RESUMO
A central paradigm of immunity is that interferon (IFN)-mediated antiviral responses precede pro-inflammatory ones, optimizing host protection and minimizing collateral damage1,2. Here, we report that for coronavirus disease 2019 (COVID-19) this paradigm does not apply. By investigating temporal IFN and inflammatory cytokine patterns in 32 moderate-to-severe patients with COVID-19 hospitalized for pneumonia and longitudinally followed for the development of respiratory failure and death, we reveal that IFN-λ and type I IFN production were both diminished and delayed, induced only in a fraction of patients as they became critically ill. On the contrary, pro-inflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-6 and IL-8 were produced before IFNs in all patients and persisted for a prolonged time. This condition was reflected in blood transcriptomes wherein prominent IFN signatures were only seen in critically ill patients who also exhibited augmented inflammation. By comparison, in 16 patients with influenza (flu) hospitalized for pneumonia with similar clinicopathological characteristics to those of COVID-19 and 24 nonhospitalized patients with flu with milder symptoms, IFN-λ and type I IFN were robustly induced earlier, at higher levels and independently of disease severity, whereas pro-inflammatory cytokines were only acutely produced. Notably, higher IFN-λ concentrations in patients with COVID-19 correlated with lower viral load in bronchial aspirates and faster viral clearance and a higher IFN-λ to type I IFN ratio correlated with improved outcome for critically ill patients. Moreover, altered cytokine patterns in patients with COVID-19 correlated with longer hospitalization and higher incidence of critical disease and mortality compared to flu. These data point to an untuned antiviral response in COVID-19, contributing to persistent viral presence, hyperinflammation and respiratory failure.
Assuntos
COVID-19/imunologia , Imunidade/imunologia , Influenza Humana/imunologia , Interferon Tipo I/imunologia , Interferons/imunologia , SARS-CoV-2/imunologia , Antivirais/imunologia , Antivirais/metabolismo , COVID-19/genética , COVID-19/virologia , Citocinas/genética , Citocinas/imunologia , Progressão da Doença , Expressão Gênica/genética , Expressão Gênica/imunologia , Perfilação da Expressão Gênica/métodos , Humanos , Imunidade/genética , Inflamação/genética , Inflamação/imunologia , Influenza Humana/genética , Interferon Tipo I/genética , Interferons/genética , Tempo de Internação , Prognóstico , SARS-CoV-2/fisiologia , Carga Viral/genética , Carga Viral/imunologia , Interferon lambdaRESUMO
Lambda interferons (IFNλs) or type III IFNs share homology, expression patterns, signaling cascades, and antiviral functions with type I IFNs. This has complicated the unwinding of their unique non-redundant roles. Through the systematic study of influenza virus infection in mice, we herein show that IFNλs are the first IFNs produced that act at the epithelial barrier to suppress initial viral spread without activating inflammation. If infection progresses, type I IFNs come into play to enhance viral resistance and induce pro-inflammatory responses essential for confronting infection but causing immunopathology. Central to this are neutrophils which respond to both cytokines to upregulate antimicrobial functions but exhibit pro-inflammatory activation only to type I IFNs. Accordingly, Ifnlr1-/- mice display enhanced type I IFN production, neutrophilia, lung injury, and lethality, while therapeutic administration of PEG-IFNλ potently suppresses these effects. IFNλs therefore constitute the front line of antiviral defense in the lung without compromising host fitness.
