RESUMO
Poor maternal diet during pregnancy is a risk factor for severe lower respiratory infections (sLRIs) in the offspring, but the underlying mechanisms remain elusive. Here, we demonstrate that in mice a maternal low-fiber diet (LFD) led to enhanced LRI severity in infants because of delayed plasmacytoid dendritic cell (pDC) recruitment and perturbation of regulatory T cell expansion in the lungs. LFD altered the composition of the maternal milk microbiome and assembling infant gut microbiome. These microbial changes reduced the secretion of the DC growth factor Flt3L by neonatal intestinal epithelial cells and impaired downstream pDC hematopoiesis. Therapy with a propionate-producing bacteria isolated from the milk of high-fiber diet-fed mothers, or supplementation with propionate, conferred protection against sLRI by restoring gut Flt3L expression and pDC hematopoiesis. Our findings identify a microbiome-dependent Flt3L axis in the gut that promotes pDC hematopoiesis in early life and confers disease resistance against sLRIs.
Assuntos
Microbiota , Infecções Respiratórias , Animais , Feminino , Camundongos , Gravidez , Células Dendríticas , Dieta , PropionatosRESUMO
Rationale: The alarmins IL-33 and HMGB1 (high mobility group box 1) contribute to type 2 inflammation and asthma pathogenesis. Objectives: To determine whether P2Y13-R (P2Y13 receptor), a purinergic GPCR (G protein-coupled receptor) and risk allele for asthma, regulates the release of IL-33 and HMGB1. Methods: Bronchial biopsy specimens were obtained from healthy subjects and subjects with asthma. Primary human airway epithelial cells (AECs), primary mouse AECs, or C57Bl/6 mice were inoculated with various aeroallergens or respiratory viruses, and the nuclear-to-cytoplasmic translocation and release of alarmins was measured by using immunohistochemistry and an ELISA. The role of P2Y13-R in AEC function and in the onset, progression, and exacerbation of experimental asthma was assessed by using pharmacological antagonists and mice with P2Y13-R gene deletion. Measurements and Main Results: Aeroallergen exposure induced the extracellular release of ADP and ATP, nucleotides that activate P2Y13-R. ATP, ADP, and aeroallergen (house dust mite, cockroach, or Alternaria antigen) or virus exposure induced the nuclear-to-cytoplasmic translocation and subsequent release of IL-33 and HMGB1, and this response was ablated by genetic deletion or pharmacological antagonism of P2Y13. In mice, prophylactic or therapeutic P2Y13-R blockade attenuated asthma onset and, critically, ablated the severity of a rhinovirus-associated exacerbation in a high-fidelity experimental model of chronic asthma. Moreover, P2Y13-R antagonism derepressed antiviral immunity, increasing IFN-λ production and decreasing viral copies in the lung. Conclusions: We identify P2Y13-R as a novel gatekeeper of the nuclear alarmins IL-33 and HMGB1 and demonstrate that the targeting of this GPCR via genetic deletion or treatment with a small-molecule antagonist protects against the onset and exacerbations of experimental asthma.
Assuntos
Asma/imunologia , Proteína HMGB1/metabolismo , Interleucina-33/metabolismo , Receptores Purinérgicos P2/metabolismo , Animais , Asma/metabolismo , Asma/fisiopatologia , Biomarcadores/metabolismo , Estudos de Casos e Controles , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Células Epiteliais/metabolismo , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Type-2 immunity elicits tissue repair and homeostasis, however dysregulated type-2 responses cause aberrant tissue remodelling, as observed in asthma. Severe respiratory viral infections in infancy predispose to later asthma, however, the processes that mediate tissue damage-induced type-2 inflammation and the origins of airway remodelling remain ill-defined. Here, using a preclinical mouse model of viral bronchiolitis, we find that increased epithelial and mesenchymal high-mobility group box 1 (HMGB1) expression is associated with increased numbers of IL-13-producing type-2 innate lymphoid cell (ILC2s) and the expansion of the airway smooth muscle (ASM) layer. Anti-HMGB1 ablated lung ILC2 numbers and ASM growth in vivo, and inhibited ILC2-mediated ASM cell proliferation in a co-culture model. Furthermore, we identified that HMGB1/RAGE (receptor for advanced glycation endproducts) signalling mediates an ILC2-intrinsic IL-13 auto-amplification loop. In summary, therapeutic targeting of the HMGB1/RAGE signalling axis may act as a novel asthma preventative by dampening ILC2-mediated type-2 inflammation and associated ASM remodelling.
