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1.
J Med Microbiol ; 70(4)2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33830909

RESUMEN

Introduction. In recent years, the Herbaspirillum genus has emerged as a pathogen in healthcare-related infections and has became stablished as an opportunistic pathogen.Hypothesis/Gap Statement. Little is known about the pathogenesis induced by Herbaspirillum genus.Aim. To evaluate the cytotoxic effects of genus Herbaspirillum, its ability to adhere to lung human cells and the ability of environmental and clinical strains of Herbaspirillum to induce pneumonia in mice.Methodology. Environmental and clinical isolates of Herbaspirillum were examined for their cytotoxic effects on the Calu-3 cell lineage. Cytotoxic activity of secretome was tested using MTT/neutral red assays and cell morphology analysis. Herbaspirillum adhesion on Calu-3 cells was assessed using bright-field microscopy and cell-associated bacteria were counted. A mouse model of acute lung infection was done using a clinical and an environmental strain. Adult male mice were used, and the pneumonia was inducted by intra-tracheal inoculation of 108 or 109 bacteria. Mice weight variations were evaluated at the end of the experiment. Bronchoalveolar lavage was collected and evaluated for total and differential cytology. A histological examination of lungs was performed giving a histological score.Results. The secretomes of all the strains induced morphological alterations in cells, but only H. seropedicae SmR1 were cytotoxic in MTT and neutral red assays. Clinical strains of H. frisingense AU14459 and H. hutttiense subsp. huttiense AU11883 exhibited low adherence to lung cells, while SmR1 was non-adhesive. Following intratracheal inoculation, mice treated with 109 c.f.u. of the SmR1 and AU11883 strains lost 18 and 6% of their weight over 7 days, respectively, and presented moderate clinical signs. Infected mice showed inflammatory cell infiltration in the perivascular and peribroncheal/peribronchiolar spaces. Bronchoalveolar fluid of mice inoculated with SmR1 109 c.f.u. presented an increase in total leucocyte cells and in neutrophils population.Conclusion. These in vivo and in vitro results provide insights into how some Herbaspirillum strains cause infection in humans, providing a basis for the characterization of pathogenesis studies on this emerging infectious agent.


Asunto(s)
Exosomas/metabolismo , Infecciones por Bacterias Gramnegativas/microbiología , Herbaspirillum/patogenicidad , Neumonía/microbiología , Animales , Adhesión Bacteriana , Líquido del Lavado Bronquioalveolar/citología , Línea Celular , Supervivencia Celular , Infecciones por Bacterias Gramnegativas/patología , Herbaspirillum/aislamiento & purificación , Herbaspirillum/metabolismo , Humanos , Pulmón/microbiología , Pulmón/patología , Masculino , Ratones , Neumonía/patología , Virulencia
2.
Respir Res ; 22(1): 99, 2021 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-33823870

RESUMEN

BACKGROUND: COVID-19 pneumonia has been associated with severe acute hypoxia, sepsis-like states, thrombosis and chronic sequelae including persisting hypoxia and fibrosis. The molecular hypoxia response pathway has been associated with such pathologies and our recent observations on anti-hypoxic and anti-inflammatory effects of whole aqueous extract of Adhatoda Vasica (AV) prompted us to explore its effects on relevant preclinical mouse models. METHODS: In this study, we tested the effect of whole aqueous extract of AV, in murine models of bleomycin induced pulmonary fibrosis, Cecum Ligation and Puncture (CLP) induced sepsis, and siRNA induced hypoxia-thrombosis phenotype. The effect on lung of AV treated naïve mice was also studied at transcriptome level. We also determined if the extract may have any effect on SARS-CoV2 replication. RESULTS: Oral administration AV extract attenuates increased airway inflammation, levels of transforming growth factor-ß1 (TGF-ß1), IL-6, HIF-1α and improves the overall survival rates of mice in the models of pulmonary fibrosis and sepsis and rescues the siRNA induced inflammation and associated blood coagulation phenotypes in mice. We observed downregulation of hypoxia, inflammation, TGF-ß1, and angiogenesis genes and upregulation of adaptive immunity-related genes in the lung transcriptome. AV treatment also reduced the viral load in Vero cells infected with SARS-CoV2. CONCLUSION: Our results provide a scientific rationale for this ayurvedic herbal medicine in ameliorating the hypoxia-hyperinflammation features and highlights the repurposing potential of AV in COVID-19-like conditions.


Asunto(s)
Antiinflamatorios/farmacología , Reposicionamiento de Medicamentos , Hipoxia/tratamiento farmacológico , Justicia , Pulmón/efectos de los fármacos , Extractos Vegetales/farmacología , Neumonía/prevención & control , Fibrosis Pulmonar/tratamiento farmacológico , Sepsis/tratamiento farmacológico , Animales , Antiinflamatorios/aislamiento & purificación , Bleomicina , /virología , Ciego/microbiología , Ciego/cirugía , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Hipoxia/genética , Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Prolina Dioxigenasas del Factor Inducible por Hipoxia/genética , Prolina Dioxigenasas del Factor Inducible por Hipoxia/metabolismo , Mediadores de Inflamación/metabolismo , Justicia/química , Ligadura , Pulmón/metabolismo , Pulmón/microbiología , Pulmón/patología , Masculino , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Extractos Vegetales/aislamiento & purificación , Neumonía/genética , Neumonía/metabolismo , Neumonía/microbiología , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/genética , Fibrosis Pulmonar/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Sepsis/genética , Sepsis/metabolismo , Sepsis/microbiología , Transcriptoma
3.
Int J Mol Sci ; 22(6)2021 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-33803907