Assuntos
Aptidão Genética , Interações Hospedeiro-Patógeno , Vírus da Influenza A/imunologia , Influenza Humana/imunologia , Influenza Humana/metabolismo , Interferon gama/metabolismo , Animais , Análise por Conglomerados , Citocinas/biossíntese , Modelos Animais de Doenças , Resistência à Doença/genética , Resistência à Doença/imunologia , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Genes Reporter , Humanos , Mediadores da Inflamação/metabolismo , Vírus da Influenza A/genética , Influenza Humana/tratamento farmacológico , Influenza Humana/virologia , Interferon gama/genética , Interferon gama/farmacologia , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Masculino , Camundongos , Camundongos Knockout , Neutrófilos/imunologia , Neutrófilos/metabolismo , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/metabolismo , Infecções por Orthomyxoviridae/mortalidade , Infecções por Orthomyxoviridae/virologia , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Mucosa Respiratória/virologia , Carga Viral , Replicação ViralRESUMO
BACKGROUND: Although acute exacerbations, mostly triggered by viruses, account for the majority of hospitalizations in asthmatic patients, there is still very little known about the pathophysiologic mechanisms involved. Plasmacytoid dendritic cells (pDCs), prominent cells of antiviral immunity, exhibit proinflammatory or tolerogenic functions depending on the context, yet their involvement in asthma exacerbations remains unexplored. OBJECTIVES: We sought to investigate the role of pDCs in allergic airway inflammation and acute asthma exacerbations. METHODS: Animal models of allergic airway disease (AAD) and virus-induced AAD exacerbations were used to dissect pDC function in vivo and unwind the potential mechanisms involved. Sputum from asthmatic patients with stable disease or acute exacerbations was further studied to determine the presence of pDCs and correlation with inflammation. RESULTS: pDCs were key mediators of the immunoinflammatory cascade that drives asthma exacerbations. In animal models of AAD and rhinovirus-induced AAD exacerbations, pDCs were recruited to the lung during inflammation and migrated to the draining lymph nodes to boost TH2-mediated effector responses. Accordingly, pDC depletion after allergen challenge or during rhinovirus infection abrogated exacerbation of inflammation and disease. Central to this process was IL-25, which was induced by allergen challenge or rhinovirus infection and conditioned pDCs for proinflammatory function. Consistently, in asthmatic patients pDC numbers were markedly increased during exacerbations and correlated with the severity of inflammation and the risk for asthma attacks. CONCLUSIONS: Our studies uncover a previously unsuspected role of pDCs in asthma exacerbations with potential diagnostic and prognostic implications. They also propose the therapeutic targeting of pDCs and IL-25 for the treatment of acute asthma.
Assuntos
Asma/imunologia , Células Dendríticas/imunologia , Interleucinas/metabolismo , Infecções por Picornaviridae/imunologia , Hipersensibilidade Respiratória/imunologia , Rhinovirus/fisiologia , Células Th2/imunologia , Doença Aguda , Animais , Asma/complicações , Movimento Celular , Células Cultivadas , Modelos Animais de Doenças , Progressão da Doença , Humanos , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Infecções por Picornaviridae/complicações , Hipersensibilidade Respiratória/complicaçõesRESUMO
Interleukin (IL)-18 is a pro-inflammatory cytokine that was firstly described as an interferon (IFN)-γ-inducing factor. Similar to IL-1ß, IL-18 is synthesized as an inactive precursor requiring processing by caspase-1 into an active cytokine. The platform for activating caspase-1 is known as the inflammasome, a multiple protein complex. Macrophages and dendritic cells are the primary sources for the release of active IL-18, whereas the inactive precursor remains in the intracellular compartment of mesenchymal cells. Finally, the IL-18 precursor is released from dying cells and processed extracellularly. IL-18 has crucial host defense and antitumor activities, and gene therapy to increase IL-18 levels in tissues protects experimental animals from infection and tumor growth and metastasis. Moreover, multiple studies in experimental animal models have shown that IL-18 over-expression results to emphysematous lesions in mice. The published data prompt to the hypothesis that IL-18 induces a broad spectrum of COPD-like inflammatory and remodeling responses in the murine lung and also induces a mixed type 1, type 2, and type 17 cytokine responses. The majority of studies identify IL-18 as a potential target for future COPD therapeutics to limit both the destructive and remodeling processes occurring in COPD lungs.
Assuntos
Células Dendríticas/imunologia , Interleucina-18/imunologia , Pulmão/imunologia , Macrófagos/imunologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Caspase 1/imunologia , Células Dendríticas/patologia , Modelos Animais de Doenças , Humanos , Pulmão/patologia , Macrófagos/patologia , Camundongos , Doença Pulmonar Obstrutiva Crônica/patologia , Doença Pulmonar Obstrutiva Crônica/terapia , Linfócitos T Auxiliares-Indutores/patologiaRESUMO
Lambda interferons (IFN-λs), type III interferons or interleukins 28 and 29 are the latest addition to the class II cytokine family. They share low homology with the interferon (IFN) and IL-10 cytokine families, yet they exhibit common and unique activities, the full spectrum of which still remains incompletely understood. Although initially described for their antiviral functions, it is now appreciated that IFN-λs also mediate diverse antitumor and immune-modulatory effects, and are key determinants of innate immunity at mucosal sites such as the gastrointestinal and respiratory tracks. Here, we are reviewing the biological functions of IFN-λs, the mechanisms controlling their expression, their downstream effects and their role in the maintenance of homeostasis and disease. We are also exploring the potential application of IFN-λs as novel therapeutics.