Assuntos
Remodelação das Vias Aéreas/imunologia , Proteína HMGB1/imunologia , Inflamação/imunologia , Linfócitos/imunologia , Músculo Liso/imunologia , Animais , Camundongos , Músculo Liso/patologia , Receptor para Produtos Finais de Glicação Avançada/imunologiaRESUMO
Collection methods critical load values and total nitrogen budgets for high-elevation and fog-impacted sites requires reliable cloud and fog water deposition estimates. The cost and labor intensity of cloud/fog water sample collection have made it difficult to conduct long-term studies that would provide the data needed to develop accurate estimates. Current understanding of fog formation, transport, and the role of fog and cloud deposition in hydrogeological and biogeochemical cycles is incomplete due, in part, to lack of a concerted interdisciplinary approach to the problem. Historically, these obstacles have limited interest in and collection of cloud and fog water samples. In addition to measurements of cloud/fog chemical composition, documenting fog/cloud deposition fluxes of pollutant and nutrient species requires knowledge of cloud/fog physical properties, frequency and duration of fog/cloud interception with landscapes, properties of vegetation on those landscapes, and properties of the wind that drive droplet/vegetation interactions. Because drop deposition efficiency is dependent on drop size, it is also important to consider variations in fog/cloud drop composition with drop size as species enriched in larger/ smaller drops will experience enhanced/reduced deposition rates. This paper presents summary results from a small U.S. cloud water monitoring network that operated from the mid-nineties through 2011, as well as a brief qualitative review of other cloud and fog water studies conducted in the United States (including Puerto Rico), Europe, South America/Pacific, and Asia. Current collection methods are also reviewed. Recent scientific efforts by the National Atmospheric Deposition Program's (NADP) Total Deposition Science Committee and NADP's Critical Loads of Atmospheric Deposition Science Committee have identified occult (cloud/fog) deposition as a "need" in developing critical loads for ecosystems that experience.
RESUMO
Light-matter coupling in excitonic materials has been the subject of intense recent investigations due to emergence of new materials. Two-dimensional layered hybrid organic/inorganic perovskites (2D HOIPs) support strongly bound excitons at room temperature with some of the highest oscillator strengths and electric loss tangents among the known excitonic materials. Here, we report strong light-matter coupling in Ruddlesden-Popper phase 2D HOIP crystals without the necessity of an external cavity. We report the concurrent occurrence of multiple orders of hybrid light-matter states via both reflectance and luminescence spectroscopy in thick (>100 nm) crystals and near-unity absorption in thin (<20 nm) crystals. We observe resonances with quality factors of >250 in hybridized exciton-polaritons and identify a linear correlation between exciton-polariton mode splitting and extinction coefficient of the various 2D HOIPs. Our work opens the door to studying polariton dynamics in self-hybridized and open cavity systems with broad applications in optoelectronics and photochemistry.
RESUMO
Rationale: Respiratory syncytial virus (RSV) bronchiolitis causes significant infant mortality. Bronchiolitis is characterized by airway epithelial cell (AEC) death; however, the mode of death remains unknown.Objectives: To determine whether necroptosis contributes to RSV bronchiolitis pathogenesis via HMGB1 (high mobility group box 1) release.Methods: Nasopharyngeal samples were collected from children presenting to the hospital with acute respiratory infection. Primary human AECs and neonatal mice were inoculated with RSV and murine Pneumovirus, respectively. Necroptosis was determined via viability assays and immunohistochemistry for RIPK1 (receptor-interacting protein kinase-1), MLKL (mixed lineage kinase domain-like pseudokinase) protein, and caspase-3. Necroptosis was blocked using pharmacological inhibitors and RIPK1 kinase-dead knockin mice.Measurements and Main Results: HMGB1 levels were elevated in nasopharyngeal samples of children with acute RSV infection. RSV-induced epithelial cell death was associated with increased phosphorylated RIPK1 and phosphorylated MLKL but not active caspase-3 expression. Inhibition of RIPK1 or MLKL attenuated RSV-induced HMGB1 translocation and release, and lowered viral load. MLKL inhibition increased active caspase-3 expression in a caspase-8/9-dependent manner. In susceptible mice, Pneumovirus infection upregulated RIPK1 and MLKL expression in the airway epithelium at 8 to 10 days after infection, coinciding with AEC sloughing, HMGB1 release, and neutrophilic inflammation. Genetic or pharmacological inhibition of RIPK1 or MLKL attenuated these pathologies, lowered viral load, and prevented type 2 inflammation and airway remodeling. Necroptosis inhibition in early life ameliorated asthma progression induced by viral or allergen challenge in later life.Conclusions: Pneumovirus infection induces AEC necroptosis. Inhibition of necroptosis may be a viable strategy to limit the severity of viral bronchiolitis and break its nexus with asthma.