RESUMEN

Pseudomonas aeruginosa is a dominant pathogen in people with cystic fibrosis (CF) contributing to morbidity and mortality. Its tremendous ability to adapt greatly facilitates its capacity to cause chronic infections. The adaptability and flexibility of the pathogen are afforded by the extensive number of virulence factors it has at its disposal, providing P. aeruginosa with the facility to tailor its response against the different stressors in the environment. A deep understanding of these virulence mechanisms is crucial for the design of therapeutic strategies and vaccines against this multi-resistant pathogen. Therefore, this review describes the main virulence factors of P. aeruginosa and the adaptations it undergoes to persist in hostile environments such as the CF respiratory tract. The very large P. aeruginosa genome (5 to 7 MB) contributes considerably to its adaptive capacity; consequently, genomic studies have provided significant insights into elucidating P. aeruginosa evolution and its interactions with the host throughout the course of infection.


Asunto(s)
Adaptación Fisiológica , Pseudomonas aeruginosa/fisiología , Pseudomonas aeruginosa/patogenicidad , Factores de Virulencia/metabolismo , Animales , Biopelículas/crecimiento & desarrollo , Humanos , Pulmón/microbiología , Pseudomonas aeruginosa/genética , Percepción de Quorum
4.
Nat Commun ; 12(1): 2126, 2021 04 09.
Artículo en Inglés | MEDLINE | ID: mdl-33837203

RESUMEN

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.


Asunto(s)
Rechazo de Injerto/microbiología , Trasplante de Pulmón/efectos adversos , Pulmón/microbiología , Microbiota/inmunología , Neumonía Bacteriana/microbiología , Adulto , Aloinjertos/inmunología , Aloinjertos/microbiología , Bacterias/genética , Bacterias/inmunología , Bacterias/aislamiento & purificación , Bacterias/patogenicidad , Carga Bacteriana/inmunología , Técnicas Bacteriológicas , Líquido del Lavado Bronquioalveolar/microbiología , Broncoscopía , ADN Bacteriano/aislamiento & purificación , Femenino , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/inmunología , Humanos , Tolerancia Inmunológica , Estudios Longitudinales , Pulmón/inmunología , Masculino , Metagenómica , Microbiota/genética , Persona de Mediana Edad , Neumonía Bacteriana/diagnóstico , Neumonía Bacteriana/inmunología , Estudios Prospectivos , ARN Ribosómico 16S/genética
5.
Front Immunol ; 12: 635471, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33717181

RESUMEN

COVID-19 is an infectious disease caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), and according to the World Health Organization (WHO), to date, SARS-CoV-2 has already infected more than 91.8 million people worldwide with 1,986,871 deaths. This virus affects mainly the respiratory system, but the gastrointestinal tract (GIT) is also a target, meanwhile SARS-CoV-2 was already detected in oesophagus, stomach, duodenum, rectum, and in fecal samples from COVID-19 patients. Prolonged GIT manifestations in COVID-19, mainly the diarrhea, were correlated with decreased richness and diversity of the gut microbiota, immune deregulation and delayed SARS-CoV-2 clearance. So, the bidirectional interactions between the respiratory mucosa and the gut microbiota, known as gut-lung axis, are supposed to be involved in the healthy or pathologic immune responses to SARS-CoV-2. In accordance, the intestinal dysbiosis is associated with increased mortality in other respiratory infections, due to an exacerbated inflammation and decreased regulatory or anti-inflammatory mechanisms in the lungs and in the gut, pointing to this important relationship between both mucosal compartments. Therefore, since the mucous membranes from the respiratory and gastrointestinal tracts are affected, in addition to dysbiosis and inflammation, it is plausible to assume that adjunctive therapies based on the modulation of the gut microbiota and re-establishment of eubiosis conditions could be an important therapeutic approach for constraining the harmful consequences of COVID-19. Then, in this review, we summarized studies showing the persistence of SARS-CoV-2 in the gastrointestinal system and the related digestive COVID-19 manifestations, in addition to the literature demonstrating nasopharyngeal, pulmonary and intestinal dysbiosis in COVID-19 patients. Lastly, we showed the potential beneficial role of probiotic administration in other respiratory infections, and discuss the possible role of probiotics as an adjunctive therapy in SARS-CoV-2 infection.