Assuntos
Imunidade nas Mucosas/efeitos dos fármacos , Interleucinas/imunologia , Receptores de Interferon/imunologia , Viroses/tratamento farmacológico , Animais , Cromossomos Humanos Par 19 , Éxons , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/virologia , Regulação da Expressão Gênica , Humanos , Imunidade Inata , Interleucinas/genética , Interleucinas/farmacologia , Camundongos , Fases de Leitura Aberta , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Isoformas de Proteínas/farmacologia , Receptores de Interferon/genética , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/imunologia , Sistema Respiratório/virologia , Transdução de Sinais , Viroses/imunologia , Viroses/virologia , Receptor de Interferon gamaRESUMO
RATIONALE: Toll-like receptor (TLR) 7/8 ligands are promising candidate drugs for the treatment of allergic asthma and rhinitis. Although their clinical application depends on the development of strategies for topical administration to the lung, this has not been explored in preclinical disease models. OBJECTIVES: To examine the therapeutic effectiveness, persistence of effect, and mode of action of intranasal TLR7 ligand administration in allergic airway disease. METHODS: Wild-type, IFN-alpha receptor (IFN-alphaR)(-/-), IFN-gamma(-/-), CD8(-/-), TLR7(-/-), and radiation-induced chimeric mice deficient in hematopoietic TLR7 expression were subjected to an established model of allergic airway disease. R-848, a specific TLR7 agonist in mice, was administered prophylactically or therapeutically and effects of treatment on helper T-cell type 2 (Th2) responses, eosinophilia, goblet cell metaplasia, and airway hyperresponsiveness were assessed. MEASUREMENTS AND MAIN RESULTS: Intranasal R-848 administration induced a transient immune response characterized by type I interferon production and infiltration of innate immune cells into the lung. This conferred long-term suppression of allergic airway disease via two complementary molecular processes, one mediated by type I interferons and providing acute protection by directly inhibiting effector Th2 responses, and one mediated by immunoregulatory CD8(+) T cells and inducing long-lasting protection by suppressing Th2 responses in an IFN-gamma-dependent manner. CONCLUSIONS: Intranasal R-848 administration is an effective treatment for allergic airway disease. It hijacks an otherwise proinflammatory immune process triggered by TLR7 to mediate long-lasting disease suppression. This provides important insight into the efficacy and mode of action of TLR7 ligands in murine models of allergic airway disease and paves the way for their clinical application in humans.
Assuntos
Asma/imunologia , Imidazóis/farmacologia , Administração Intranasal , Animais , Líquido da Lavagem Broncoalveolar/citologia , Linfócitos T CD8-Positivos/metabolismo , Citocinas/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células Caliciformes/efeitos dos fármacos , Células Caliciformes/patologia , Imunomodulação , Interferons/metabolismo , Leucócitos/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Macrófagos/metabolismo , Metaplasia , Camundongos , Camundongos Endogâmicos C57BL , Células Th2/metabolismo , Fatores de Tempo , Receptor 7 Toll-Like/agonistas , Receptor 8 Toll-Like/agonistas , Regulação para CimaRESUMO
INTRODUCTION: Septic patients undergoing mechanical ventilation (MV) often experience difficulty in weaning. Th aim of this study was to determine whether inflammatory biomarkers of sepsis could be indicative of the failure or success of spontaneous breathing trial (SBT) in these patients. METHODS: Sixty-five patients on MV (42 septic and 23 intubated for other reasons) fulfilling the criteria for SBT were included in the study. Blood samples were collected right before, at the end of (30 min) and 24 h after the SBT. Serum inflammatory mediators associated with sepsis (IL-18, IL-18BP, TNF) were determined and correlated with the outcome of SBT. RESULTS: A successful SBT was achieved in 45 patients (69.2%). Septic patients had a higher percentage of SBT failure as compared to non-septic patients (85% vs. 15%, p = 0.026), with an odds ratio for failing 4.5 times (OR = 4.5 95%CI: 1.16-17.68, p 0.022). IL-18 levels and the relative mRNA expression in serum were significantly higher in septic as compared to non-septic patients (p < 0.05). Sepsis was independently associated with higher serum IL-18 and TNF levels in two time-point GEE models (53-723, p = 0.023 and 0.3-64, p = 0.048, respectively). IL-18BP displayed independent negative association with rapid shallow breathing index (RSBI) (95% CI: -17.6 to -4, p = 0.002). CONCLUSION: Sustained increased levels of IL-18 and IL-18BP, acknowledged markers of sepsis, were found to be indicative of SBT failure in patients recovering from sepsis. Our results show that, although subclinical, remaining septic inflammation that sustaines for a long time complicates the weaning procedure. Biomarkers for the estimation of the septic burden and the right time for weaning are needed.