Assuntos
Bronquiolite/virologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Proteína HMGB1/metabolismo , Necroptose , Mucosa Respiratória/citologia , Infecções por Vírus Respiratório Sincicial/metabolismo , Animais , Pré-Escolar , Humanos , Lactente , Camundongos , Estudos ProspectivosRESUMO
BACKGROUND: Rhinovirus infection triggers acute asthma exacerbations. IL-33 is an instructive cytokine of type 2 inflammation whose expression is associated with viral load during experimental rhinovirus infection of asthmatic patients. OBJECTIVE: We sought to determine whether anti-IL-33 therapy is effective during disease progression, established disease, or viral exacerbation using a preclinical model of chronic asthma and in vitro human primary airway epithelial cells (AECs). METHODS: Mice were exposed to pneumonia virus of mice and cockroach extract in early and later life and then challenged with rhinovirus to model disease onset, progression, and chronicity. Interventions included anti-IL-33 or dexamethasone at various stages of disease. AECs were obtained from asthmatic patients and healthy subjects and treated with anti-IL-33 after rhinovirus infection. RESULTS: Anti-IL-33 decreased type 2 inflammation in all phases of disease; however, the ability to prevent airway smooth muscle growth was lost after the progression phase. After the chronic phase, IL-33 levels were persistently high, and rhinovirus challenge exacerbated the type 2 inflammatory response. Treatment with anti-IL-33 or dexamethasone diminished exacerbation severity, and anti-IL-33, but not dexamethasone, promoted antiviral interferon expression and decreased viral load. Rhinovirus replication was higher and IFN-λ levels were lower in AECs from asthmatic patients compared with those from healthy subjects. Anti-IL-33 decreased rhinovirus replication and increased IFN-λ levels at the gene and protein levels. CONCLUSION: Anti-IL-33 or dexamethasone suppressed the magnitude of type 2 inflammation during a rhinovirus-induced acute exacerbation; however, only anti-IL-33 boosted antiviral immunity and decreased viral replication. The latter phenotype was replicated in rhinovirus-infected human AECs, suggesting that anti-IL-33 therapy has the additional benefit of enhancing host defense.
Assuntos
Antivirais/farmacologia , Asma/tratamento farmacológico , Asma/imunologia , Inflamação/imunologia , Interleucina-33/imunologia , Vírus da Pneumonia Murina/efeitos dos fármacos , Vírus da Pneumonia Murina/imunologia , Animais , Antivirais/imunologia , Asma/virologia , Suscetibilidade a Doenças/imunologia , Suscetibilidade a Doenças/virologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Células Epiteliais/virologia , Inflamação/tratamento farmacológico , Inflamação/virologia , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Pneumovirus/tratamento farmacológico , Infecções por Pneumovirus/imunologia , Infecções por Pneumovirus/virologia , Carga Viral/efeitos dos fármacos , Carga Viral/imunologiaRESUMO
Atmospheric deposition of nitrogen (N) and sulfur (S) has increased dramatically over pre-industrial levels, with many potential impacts on terrestrial and aquatic ecosystems. Quantitative thresholds, termed "critical loads" (CLs), have been developed to estimate the deposition rate above which damage is thought to occur. However, there remains no comprehensive comparison of when, where, and over what time periods individual CLs have been exceeded. We addressed this knowledge gap by combining several published data sources for historical and contemporary deposition, and overlaying these on six CL types from the National Critical Loads Database (NCLDv2.5; terrestrial acidification, aquatic acidification, lichen, nitrate leaching, plant community composition, and forest-tree health) to examine exceedances from 1800 to 2011. We expressed CLs as the minimum, 10th, and 50th percentiles within 12-km grid cells. Minimum CLs were relatively uniform across the country (200-400 eq·ha-1 ·yr-1 ), and have been exceeded for decades beginning in the early 20th century. The area exceeding minimum CLs peaked in the 1970s and 1980s, exposing 300,000 to 3 million km2 (depending on the CL type) to harmful levels of deposition, with a total area exceeded of 5.8 million km2 (~70% of the conterminous United States). Since then, deposition levels have dropped, especially for S, with modest reductions in exceedance by 2011 for all CL types, totaling 5.2 million km2 in exceedance. The 10th and 50th percentile CLs followed similar trends, but were not consistently available at the 12-km grid scale. We also examined near-term future deposition and exceedances in 2025 under current air quality regulations, and under various scenarios of climate change and additional nitrogen management controls. Current regulations were projected to reduce exceedances of any CL from 5.2 million km2 in 2011 to 4.8 million km2 in 2025. None of the additional N management or climate scenarios significantly affected areal exceedances, although exceedance severity declined. In total, it is clear that many CLs have been exceeded for decades, and are likely to remain so in the short term under current policies. Additionally, we suggest many areas for improvement to enhance our understanding of deposition and its effects to support informed decision making.