Asunto(s)
/microbiología , Intestinos/microbiología , Pulmón/microbiología , /fisiología , /terapia , Disbiosis , Microbioma Gastrointestinal , Humanos , Intestinos/virología , Pulmón/virología , Probióticos
6.
Front Immunol ; 12: 618807, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33679760

RESUMEN

Type 2 inflammation is found in most forms of asthma, which may co-exist with recurrent viral infections, bacterial colonization, and host cell death. These processes drive the accumulation of intracellular cyclic-di-nucleotides such as cyclic-di-GMP (CDG). Group 2 innate lymphoid cells (ILC2s) are critical drivers of type 2 lung inflammation during fungal allergen exposure in mice; however, it is unclear how CDG regulates lung ILC responses during lung inflammation. Here, we show that intranasal CDG induced early airway type 1 interferon (IFN) production and dramatically suppressed CD127+ST2+ ILC2s and type 2 lung inflammation during Alternaria and IL-33 exposure. Further, CD127-ST2-Thy1.2+ lung ILCs, which showed a transcriptomic signature consistent with ILC1s, were expanded and activated by CDG combined with either Alternaria or IL-33. CDG-mediated suppression of type 2 inflammation occurred independent of IL-18R, IL-12, and STAT6 but required the stimulator of interferon genes (STING) and type 1 IFN signaling. Thus, CDG potently suppresses ILC2-driven lung inflammation and promotes ILC1 responses. These results suggest potential therapeutic modulation of STING to suppress type 2 inflammation and/or increase anti-viral responses during respiratory infections.


Asunto(s)
Alternaria/inmunología , Alternariosis/inmunología , GMP Cíclico/análogos & derivados , Inmunidad Innata , Pulmón/inmunología , Proteínas de la Membrana/inmunología , Neumonía/inmunología , Alternariosis/genética , Alternariosis/patología , Animales , GMP Cíclico/genética , GMP Cíclico/inmunología , Citocinas/genética , Citocinas/inmunología , Inflamación/genética , Inflamación/inmunología , Inflamación/microbiología , Inflamación/patología , Pulmón/microbiología , Pulmón/patología , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Neumonía/genética , Neumonía/microbiología , Neumonía/patología , Transducción de Señal/genética , Transducción de Señal/inmunología
7.
Biomed Res Int ; 2021: 6670798, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33681368

RESUMEN

Recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of coronavirus disease 2019 (COVID-19), has led to a worldwide pandemic with millions of infected patients. Alteration in humans' microbiota was also reported in COVID-19 patients. The alteration in human microbiota may contribute to bacterial or viral infections and affect the immune system. Moreover, human's microbiota can be altered due to SARS-CoV-2 infection, and these microbiota changes can indicate the progression of COVID-19. While current studies focus on the gut microbiota, it seems necessary to pay attention to the lung microbiota in COVID-19. This study is aimed at reviewing respiratory microbiota dysbiosis among COVID-19 patients to encourage further studies on the field for assessment of SARS-CoV-2 and respiratory microbiota interaction.


Asunto(s)
Disbiosis , Pulmón , Micobioma/inmunología , /inmunología , /inmunología , Disbiosis/inmunología , Disbiosis/microbiología , Disbiosis/virología , Microbioma Gastrointestinal/inmunología , Humanos , Pulmón/inmunología , Pulmón/microbiología , Pulmón/virología
8.
Pharmacol Res ; 167: 105548, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33722710

RESUMEN

Acute Respiratory Distress Syndrome (ARDS) is triggered by a variety of agents, including Staphylococcal Enterotoxin B (SEB). Interestingly, a significant proportion of patients with COVID-19, also develop ARDS. In the absence of effective treatments, ARDS results in almost 40% mortality. Previous studies from our laboratory demonstrated that resveratrol (RES), a stilbenoid, with potent anti-inflammatory properties can attenuate SEB-induced ARDS. In the current study, we investigated the role of RES-induced alterations in the gut and lung microbiota in the regulation of ARDS. Our studies revealed that SEB administration induced inflammatory cytokines, ARDS, and 100% mortality in C3H/HeJ mice. Additionally, SEB caused a significant increase in pathogenic Proteobacteria phylum and Propionibacterium acnes species in the lungs. In contrast, RES treatment attenuated SEB-mediated ARDS and mortality in mice, and significantly increased probiotic Actinobacteria phylum, Tenericutes phylum, and Lactobacillus reuteri species in both the colon and lungs. Colonic Microbiota Transplantation (CMT) from SEB-injected mice that were treated with RES as well as the transfer of L. reuteri into recipient mice inhibited the production of SEB-mediated induction of pro-inflammatory cytokines such as IFN-γ and IL-17 but increased that of anti-inflammatory IL-10. Additionally, such CMT and L. reuteri recipient mice exposed to SEB, showed a decrease in lung-infiltrating mononuclear cells, cytotoxic CD8+ T cells, NKT cells, Th1 cells, and Th17 cells, but an increase in the population of regulatory T cells (Tregs) and Th3 cells, and increase in the survival of mice from SEB-mediated ARDS. Together, the current study demonstrates that ARDS induced by SEB triggers dysbiosis in the lungs and gut and that attenuation of ARDS by RES may be mediated, at least in part, by alterations in microbiota in the lungs and the gut, especially through the induction of beneficial bacteria such as L. reuteri.


