , Mucosa Respiratória/imunologia , SARS-CoV-2/imunologia , Bactérias/imunologia , COVID-19/mortalidade , COVID-19/patologia , Imunidade Inata/imunologia , Inflamação/imunologia , Interleucina-17/metabolismo , Interleucinas/metabolismo , Pulmão/imunologia , Ativação Linfocitária/imunologia , Mucosa Respiratória/citologia
17.
J Trauma Acute Care Surg ; 90(6): 924-934, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34016916

RESUMO

BACKGROUND: Forty percent of critically ill trauma patients will develop an infectious complication. Pneumonia is the most common cause of death of trauma patients surviving their initial insult. We previously demonstrated that polytrauma (PT), defined as two or more severe injuries in at least two areas of the body, induces emergency hematopoiesis characterized by accelerated myelopoiesis in the bone marrow and increased myeloid cell frequency in the peripheral tissues. We hypothesized that PT alone induces priming of neutrophils, resulting in hyperactivation upon secondary exposure to bacteria and causing acute lung injury and increased susceptibility to secondary exposure to Pseudomonas aeruginosa pneumonia. METHODS: C57BL/6 mice were subjected to PT consisting of a lower extremity pseudofracture, liver crush injury, and 15% blood-volume hemorrhage. Pneumonia was induced by intratracheal injection of 5 × 106 CFU live P. aeruginosa or 1 × 107 of heat-killed P. aeruginosa (HKPA). For reactive oxygen species (ROS), studies polymorphonuclear neutrophils (PMNs) were isolated by immunomagnetic bead negative selection and stimulated ex-vivo with HKPA. Reactive oxygen species production was measured by immunofluorescence. For histology, lung sections were stained by hematoxylin-eosin and analyzed by a blinded grader. RESULTS: Polytrauma induced persistent changes in immune function at baseline and to secondary infection. Pneumonia after injury resulted in increased mortality (60% vs. 5% p < 0.01). Blood neutrophils from PT mice had higher resting (unstimulated) ROS production than in naive animals (p < 0.02) demonstrating priming of the neutrophils following PT. After intratracheal HKPA injection, bronchoalveolar lavage PMNs from injured mice had higher ROS production compared with naive mice (p < 0.01), demonstrating an overexuberant immunopathologic response of neutrophils following PT. CONCLUSION: Polytrauma primes neutrophils and causes immunopathologic PMN ROS production, increased lung injury and susceptibility to secondary bacterial pneumonia. These results suggest that trauma-induced immune dysfunction can cause immunopathologic response to secondary infection and suggests neutrophil-mediated pulmonary damage as a therapeutic target for posttrauma pneumonia.


Assuntos
Lesão Pulmonar Aguda/imunologia , Traumatismo Múltiplo/complicações , Neutrófilos/imunologia , Pneumonia Bacteriana/imunologia , Infecções por Pseudomonas/imunologia , Lesão Pulmonar Aguda/sangue , Lesão Pulmonar Aguda/microbiologia , Lesão Pulmonar Aguda/patologia , Animais , Modelos Animais de Doenças , Humanos , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Masculino , Camundongos , Traumatismo Múltiplo/sangue , Traumatismo Múltiplo/diagnóstico , Traumatismo Múltiplo/imunologia , Neutrófilos/metabolismo , Pneumonia Bacteriana/sangue , Pneumonia Bacteriana/microbiologia , Pneumonia Bacteriana/patologia , Infecções por Pseudomonas/sangue , Infecções por Pseudomonas/microbiologia , Infecções por Pseudomonas/patologia , Pseudomonas aeruginosa/imunologia , Espécies Reativas de Oxigênio/metabolismo , Índices de Gravidade do Trauma
18.
mSphere ; 6(3)2021 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-34011681

RESUMO

Staphylococcus aureus is both a commensal and a pathogenic bacterium for humans. Its ability to induce severe infections is based on a wide range of virulence factors. S. aureus community-acquired pneumonia (SA-CAP) is rare and severe, and the contribution of certain virulence factors in this disease has been recognized over the past 2 decades. First, the factors involved in metabolism adaptation are crucial for S. aureus survival in the lower respiratory tract, and toxins and enzymes are required for it to cross the pulmonary epithelial barrier. S. aureus subsequently faces host defense mechanisms, including the epithelial barrier, but most importantly the immune system. Here, again, S. aureus uses myriad virulence factors to successfully escape from the host's defenses and takes advantage of them. The impact of S. aureus virulence, combined with the collateral damage caused by an overwhelming immune response, leads to severe tissue damage and adverse clinical outcomes. In this review, we summarize step by step all of the S. aureus factors implicated in CAP and described to date, and we provide an outlook for future research.