Assuntos
Poluição do Ar/história , Ciclo do Nitrogênio , Óxidos de Enxofre , Amônia , História do Século XIX , História do Século XX , História do Século XXI , Óxidos de Nitrogênio , Estados UnidosRESUMO
Excess nitrogen and phosphorus ("nutrients") loadings continue to affect ecosystem function and human health across the U.S. Our ability to connect atmospheric inputs of nutrients to aquatic end points remains limited due to uncoupled air and water quality monitoring. Where connections exist, the information provides insights about source apportionment, trends, risk to sensitive ecosystems, and efficacy of pollution reduction efforts. We examine several issues driving the need for better integrated monitoring, including: coastal eutrophication, urban hotspots of deposition, a shift from oxidized to reduced nitrogen deposition, and the disappearance of pristine lakes. Successful coordination requires consistent data reporting; collocating deposition and water quality monitoring; improving phosphorus deposition measurements; and filling coverage gaps in urban corridors, agricultural areas, undeveloped watersheds, and coastal zones.
Assuntos
Ecossistema , Qualidade da Água , Monitoramento Ambiental , Eutrofização , Humanos , Nitrogênio , Nutrientes , Fósforo , ÁguaRESUMO
Inducible BALT (iBALT) can amplify pulmonary or systemic inflammatory responses to the benefit or detriment of the host. We took advantage of the age-dependent formation of iBALT to interrogate the underlying mechanisms that give rise to this ectopic, tertiary lymphoid organ. In this study, we show that the reduced propensity for weanling as compared with neonatal mice to form iBALT in response to acute LPS exposure is associated with greater regulatory T cell expansion in the mediastinal lymph nodes. Ab- or transgene-mediated depletion of regulatory T cells in weanling mice upregulated the expression of IL-17A and CXCL9 in the lungs, induced a tissue neutrophilia, and increased the frequency of iBALT to that observed in neonatal mice. Remarkably, neutrophil depletion in neonatal mice decreased the expression of the B cell active cytokines, a proliferation-inducing ligand and IL-21, and attenuated LPS-induced iBALT formation. Taken together, our data implicate a role for neutrophils in lymphoid neogenesis. Neutrophilic inflammation is a common feature of many autoimmune diseases in which iBALT are present and pathogenic, and hence the targeting of neutrophils or their byproducts may serve to ameliorate detrimental lymphoid neogenesis in a variety of disease contexts.
Assuntos
Inflamação/imunologia , Tecido Linfoide/imunologia , Neutrófilos/imunologia , Linfócitos T Reguladores/imunologia , Animais , Animais Recém-Nascidos , Microambiente Celular/imunologia , Citocinas/biossíntese , Inflamação/metabolismo , Inflamação/patologia , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/imunologia , Depleção Linfocítica , Tecido Linfoide/metabolismo , Masculino , Camundongos , Neutrófilos/metabolismo , Linfócitos T Reguladores/metabolismo , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismoRESUMO
BACKGROUND: Frequent viral lower respiratory infections in early life are an independent risk factor for asthma onset. This risk and the development of persistent asthma are significantly greater in children who later become sensitized. OBJECTIVE: We sought to elucidate the pathogenic processes that underlie the synergistic interplay between allergen exposures and viral infections. METHODS: Mice were inoculated with a murine-specific Pneumovirus species (pneumonia virus of mice [PVM]) and exposed to low-dose cockroach extract (CRE) in early and later life, and airway inflammation, remodeling, and hyperreactivity assessed. Mice were treated with anti-IL-33 or apyrase to neutralize or block IL-33 release. RESULTS: PVM infection or CRE exposure alone did not induce disease, whereas PVM/CRE coexposure acted synergistically to induce the hallmark features of asthma. CRE exposure during viral infection in early life induced a biphasic IL-33 response and impaired IFN-α and IFN-λ production, which in turn increased epithelial viral burden, airway smooth muscle growth, and type 2 inflammation. These features were ameliorated when CRE-induced IL-33 release was blocked or neutralized, whereas substitution of CRE with exogenous IL-33 recapitulated the phenotype observed in PVM/CRE-coexposed mice. Mechanistically, IL-33 downregulated viperin and interferon regulatory factor 7 gene expression and rapidly degraded IL-1 receptor-associated kinase 1 expression in plasmacytoid dendritic cells both in vivo and in vitro, leading to Toll-like receptor 7 hyporesponsiveness and impaired IFN-α production. CONCLUSION: We identified a hitherto unrecognized function of IL-33 as a potent suppressor of innate antiviral immunity and demonstrate that IL-33 contributes significantly to the synergistic interplay between respiratory virus and allergen exposures in the onset and progression of asthma.