Asunto(s)
Antiinflamatorios/farmacología , Colon/efectos de los fármacos , Enterotoxinas , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal/efectos de los fármacos , Pulmón/efectos de los fármacos , Resveratrol/farmacología , Superantígenos , Animales , Línea Celular , Colon/inmunología , Colon/metabolismo , Colon/microbiología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Disbiosis , Femenino , Mediadores de Inflamación/metabolismo , Lactobacillus reuteri/efectos de los fármacos , Lactobacillus reuteri/crecimiento & desarrollo , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/microbiología , Ratones Endogámicos C3H , /metabolismo , /microbiología
9.
Medicine (Baltimore) ; 100(11): e24894, 2021 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-33725960

RESUMEN

OBJECTIVES: Refractory mycoplasma pneumoniae pneumonia (RMPP) in children has been increasing worldwide. In this study, we conducted a meta-analysis to generate large-scale evidence on the risk factors of RMPP to provide suggestions on prevention and controlling for children. METHODS: Web of Science, PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, and Wanfang (Chinese) were searched to identify relevant articles. All analyses were performed using Stata 14.0. RESULTS: We conducted a meta-analysis of 15 separate studies. Fever for more than 10 days (odds ratio [OR] 3.965, 95% confidence interval [CI] 2.109-7.456), pleural effusion (OR 6.922, 95% CI 2.058-23.282), extra-pulmonary complications (OR 17.762, 95% CI 11.146-28.305), pulmonary X-ray consolidation ≥2/3 (OR 8.245, 95% CI 1.990-34.153), CRP >40 mg/L (OR 4.975, 95% CI 2.116-11.697) were significantly related to the risk of RMPP. We did not find an association between male sex (OR 0.808, 95% CI 0.548-1.189), LDH >410IU/L (OR 1.033, 95% CI 0.979-1.091) and the risk of RMPP. CONCLUSIONS: Fever for more than 10 days, pleural effusion, extra-pulmonary complications, pulmonary X-ray consolidation≥ 2/3 and CRP >40 mg/L are risk factors for early evaluation of RMPP.


Asunto(s)
Mycoplasma pneumoniae , Neumonía por Mycoplasma/etiología , Proteína C-Reactiva/análisis , Niño , Preescolar , Infecciones Comunitarias Adquiridas/etiología , Infecciones Comunitarias Adquiridas/microbiología , Farmacorresistencia Bacteriana , Femenino , Fiebre/microbiología , Humanos , Pulmón/diagnóstico por imagen , Pulmón/microbiología , Masculino , Derrame Pleural/microbiología , Neumonía por Mycoplasma/microbiología , Radiografía , Medición de Riesgo , Factores de Riesgo
10.
BMC Infect Dis ; 21(1): 251, 2021 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-33691626

RESUMEN

BACKGROUND: Mycobacterium (M) talmoniae isolated from a patient with cystic fibrosis was first described in 2017, and cases of M. talmoniae remain exceedingly rare. CASE PRESENTATION: A 51-year-old woman had respiratory symptoms for 10 years. Diffuse panbronchiolitis (DPB) was detected at the first visit at our hospital. A cavity lesion in the apex of the left lung was found, and sputum and bronchoalveolar lavage fluid were acid-fast bacillus (AFB) smear- and culture-positive besides Pseudomonas aeruginosa. M. talmoniae was finally identified, and the standard combination therapy for non-tuberculous mycobacteria (NTM) was administered for 2 y referring to the drug-susceptibility test. Thereafter, the AFB culture was negative, the wall thickness of the lung cavity was ameliorated, and oxygen saturation improved. CONCLUSIONS: We encountered a rare case of M. talmoniae with DPB, for which standard combination therapy was effective. M. talmoniae may be considered a potential pathogen of lung disease, especially in patients with bronchiectatic lesions.


Asunto(s)
Bronquiolitis/microbiología , Infecciones por Haemophilus/microbiología , Mycobacterium/aislamiento & purificación , Líquido del Lavado Bronquioalveolar/microbiología , Fibrosis Quística/microbiología , Femenino , Humanos , Pulmón/microbiología , Persona de Mediana Edad , Esputo/microbiología
11.
Sci Rep ; 11(1): 6433, 2021 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-33742096

RESUMEN

In response to the ongoing global pandemic, characterizing the molecular-level host interactions of the new coronavirus SARS-CoV-2 responsible for COVID-19 has been at the center of unprecedented scientific focus. However, when the virus enters the body it also interacts with the micro-organisms already inhabiting the host. Understanding the virus-host-microbiome interactions can yield additional insights into the biological processes perturbed by viral invasion. Alterations in the gut microbiome species and metabolites have been noted during respiratory viral infections, possibly impacting the lungs via gut-lung microbiome crosstalk. To better characterize microbial functions in the lower respiratory tract during COVID-19 infection, we carry out a functional analysis of previously published metatranscriptome sequencing data of bronchoalveolar lavage fluid from eight COVID-19 cases, twenty-five community-acquired pneumonia patients, and twenty healthy controls. The functional profiles resulting from comparing the sequences against annotated microbial protein domains clearly separate the cohorts. By examining the associated metabolic pathways, distinguishing functional signatures in COVID-19 respiratory tract microbiomes are identified, including decreased potential for lipid metabolism and glycan biosynthesis and metabolism pathways, and increased potential for carbohydrate metabolism pathways. The results include overlap between previous studies on COVID-19 microbiomes, including decrease in the glycosaminoglycan degradation pathway and increase in carbohydrate metabolism. The results also suggest novel connections to consider, possibly specific to the lower respiratory tract microbiome, calling for further research on microbial functions and host-microbiome interactions during SARS-CoV-2 infection.