Assuntos
Pneumonia Bacteriana/imunologia , Doenças Respiratórias/microbiologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/fisiologia , Animais , Infecções Comunitárias Adquiridas/imunologia , Infecções Comunitárias Adquiridas/microbiologia , Humanos , Camundongos , Pneumonia Bacteriana/patologia , Doenças Respiratórias/imunologia , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/genética , Staphylococcus aureus/imunologia , Virulência , Fatores de Virulência
19.
Nat Commun ; 12(1): 2126, 2021 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-33837203

RESUMO

There is accumulating evidence that the lower airway microbiota impacts lung health. However, the link between microbial community composition and lung homeostasis remains elusive. We combine amplicon sequencing and bacterial culturing to characterize the viable bacterial community in 234 longitudinal bronchoalveolar lavage samples from 64 lung transplant recipients and establish links to viral loads, host gene expression, lung function, and transplant health. We find that the lung microbiota post-transplant can be categorized into four distinct compositional states, 'pneumotypes'. The predominant 'balanced' pneumotype is characterized by a diverse bacterial community with moderate viral loads, and host gene expression profiles suggesting immune tolerance. The other three pneumotypes are characterized by being either microbiota-depleted, or dominated by potential pathogens, and are linked to increased immune activity, lower respiratory function, and increased risks of infection and rejection. Collectively, our findings establish a link between the lung microbial ecosystem, human lung function, and clinical stability post-transplant.


Assuntos
Rejeição de Enxerto/microbiologia , Transplante de Pulmão/efeitos adversos , Pulmão/microbiologia , Microbiota/imunologia , Pneumonia Bacteriana/microbiologia , Adulto , Aloenxertos/imunologia , Aloenxertos/microbiologia , Bactérias/genética , Bactérias/imunologia , Bactérias/isolamento & purificação , Bactérias/patogenicidade , Carga Bacteriana/imunologia , Técnicas Bacteriológicas , Líquido da Lavagem Broncoalveolar/microbiologia , Broncoscopia , DNA Bacteriano/isolamento & purificação , Feminino , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/imunologia , Humanos , Tolerância Imunológica , Estudos Longitudinais , Pulmão/imunologia , Masculino , Metagenômica , Microbiota/genética , Pessoa de Meia-Idade , Pneumonia Bacteriana/diagnóstico , Pneumonia Bacteriana/imunologia , Estudos Prospectivos , RNA Ribossômico 16S/genética
20.
Am J Respir Cell Mol Biol ; 65(2): 176-188, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33848212

RESUMO

Macrophages undergo profound metabolic reprogramming to join key immunoregulatory functions, which can be initiated by pattern recognition receptors. TREM2 (triggering receptor expressed on myeloid cells 2), a macrophage phagocytic receptor, plays pivotal roles in sepsis by enhancing bacterial clearance, which is associated with regulation of reactive oxygen species (ROS) production. However, how intracellular ROS participate in TREM2-mediated bactericidal activity remains unclear. This study was designed to investigate the organelle source and biological activity of ROS in the context of TREM2-mediated immune defense during Escherichiacoli infection. Bone marrow-derived macrophages (BMDMs) were transfected with TREM2-overexpressing adenoviruses or control viruses and challenged with E. coli. The BMDMs were administered to mouse models with local E. coli infection. In addition, monocytic TREM2 expression, NOX2 concentrations, and pyroptosis were detected in patients with bacterial sepsis. General ROS production was found to be comparable between TREM2-overexpressing and control BMDMs upon E. coli challenge. The deficiency of Nox2 led to impaired phagosome degradation and lack of bactericidal ability and abolished TREM2-mediated protective activity against pulmonary E. coli infection. Overexpression of TREM2 suppressed mitochondrial ROS generation, inhibited NLRP3/caspase-1 inflammasome activation, and finally protected BMDMs from gasdermin D-mediated pyroptosis during pulmonary E. coli infection. The protective role of TREM2 was further confirmed in mice with abdominal E. coli infection. Moreover, monocytic TREM2 expression was positively correlated with NOX2 concentrations and negatively correlated with pyroptosis and disease severity in patients with bacterial sepsis. Collectively, TREM2 controls macrophage immune functions by fine-tuning ROS generation and enhances the host defense against bacterial infection. Our data suggest that TREM2 is a promising candidate target for sepsis therapy.


Assuntos
Células da Medula Óssea/imunologia , Infecções por Escherichia coli/imunologia , Escherichia coli/imunologia , Macrófagos/imunologia , Glicoproteínas de Membrana/imunologia , Pneumonia Bacteriana/imunologia , Receptores Imunológicos/imunologia , Animais , Células da Medula Óssea/patologia , Infecções por Escherichia coli/genética , Regulação da Expressão Gênica/imunologia , Macrófagos/patologia , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Knockout , NADPH Oxidase 2/genética , NADPH Oxidase 2/imunologia , Fagossomos/genética , Fagossomos/imunologia , Pneumonia Bacteriana/genética , Pneumonia Bacteriana/patologia , Receptores Imunológicos/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...