Assuntos
Alérgenos/imunologia , Asma/imunologia , Baratas , Citocinas/imunologia , Proteínas de Insetos/imunologia , Vírus da Pneumonia Murina , Infecções por Pneumovirus/imunologia , Poluentes Atmosféricos/imunologia , Animais , Asma/virologia , Líquido da Lavagem Broncoalveolar/imunologia , Líquido da Lavagem Broncoalveolar/virologia , Células Dendríticas/imunologia , Pulmão/virologia , Camundongos Endogâmicos BALB C , Infecções por Pneumovirus/virologia , Carga ViralRESUMO
C3a is a key complement activation fragment, yet its neutrophil-expressed receptor (C3aR) still has no clearly defined role. In this study, we used a neutrophil-dependent mouse model of intestinal ischemia-reperfusion (IR) injury to explore the role of C3aR in acute tissue injuries. C3aR deficiency worsened intestinal injury, which corresponded with increased numbers of tissue-infiltrating neutrophils. Circulating neutrophils were significantly increased in C3aR(-/-) mice after intestinal ischemia, and C3aR(-/-) mice also mobilized more circulating neutrophils after granulocyte colony-stimulating factor infusion compared with WT mice, indicating a specific role for C3aR in constraining neutrophil mobilization in response to intestinal injury. In support of this role, C3aR(-/-) mice reconstituted with WT bone marrow reversed IR pathology back to WT levels. Complement C5a receptor (C5aR) antagonism in C3aR(-/-) mice also rectified the worsened pathology after intestinal IR injury but had no effect on circulating neutrophils, highlighting the opposing roles of C3a and C5a in disease pathogenesis. Finally, we found that using a potent C3a agonist to activate C3aR in vivo reduced neutrophil mobilization and ameliorated intestinal IR pathology in WT, but not C3aR(-/-), mice. This study identifies a role for C3aR in regulating neutrophil mobilization after acute intestinal injury and highlights C3aR agonism as a potential treatment option for acute, neutrophil-driven pathologies.
Assuntos
Intestinos/imunologia , Neutrófilos/imunologia , Receptores de Complemento/imunologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Apoptose/imunologia , Citocinas/sangue , Hemoglobinas/metabolismo , Técnicas Histológicas , Intestinos/citologia , Camundongos , Camundongos Knockout , Receptores de Complemento/genética , Receptores de Complemento/metabolismo , Traumatismo por Reperfusão/imunologiaRESUMO
Allergic asthma is underpinned by T helper 2 (Th2) inflammation. Redundancy in Th2 cytokine function and production by innate and adaptive immune cells suggests that strategies aimed at immunomodulation may prove more beneficial. Hence, we sought to determine whether administration of mesenchymal stromal cells (MSCs) to house dust mite (HDM) (Dermatophagoides pteronyssinus)-sensitized mice would suppress the development of Th2 inflammation and airway hyperresponsiveness (AHR) after HDM challenge. We report that the intravenous administration of allogeneic donor MSCs 1 hour before allergen challenge significantly attenuated the features of allergic asthma, including tissue eosinophilia, Th2 cytokine (IL-5 and IL-13) levels in bronchoalveolar lavage fluid, and AHR. The number of infiltrating type 2 innate lymphoid cells was not affected by MSC transfer, suggesting that MSCs may modulate the adaptive arm of Th2 immunity. The effect of MSC administration was long lasting; all features of allergic airway disease were significantly suppressed in response to a second round of HDM challenge 4 weeks after MSC administration. Further, we observed that MSCs decreased the release of epithelial cell-derived alarmins IL-1α and high mobility group box-1 in an IL-1 receptor antagonist-dependent manner. This significantly decreased the expression of the pro-Th2 cytokine IL-25 and reduced the number of activated and antigen-acquiring CD11c(+)CD11b(+) dendritic cells in the lung and mediastinal lymph nodes. Our findings suggest that MSC administration can ameliorate allergic airway inflammation by blunting the amplification of epithelial-derived inflammatory cytokines induced by HDM exposure and may offer long-term protection against Th2-mediated allergic airway inflammation and AHR.