Asunto(s)
/microbiología , Interacciones Microbianas , Microbiota , Sistema Respiratorio/microbiología , /fisiología , Líquido del Lavado Bronquioalveolar/microbiología , Humanos , Pulmón/microbiología
12.
Int J Nanomedicine ; 16: 1819-1836, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33707942

RESUMEN

Background: The development of vaccines is a promising and cost-effective strategy to prevent emerging multidrug-resistant (MDR) Acinetobacter baumannii (A. baumannii) infections. The purpose of this study was to prepare a multiepitope peptide nanovaccine and evaluate its immunogenicity and protective effect in BALB/c mice. Methods: The B-cell and T-cell epitopes of Omp22 from A. baumannii were predicted using bioinformatics methods and identified by immunological experiments. The optimal epitopes were conjugated in series by 6-aminocaproic acid and chemically synthesized multiepitope polypeptide rOmp22. Then, rOmp22 was encapsulated by chitosan (CS) and poly (lactic-co-glycolic) acid (PLGA) to prepare CS-PLGA-rOmp22 nanoparticles (NPs). The immunogenicity and immunoprotective efficacy of the vaccine were evaluated in BALB/c mice. Results: CS-PLGA-rOmp22 NPs were small (mean size of 272.83 nm) with apparently spherical structures, positively charged (4.39 mV) and nontoxic to A549 cells. A high encapsulation efficiency (54.94%) and a continuous slow release pattern were achieved. Compared with nonencapsulated rOmp22, CS-PLGA-rOmp22 immunized BALB/c mice induced higher levels of rOmp22-specific IgG in serum and IFN-γ in splenocyte supernatant. Additionally, lung injury and bacterial burdens in the lung and blood were suppressed, and potent protection (57.14%-83.3%) against acute lethal intratracheal A. baumannii challenge was observed in BALB/c mice vaccinated with CS-PLGA-rOmp22. Conclusion: CS-PLGA-rOmp22 NPs elicited specific IgG antibodies, Th1 cellular immunity and protection against acute lethal intratracheal A. baumannii challenge. Our results indicate that this nanovaccine is a desirable candidate for preventing A. baumannii infection.


Asunto(s)
Infecciones por Acinetobacter/inmunología , Acinetobacter baumannii/inmunología , Vacunas Bacterianas/inmunología , Quitosano/química , Epítopos/inmunología , Nanopartículas/química , Péptidos/inmunología , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Células A549 , Infecciones por Acinetobacter/sangre , Infecciones por Acinetobacter/microbiología , Secuencia de Aminoácidos , Animales , Anticuerpos Antibacterianos/inmunología , Carga Bacteriana , Peso Corporal , Epítopos/química , Femenino , Humanos , Inmunidad Humoral , Inmunización , Inmunoglobulina G/inmunología , Interferón gamma/metabolismo , Interleucina-4/metabolismo , Pulmón/inmunología , Pulmón/microbiología , Pulmón/patología , Ratones , Ratones Endogámicos BALB C , Nanopartículas/ultraestructura , Péptidos/química , Proteínas Recombinantes/aislamiento & purificación , Bazo/patología , Análisis de Supervivencia
13.
Nat Commun ; 12(1): 1707, 2021 03 17.
Artículo en Inglés | MEDLINE | ID: mdl-33731708

RESUMEN

Invasive pulmonary aspergillosis (IPA) is a life-threatening lung disease of immunocompromised humans, caused by the opportunistic fungal pathogen Aspergillus fumigatus. Inadequacies in current diagnostic procedures mean that early diagnosis of the disease, critical to patient survival, remains a major clinical challenge, and is leading to the empiric use of antifungal drugs and emergence of azole resistance. A non-invasive procedure that allows both unambiguous detection of IPA and its response to azole treatment is therefore needed. Here, we show that a humanised Aspergillus-specific monoclonal antibody, dual labelled with a radionuclide and fluorophore, can be used in immunoPET/MRI in vivo in a neutropenic mouse model and 3D light sheet fluorescence microscopy ex vivo in the infected mouse lungs to quantify early A. fumigatus lung infections and to monitor the efficacy of azole therapy. Our antibody-guided approach reveals that early drug intervention is critical to prevent complete invasion of the lungs by the fungus, and demonstrates the power of molecular imaging as a non-invasive procedure for tracking IPA in vivo.


Asunto(s)
Anticuerpos Monoclonales Humanizados/inmunología , Antifúngicos/uso terapéutico , Aspergillus fumigatus/inmunología , Pulmón/efectos de los fármacos , Pulmón/diagnóstico por imagen , Radiofármacos/inmunología , Animales , Anticuerpos Antifúngicos/química , Anticuerpos Antifúngicos/inmunología , Anticuerpos Monoclonales Humanizados/química , Aspergillus fumigatus/efectos de los fármacos , Aspergillus fumigatus/patogenicidad , Azoles/uso terapéutico , Radioisótopos de Cobre/química , Monitoreo de Drogas , Colorantes Fluorescentes/química , Humanos , Aspergilosis Pulmonar Invasiva/diagnóstico por imagen , Aspergilosis Pulmonar Invasiva/tratamiento farmacológico , Aspergilosis Pulmonar Invasiva/microbiología , Pulmón/microbiología , Imagen por Resonancia Magnética , Ratones , Microscopía Fluorescente , Tomografía de Emisión de Positrones , Radioinmunodetección , Radiofármacos/química
14.
Ecotoxicol Environ Saf ; 213: 112035, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33581487