RESUMO
Type III interferons (IFNs), also termed lambda IFNs (IFNλs) or interleukins-28/29, constitute a new addition to the IFN family. They are induced upon infection and are particularly abundant at barrier surfaces, such as the respiratory and gastrointestinal tracts. Although they signal through a unique heterodimeric receptor complex comprising IFNLR1 and IL10RB, they activate a downstream signaling pathway remarkably similar to that of type I IFNs and share many functions with them. Yet, they also have important differences which are only now starting to unfold. Here, we review the current literature implicating type III IFNs in the regulation of immunity and homeostasis in the respiratory tract. We survey the common and unique characteristics of type III IFNs in terms of expression patterns, cellular targets, and biological activities and discuss their emerging role in first line defenses against respiratory viral infections. We further explore their immune modulatory functions and their involvement in the regulation of inflammatory responses during chronic respiratory diseases, such as asthma and chronic obstructive pulmonary disease. Type III IFNs are, therefore, arising as front-line guardians of immune defenses in the respiratory tract, fine tuning inflammation, and as potential novel therapeutics for the treatment of diverse respiratory diseases, including influenza virus infection and asthma.
RESUMO
Although specialized pro-resolving mediators (SPMs) biosynthesized from polyunsaturated fatty acids are critical for the resolution of acute inflammation, the molecules and pathways that induce their production remain elusive. Here, we show that TLR7, a receptor recognizing viral ssRNA and damaged self-RNA, mobilizes the docosahexaenoic acid (DHA)-derived biosynthetic pathways that lead to the generation of D-series SPMs. In mouse macrophages and human monocytes, TLR7 activation triggered production of DHA-derived monohydroxy metabolome markers and generation of protectin D1 (PD1) and resolvin D1 (RvD1). In mouse allergic airway inflammation, TLR7 activation enhanced production of DHA-derived SPMs including PD1 and accelerated the catabasis of Th2-mediated inflammation. D-series SPMs were critical for TLR7-mediated resolution of airway inflammation as this effect was lost in Alox15(-/-) mice, while resolution was enhanced after local administration of PD1 or RvD1. Together, our findings reveal a new previously unsuspected role of TLR7 in the generation of D-series SPMs and the resolution of allergic airway inflammation. They also identify TLR stimulation as a new approach to drive SPMs and resolution of inflammatory diseases.
Assuntos
Mediadores da Inflamação/metabolismo , Receptor 7 Toll-Like/metabolismo , Animais , Araquidonato 12-Lipoxigenase/deficiência , Araquidonato 12-Lipoxigenase/genética , Araquidonato 12-Lipoxigenase/metabolismo , Araquidonato 15-Lipoxigenase/deficiência , Araquidonato 15-Lipoxigenase/genética , Araquidonato 15-Lipoxigenase/metabolismo , Araquidonato 5-Lipoxigenase/metabolismo , Líquido da Lavagem Broncoalveolar/citologia , Células Cultivadas , Ácidos Docosa-Hexaenoicos/metabolismo , Humanos , Inflamação/metabolismo , Inflamação/terapia , Macrófagos/citologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/imunologia , Monócitos/metabolismoRESUMO
IL-28 (IFN-λ) cytokines exhibit potent antiviral and antitumor function but their full spectrum of activities remains largely unknown. Recently, IL-28 cytokine family members were found to be profoundly down-regulated in allergic asthma. We now reveal a novel role of IL-28 cytokines in inducing type 1 immunity and protection from allergic airway disease. Treatment of wild-type mice with recombinant or adenovirally expressed IL-28A ameliorated allergic airway disease, suppressed Th2 and Th17 responses and induced IFN-γ. Moreover, abrogation of endogenous IL-28 cytokine function in IL-28Rα(-/-) mice exacerbated allergic airway inflammation by augmenting Th2 and Th17 responses, and IgE levels. Central to IL-28A immunoregulatory activity was its capacity to modulate lung CD11c(+) dendritic cell (DC) function to down-regulate OX40L, up-regulate IL-12p70 and promote Th1 differentiation. Consistently, IL-28A-mediated protection was absent in IFN-γ(-/-) mice or after IL-12 neutralization and could be adoptively transferred by IL-28A-treated CD11c(+) cells. These data demonstrate a critical role of IL-28 cytokines in controlling T cell responses in vivo through the modulation of lung CD11c(+) DC function in experimental allergic asthma.