Assuntos
Alérgenos/farmacologia , Dermatophagoides pteronyssinus/imunologia , Eosinofilia/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/imunologia , Hipersensibilidade Respiratória/terapia , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/patologia , Eosinofilia/etiologia , Eosinofilia/genética , Eosinofilia/imunologia , Feminino , Expressão Gênica , Imunomodulação/efeitos dos fármacos , Interleucina-13/genética , Interleucina-13/imunologia , Interleucina-1alfa/genética , Interleucina-1alfa/imunologia , Interleucina-5/genética , Interleucina-5/imunologia , Interleucinas/genética , Interleucinas/imunologia , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Linfonodos/patologia , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Endogâmicos BALB C , Hipersensibilidade Respiratória/etiologia , Hipersensibilidade Respiratória/genética , Hipersensibilidade Respiratória/imunologia , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/imunologia , Mucosa Respiratória/patologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Células Th2/patologia , Transplante HomólogoRESUMO
Human metapneumovirus (hMPV) is a leading cause of respiratory tract disease in children and is associated with acute bronchiolitis, pneumonia, and asthma exacerbations, yet the mechanisms by which the host immune response to hMPV is regulated are poorly understood. By using gene-deleted neonatal mice, we examined the contributions of the innate receptor signaling molecules interferon (IFN)-ß promoter stimulator 1 (IPS-1), IFN regulatory factor (IRF) 3, and IRF7. Viral load in the lungs was markedly greater in IPS-1(-/-) > IRF3/7(-/-) > IRF3(-/-), but not IRF7(-/-), mice compared with wild-type mice. IFN-ß and IFN-λ2/3 (IL-28A/B) production was attenuated in the bronchoalveolar lavage fluid in all factor-deficient mice compared with wild-type mice at 1 day after infection, although IFN-λ2/3 was greater in IRF3/7(-/-) mice at 5 days after infection. IRF7(-/-) and IRF3/7(-/-) mice presented with airway eosinophilia, whereas only IRF3/7(-/-) mice developed an exaggerated type 1 and 17 helper T-cell response, characterized by natural killer T-cell and neutrophilic inflammation. Despite having the highest viral load, IPS-1(-/-) mice did not develop a proinflammatory cytokine or granulocytic response to hMPV infection. Our findings demonstrate that IFN-ß, but not IFN-λ2/3, produced via an IPS-1-IRF3 signaling pathway, is important for hMPV clearance. In the absence of a robust type I IFN-α/ß response, targeting the IPS-1 signaling pathway may limit the overexuberant inflammatory response that occurs as a consequence of viral persistence.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/imunologia , Fator Regulador 3 de Interferon/imunologia , Fator Regulador 7 de Interferon/imunologia , Metapneumovirus/imunologia , Infecções por Paramyxoviridae/imunologia , Células Th1/imunologia , Células Th17/imunologia , Doença Aguda , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Humanos , Fator Regulador 3 de Interferon/genética , Fator Regulador 7 de Interferon/genética , Interferons/genética , Interferons/imunologia , Metapneumovirus/genética , Camundongos , Camundongos Knockout , Infecções por Paramyxoviridae/genética , Infecções por Paramyxoviridae/patologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Células Th1/patologia , Células Th17/patologiaRESUMO
The onset, progression and exacerbations of asthma are frequently associated with viral infections of the lower respiratory tract. An emerging paradigm suggests that this relationship may be underpinned by a defect in the host's antiviral response, typified by the impaired production of type I and type III interferons (IFNs). The failure to control viral burden probably causes damage to the lung architecture and contributes to an aberrant immune response, which together compromise lung function. Although a relatively rare cell type, the plasmacytoid dendritic cell dedicates much of its transcriptome to the synthesis of IFNs and is pre-armed with virus-sensing pattern recognition receptors. Thus, plasmacytoid dendritic cells are specialised to ensure early viral detection and the rapid induction of the antiviral state to block viral replication and spread. In addition, plasmacytoid dendritic cells can limit immunopathology, and promote peripheral tolerance to prevent allergic sensitisation to harmless antigens, possibly through the induction of regulatory T-cells. Thus, this enigmatic cell may lie at an important intersection, orchestrating the immediate phase of antiviral immunity to effect viral clearance while regulating tolerance. Here, we review the evidence to support the hypothesis that a primary defect in plasmacytoid dendritic function may underlie the development of asthma.