RESUMEN

Air pollution has been documented to contribute to severe respiratory diseases like asthma and chronic obstructive pulmonary disorder (COPD). Although these diseases demonstrate a shift in the lung microbiota towards Proteobacteria, the effects of traffic generated emissions on lung microbiota profiles have not been well-characterized. Thus, we investigated the hypothesis that exposure to traffic-generated emissions can alter lung microbiota and immune defenses. Since a large population of the Western world consumes a diet rich in fats, we sought to investigate the synergistic effects of mixed vehicle emissions and high-fat diet consumption. We exposed 3-month-old male C57Bl/6 mice placed either on regular chow (LF) or a high-fat (HF: 45% kcal fat) diet to mixed emissions (ME: 30 µg PM/m3 gasoline engine emissions+70 µg PM/m3 diesel engine emissions) or filtered air (FA) for 6 h/d, 7 d/wk for 30 days. Levels of pulmonary immunoglobulins IgA, IgG, and IgM were analyzed by ELISA, and lung microbial profiling was done using qPCR and Illumina 16 S sequencing. We observed a significant decrease in lung IgA in the ME-exposed animals, compared to the FA-exposed animals, both fed a HF diet. Our results also revealed a significant decrease in lung IgG in the ME-exposed animals both on the LF diet and HF diet, in comparison to the FA-exposed animals. We also observed an expansion of Enterobacteriaceae belonging to the Proteobacteria phylum in the ME-exposed groups on the HF diet. Collectively, we show that the combined effects of ME and HF diet result in decreased immune surveillance and lung bacterial dysbiosis, which is of significance in lung diseases.


Asunto(s)
Pulmón/microbiología , Proteobacteria , Emisiones de Vehículos/toxicidad , Contaminación del Aire , Animales , Dieta Alta en Grasa , Disbiosis , Masculino , Ratones , Ratones Endogámicos C57BL , Microbiota
15.
Am J Respir Cell Mol Biol ; 64(4): 477-491, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33600743

RESUMEN

Streptococcus pneumoniae is the leading cause of hospital community-acquired pneumonia. Patients with pneumococcal pneumonia may develop complicated parapneumonic effusions or empyema that can lead to pleural organization and subsequent fibrosis. The pathogenesis of pleural organization and scarification involves complex interactions between the components of the immune system, coagulation, and fibrinolysis. EPCR (endothelial protein C receptor) is a critical component of the protein C anticoagulant pathway. The present study was performed to evaluate the role of EPCR in the pathogenesis of S. pneumoniae infection-induced pleural thickening and fibrosis. Our studies show that the pleural mesothelium expresses EPCR. Intrapleural instillation of S. pneumoniae impairs lung compliance and lung volume in wild-type and EPCR-overexpressing mice but not in EPCR-deficient mice. Intrapleural S. pneumoniae infection induces pleural thickening in wild-type mice. Pleural thickening is more pronounced in EPCR-overexpressing mice, whereas it is reduced in EPCR-deficient mice. Markers of mesomesenchymal transition are increased in the visceral pleura of S. pneumoniae-infected wild-type and EPCR-overexpressing mice but not in EPCR-deficient mice. The lungs of wild-type and EPCR-overexpressing mice administered intrapleural S. pneumoniae showed increased infiltration of macrophages and neutrophils, which was significantly reduced in EPCR-deficient mice. An analysis of bacterial burden in the pleural lavage, the lungs, and blood revealed a significantly lower bacterial burden in EPCR-deficient mice compared with wild-type and EPCR-overexpressing mice. Overall, our data provide strong evidence that EPCR deficiency protects against S. pneumoniae infection-induced impairment of lung function and pleural remodeling.


Asunto(s)
Receptor de Proteína C Endotelial/deficiencia , Pulmón/metabolismo , Pleura/metabolismo , Derrame Pleural/metabolismo , Pleuresia/metabolismo , Neumonía Neumocócica/metabolismo , Streptococcus pneumoniae/patogenicidad , Animales , Carga Bacteriana , Células Cultivadas , Modelos Animales de Enfermedad , Receptor de Proteína C Endotelial/genética , Femenino , Fibrosis , Interacciones Huésped-Patógeno , Humanos , Pulmón/microbiología , Pulmón/patología , Pulmón/fisiopatología , Macrófagos/metabolismo , Macrófagos/microbiología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Infiltración Neutrófila , Neutrófilos/metabolismo , Neutrófilos/microbiología , Pleura/microbiología , Pleura/patología , Derrame Pleural/microbiología , Derrame Pleural/patología , Derrame Pleural/fisiopatología , Pleuresia/microbiología , Pleuresia/patología , Pleuresia/fisiopatología , Neumonía Neumocócica/microbiología , Neumonía Neumocócica/patología , Neumonía Neumocócica/fisiopatología
16.
Cell Mol Life Sci ; 78(7): 3637-3656, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33555391