Assuntos
Asma/imunologia , Células Dendríticas/imunologia , Interferons/imunologia , Pulmão/imunologia , Pneumonia Viral/imunologia , Asma/fisiopatologia , Humanos , Pulmão/fisiopatologia , Infecções por Vírus Respiratório Sincicial/imunologia , Linfócitos T Reguladores/imunologiaRESUMO
Emissions of sulfur dioxide (SO2) to the atmosphere lead to atmospheric deposition of sulfate (SO4(2-)), which is the dominant strong acid anion causing acidification of surface waters and soils in the eastern United States. Since passage of the Clean Air Act and its Amendments, atmospheric deposition of SO2 in this region has declined by over 80%, but few corresponding decreases in streamwater SO4(2-) concentrations have been observed in unglaciated watersheds. We calculated SO4(2-) mass balances for 27 forested, unglaciated watersheds from Pennsylvania to Georgia, by using total atmospheric deposition (wet plus dry) as input. Many of these watersheds still retain SO4(2-), unlike their counterparts in the northeastern U.S. and southern Canada. Our analysis showed that many of these watersheds should convert from retaining to releasing SO4(2-) over the next two decades. The specific years when the watersheds crossover from retaining to releasing SO4(2-) correspond to a general geographical pattern of later net watershed release from north to south. The single most important variable that explained the crossover year was the runoff ratio, defined as the ratio of annual mean stream discharge to precipitation. Percent clay content and mean soil depth were secondary factors in predicting crossover year. The conversion of watersheds from net SO4(2-) retention to release anticipates more widespread reductions in streamwater SO4(2-) concentrations in this region.
Assuntos
Atmosfera/química , Sulfatos/análise , Enxofre/análise , Água/química , Geografia , Modelos Lineares , Rios/química , Sudeste dos Estados UnidosRESUMO
BACKGROUND: Respiratory tract viruses are a major environmental risk factor for both the inception and exacerbations of asthma. Genetic defects in Toll-like receptor (TLR) 7-mediated signaling, impaired type I interferon responses, or both have been reported in asthmatic patients, although their contribution to the onset and exacerbation of asthma remains poorly understood. OBJECTIVE: We sought to determine whether Pneumovirus infection in the absence of TLR7 predisposes to bronchiolitis and the inception of asthma. METHODS: Wild-type and TLR7-deficient (TLR7(-/-)) mice were inoculated with the rodent-specific pathogen pneumonia virus of mice at 1 (primary), 7 (secondary), and 13 (tertiary) weeks of age, and pathologic features of bronchiolitis or asthma were assessed. In some experiments infected mice were exposed to low-dose cockroach antigen. RESULTS: TLR7 deficiency increased viral load in the airway epithelium, which became sloughed and necrotic, and promoted an IFN-α/ß(low), IL-12p70(low), IL-1ß(high), IL-25(high), and IL-33(high) cytokine microenvironment that was associated with the recruitment of type 2 innate lymphoid cells/nuocytes and increased TH2-type cytokine production. Viral challenge of TLR7(-/-) mice induced all of the cardinal pathophysiologic features of asthma, including tissue eosinophilia, mast cell hyperplasia, IgE production, airway smooth muscle alterations, and airways hyperreactivity in a memory CD4(+) T cell-dependent manner. Importantly, infections with pneumonia virus of mice promoted allergic sensitization to inhaled cockroach antigen in the absence but not the presence of TLR7. CONCLUSION: TLR7 gene defects and Pneumovirus infection interact to establish an aberrant adaptive response that might underlie virus-induced asthma exacerbations in later life.