RESUMEN

The opportunistic pathogen Pseudomonas aeruginosa has gained precedence over the years due to its ability to develop resistance to existing antibiotics, thereby necessitating alternative strategies to understand and combat the bacterium. Our previous work identified the interaction between the bacterial lectin LecA and its host cell glycosphingolipid receptor globotriaosylceramide (Gb3) as a crucial step for the engulfment of P. aeruginosa via the lipid zipper mechanism. In this study, we define the LecA-associated host cell membrane domain by pull-down and mass spectrometry analysis. We unraveled a predilection of LecA for binding to saturated, long fatty acyl chain-containing Gb3 species in the extracellular membrane leaflet and an induction of dynamic phosphatidylinositol (3,4,5)-trisphosphate (PIP3) clusters at the intracellular leaflet co-localizing with sites of LecA binding. We found flotillins and the GPI-anchored protein CD59 not only to be an integral part of the LecA-interacting membrane domain, but also majorly influencing bacterial invasion as depletion of either of these host cell proteins resulted in about 50% reduced invasiveness of the P. aeruginosa strain PAO1. In summary, we report that the LecA-Gb3 interaction at the extracellular leaflet induces the formation of a plasma membrane domain enriched in saturated Gb3 species, CD59, PIP3 and flotillin thereby facilitating efficient uptake of PAO1.


Asunto(s)
Antígenos CD59/metabolismo , Membrana Celular/metabolismo , Interacciones Huésped-Patógeno , Pulmón/microbiología , Proteínas de la Membrana/metabolismo , Pseudomonas aeruginosa/aislamiento & purificación , Trihexosilceramidas/metabolismo , Transporte Biológico , Antígenos CD59/genética , Endocitosis , Células Epiteliales/metabolismo , Células Epiteliales/microbiología , Células Epiteliales/patología , Humanos , Pulmón/metabolismo , Pulmón/patología , Proteínas de la Membrana/genética , Pseudomonas aeruginosa/fisiología , Transducción de Señal
17.
J Vis Exp ; (167)2021 01 22.
Artículo en Inglés | MEDLINE | ID: mdl-33554970

RESUMEN

The effective prescription of antibiotics for the bacterial biofilms present within the lungs of individuals with cystic fibrosis (CF) is limited by a poor correlation between antibiotic susceptibility testing (AST) results using standard diagnostic methods (e.g., broth microdilution, disk diffusion, or Etest) and clinical outcomes after antibiotic treatment. Attempts to improve AST by the use of off-the-shelf biofilm growth platforms show little improvement in results. The limited ability of in vitro biofilm systems to mimic the physicochemical environment of the CF lung and, therefore bacterial physiology and biofilm architecture, also acts as a brake on the discovery of novel therapies for CF infection. Here, we present a protocol to perform AST of CF pathogens grown as mature, in vivo-like biofilms in an ex vivo CF lung model comprised of pig bronchiolar tissue and synthetic CF sputum (ex vivo pig lung, EVPL). Several in vitro assays exist for biofilm susceptibility testing, using either standard laboratory medium or various formulations of synthetic CF sputum in microtiter plates. Both growth medium and biofilm substrate (polystyrene plate vs. bronchiolar tissue) are likely to affect biofilm antibiotic tolerance. We show enhanced tolerance of clinical Pseudomonas aeruginosa and Staphylococcus aureus isolates in the ex vivo model; the effects of antibiotic treatment of biofilms is not correlated with the minimum inhibitory concentration (MIC) in standard microdilution assays or a sensitive/resistant classification in disk diffusion assays. The ex vivo platform could be used for bespoke biofilm AST of patient samples and as an enhanced testing platform for potential antibiofilm agents during pharmaceutical research and development. Improving the prescription or acceleration of antibiofilm drug discovery through the use of more in vivo-like testing platforms could drastically improve health outcomes for individuals with CF, as well as reduce the costs of clinical treatment and discovery research.


Asunto(s)
Antibacterianos/farmacología , Biopelículas/efectos de los fármacos , Fibrosis Quística/microbiología , Pulmón/microbiología , Pseudomonas aeruginosa/fisiología , Staphylococcus aureus/fisiología , Animales , Biopelículas/crecimiento & desarrollo , Colistina/farmacología , Recuento de Colonia Microbiana , Disección , Floxacilina/farmacología , Humanos , Linezolid/farmacología , Pulmón/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Viabilidad Microbiana/efectos de los fármacos , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/aislamiento & purificación , Esputo/microbiología , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/aislamiento & purificación , Porcinos
18.
Yi Chuan ; 43(1): 30-39, 2021 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-33509772

RESUMEN

Lung microbiome exists in the respiratory tract and parenchymal tissues. It mediates lung injury through a variety of mechanisms, including bacterial disturbance, metabolites, inflammatory response, immune response, and genotoxicity. Accumulating evidences suggest that changes in lung microbiome correlates with chronic obstructive pulmonary disease (COPD) and lung cancer, and the microbiome promotes the progression from COPD to lung cancer. In this review, we mainly introduce the impairment of the homeostasis of the lung microbiome and its inflammation that leads to COPD and lung cancer, then focus on how the microbiome mediates the progression from COPD to lung cancer through inflammatory response. The review may provide a new theoretical basis for clinical prevention, optimal treatment strategy and design of new drugs for COPD and lung cancer.


Asunto(s)
Inflamación/microbiología , Neoplasias Pulmonares/microbiología , Pulmón/microbiología , Microbiota , Enfermedad Pulmonar Obstructiva Crónica/microbiología , Progresión de la Enfermedad , Humanos
19.
mBio ; 12(1)2021 01 05.
Artículo en Inglés | MEDLINE | ID: mdl-33402537

RESUMEN

Invasive bacterial infections during pregnancy are a major risk factor for preterm birth, stillbirth, and fetal injury. Group B streptococci (GBS) are Gram-positive bacteria that asymptomatically colonize the lower genital tract but infect the amniotic fluid and induce preterm birth or stillbirth. Experimental models that closely emulate human pregnancy are pivotal for the development of successful strategies to prevent these adverse pregnancy outcomes. Using a unique nonhuman primate model that mimics human pregnancy and informs temporal events surrounding amniotic cavity invasion and preterm labor, we show that the animals inoculated with hyaluronidase (HylB)-expressing GBS consistently exhibited microbial invasion into the amniotic cavity, fetal bacteremia, and preterm labor. Although delayed cytokine responses were observed at the maternal-fetal interface, increased prostaglandin and matrix metalloproteinase levels in these animals likely mediated preterm labor. HylB-proficient GBS dampened reactive oxygen species production and exhibited increased resistance to neutrophils compared to an isogenic mutant. Together, these findings demonstrate how a bacterial enzyme promotes GBS amniotic cavity invasion and preterm labor in a model that closely resembles human pregnancy.IMPORTANCE Group B streptococci (GBS) are bacteria that commonly reside in the female lower genital tract as asymptomatic members of the microbiota. However, during pregnancy, GBS can infect tissues at the maternal-fetal interface, leading to preterm birth, stillbirth, or fetal injury. Understanding how GBS evade host defenses during pregnancy is key to developing improved preventive therapies for these adverse outcomes. In this study, we used a unique nonhuman primate model to show that an enzyme secreted by GBS, hyaluronidase (HylB) promotes bacterial invasion into the amniotic cavity and fetus. Although delayed immune responses were seen at the maternal-fetal interface, animals infected with hyaluronidase-expressing GBS exhibited premature cervical ripening and preterm labor. These observations reveal that HylB is a crucial GBS virulence factor that promotes bacterial invasion and preterm labor in a pregnancy model that closely emulates human pregnancy. Therefore, hyaluronidase inhibitors may be useful in therapeutic strategies against ascending GBS infection.


Asunto(s)
Hialuronoglucosaminidasa/metabolismo , Neutrófilos/inmunología , Trabajo de Parto Prematuro/inmunología , Infecciones Estreptocócicas/inmunología , Streptococcus agalactiae/metabolismo , Líquido Amniótico/microbiología , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Hialuronoglucosaminidasa/genética , Inflamación , Pulmón/microbiología , Pulmón/patología , Macaca nemestrina , Neutrófilos/microbiología , Embarazo , Nacimiento Prematuro , Primates , Infecciones Estreptocócicas/metabolismo , Infecciones Estreptocócicas/microbiología , Streptococcus agalactiae/enzimología , Streptococcus agalactiae/genética , Streptococcus agalactiae/inmunología
20.
PLoS One ; 16(1): e0243484, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33411748

RESUMEN

Neutrophilic inflammation results in loss of lung function in chronic obstructive pulmonary disease (COPD). Gram-negative bacteria, such as nontypeable Haemophilus influenzae (NTHi), trigger acute exacerbations of COPD (AECOPD) and contribute to chronic lung inflammation. The pro-inflammatory cytokine interleukin-17C (IL-17C) is expressed by airway epithelial cells and regulates neutrophilic chemotaxis. Here, we explored the function of IL-17C in NTHi- and cigarette smoke (CS)-induced models of COPD. Neutrophilic inflammation and tissue destruction were decreased in lungs of IL-17C-deficient mice (Il-17c-/-) chronically exposed to NTHi. Numbers of pulmonary neutrophils were decreased in Il-17c-/- mice after acute exposure to the combination of NTHi and CS. However, Il-17c-/- mice were not protected from CS-induced lung inflammation. In a preliminary patient study, we show that IL-17C is present in sputum samples obtained during AECOPD and associates with disease severity. Concentrations of IL-17C were significantly increased during advanced COPD (GOLD III/IV) compared to moderate COPD (GOLD I/II). Concentrations of IL-17A and IL-17E did not associate with disease severity. Our data suggest that IL-17C promotes harmful pulmonary inflammation triggered by bacteria in COPD.


Asunto(s)
Progresión de la Enfermedad , Haemophilus influenzae/fisiología , Interleucina-17/metabolismo , Pulmón/microbiología , Pulmón/patología , Neumonía/microbiología , Enfermedad Pulmonar Obstructiva Crónica/microbiología , Esputo/microbiología , Enfermedad Aguda , Anciano , Animales , Fumar Cigarrillos/efectos adversos , Citocinas/metabolismo , Femenino , Humanos , Masculino , Ratones Endogámicos C57BL , Neutrófilos/patología
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