Assuntos
Asma/imunologia , Asma/patologia , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/genética , Vírus da Pneumonia Murina , Infecções por Pneumovirus/complicações , Receptor 7 Toll-Like/deficiência , Receptor 7 Toll-Like/genética , Animais , Animais Recém-Nascidos , Asma/etiologia , Modelos Animais de Doenças , Pulmão/patologia , Pulmão/fisiopatologia , Pulmão/virologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Vírus da Pneumonia Murina/patogenicidade , Infecções por Pneumovirus/imunologia , Infecções por Pneumovirus/patologia , Carga ViralRESUMO
Purpose: As stakeholders seek to improve patient outcomes while maintaining cost-effectiveness in an increasingly expensive healthcare system, metrics such as patient satisfaction are becoming more important. This present study sought to identify factors associated with and independently predictive of better surgical satisfaction two years following hand and wrist surgery. Methods: Patients undergoing hand and wrist surgery at an urban outpatient institution were enrolled preoperatively into a surgical registry and assessed two years postoperatively. Patient satisfaction with surgery was measured at two years postoperatively with the Surgical Satisfaction Questionnaire (SSQ-8). Bivariate analysis determined associations between postoperative satisfaction and patient demographics, injury specifiers, medical history, and multiple patient-reported outcomes (PROs). Multivariable analysis determined independent predictors of two-year postoperative satisfaction following hand and wrist surgery. Results: Better surgical satisfaction was associated with having never smoked, no preoperative opioid use, lack of an accompanying legal claim, lack of a workers compensation claim, no clinical history of depression/anxiety, less comorbidities, and higher preoperative expectations.Various PROs relating to function, pain, activity, and general health at both baseline and two years demonstrated associations with postoperative satisfaction. Multivariable analysis confirmed that never smoking, lack of a legal claim, and better preoperative Brief Michigan Hand Questionnaire scores were independently predictive of better surgical satisfaction two years following hand and wrist surgery. Conclusion: At two years following hand and wrist surgery, better patient satisfaction was best predicted by never smoking, no related legal claim, and better baseline Brief Michigan Hand Questionnaire scores. Level of evidence: III.
RESUMO
Excitons, bound electron-hole pairs, in two-dimensional hybrid organic inorganic perovskites (2D HOIPs) are capable of forming hybrid light-matter states known as exciton-polaritons (E-Ps) when the excitonic medium is confined in an optical cavity. In the case of 2D HOIPs, they can self-hybridize into E-Ps at specific thicknesses of the HOIP crystals that form a resonant optical cavity with the excitons. However, the fundamental properties of these self-hybridized E-Ps in 2D HOIPs, including their role in ultrafast energy and/or charge transfer at interfaces, remain unclear. Here, we demonstrate that >0.5 µm thick 2D HOIP crystals on Au substrates are capable of supporting multiple-orders of self-hybridized E-P modes. These E-Ps have high Q factors (>100) and modulate the optical dispersion for the crystal to enhance sub-gap absorption and emission. Through varying excitation energy and ultrafast measurements, we also confirm energy transfer from higher energy E-Ps to lower energy E-Ps. Finally, we also demonstrate that E-Ps are capable of charge transport and transfer at interfaces. Our findings provide new insights into charge and energy transfer in E-Ps opening new opportunities towards their manipulation for polaritonic devices.
RESUMO
Engineered smart microbes that deliver therapeutic payloads are emerging as treatment modalities, particularly for diseases with links to the gastrointestinal tract. Enterohemorrhagic E coli (EHEC) is a causative agent of potentially lethal hemolytic uremic syndrome. Given concerns that antibiotic treatment increases EHEC production of Shiga toxin (Stx), which is responsible for systemic disease, novel remedies are needed. EHEC encodes a type III secretion system (T3SS) that injects Tir into enterocytes. Tir inserts into the host cell membrane, exposing an extracellular domain that subsequently binds intimin, one of its outer membrane proteins, triggering the formation of attaching and effacing (A/E) lesions that promote EHEC mucosal colonization. Citrobacter rodentium (Cr), a natural A/E mouse pathogen, similarly requires Tir and intimin for its pathogenesis. Mice infected with Cr(ΦStx2dact), a variant lysogenized with an EHEC-derived phage that produces Stx2dact, develop intestinal A/E lesions and toxin-dependent disease. Stx2a is more closely associated with human disease. By developing an efficient approach to seamlessly modify the C. rodentium genome, we generated Cr_Tir-MEHEC(ΦStx2a), a variant that expresses Stx2a and the EHEC extracellular Tir domain. We found that mouse pre-colonization with HS-PROT3EcT-TD4, a human commensal E. coli strain (E. coli HS) engineered to efficiently secrete- an anti-EHEC Tir nanobody, delayed bacterial colonization and improved survival after challenge with Cr_Tir-MEHEC(ΦStx2a). This study provides the first evidence to support the efficacy of engineered commensal E. coli to intestinally deliver therapeutic payloads that block essential enteric pathogen virulence determinants, a strategy that may serve as an antibiotic-independent antibacterial therapeutic modality.