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1.
Toxicol Sci ; 176(2): 312-328, 2020 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-32514536

RESUMEN

Arsenic exposure via drinking water is a serious environmental health concern. Epidemiological studies suggest a strong association between prenatal arsenic exposure and subsequent childhood respiratory infections, as well as morbidity from respiratory diseases in adulthood, long after systemic clearance of arsenic. We investigated the impact of exclusive prenatal arsenic exposure on the inflammatory immune response and respiratory health after an adult influenza A virus (IAV) lung infection. C57BL/6J mice were exposed to 100 ppb sodium arsenite in utero, and subsequently infected with IAV (H1N1) after maturation to adulthood. Assessment of lung tissue and bronchoalveolar lavage fluid at various time points post-IAV infection reveals greater lung damage and inflammation in arsenic-exposed mice versus control mice. Single-cell RNA sequencing analysis of immune cells harvested from IAV-infected lungs suggests that the enhanced inflammatory response is mediated by dysregulation of innate immune function of monocyte-derived macrophages, neutrophils, natural killer cells, and alveolar macrophages. Our results suggest that prenatal arsenic exposure results in lasting effects on the adult host innate immune response to IAV infection, long after exposure to arsenic, leading to greater immunopathology. This study provides the first direct evidence that exclusive prenatal exposure to arsenic in drinking water causes predisposition to a hyperinflammatory response to IAV infection in adult mice, which is associated with significant lung damage.


Asunto(s)
Arsénico , Subtipo H1N1 del Virus de la Influenza A , Infecciones por Orthomyxoviridae/inmunología , Efectos Tardíos de la Exposición Prenatal , Animales , Arsénico/efectos adversos , Femenino , Expresión Génica , Humanos , Inmunidad Innata , Gripe Humana , Pulmón , Ratones , Ratones Endogámicos C57BL , Embarazo , RNA-Seq , Análisis de la Célula Individual
2.
Front Immunol ; 9: 2151, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30337919

RESUMEN

Influenza is a common respiratory virus that infects between 5 and 20% of the US population and results in 30,000 deaths annually. A primary cause of influenza-associated death is secondary bacterial pneumonia. We have previously shown that influenza induces type I interferon (IFN)-mediated inhibition of Type 17 immune responses, resulting in exacerbation of bacterial burden during influenza and Staphylococcus aureus super-infection. In this study, we investigated the role of STAT2 signaling during influenza and influenza-bacterial super-infection in mice. Influenza-infected STAT2-/- mice had increased morbidity, viral burden, and inflammation when compared to wild-type mice. Despite an exaggerated inflammatory response to influenza infection, we found increased bacterial control and survival in STAT2 deficient mice during influenza-MRSA super-infection compared to controls. Further, we found that increased bacterial clearance during influenza-MRSA super-infection is not due to rescue of Type 17 immunity. Absence of STAT2 was associated with increased accumulation of M1, M2 and M1/M2 co-expressing macrophages during influenza-bacterial super-infection. Neutralization of IFNγ (M1) and/or Arginase 1 (M2) impaired bacterial clearance in Stat2-/- mice during super-infection, demonstrating that pulmonary macrophages expressing a mixed M1/M2 phenotype promote bacterial control during influenza-bacterial super-infection. Together, these results suggest that the STAT2 signaling is involved in suppressing macrophage activation and bacterial control during influenza-bacterial super-infection. Further, these studies reveal novel mechanistic insight into the roles of macrophage subpopulations in pulmonary host defense.


Asunto(s)
Gripe Humana/inmunología , Macrófagos Alveolares/inmunología , Neumonía Estafilocócica/inmunología , Factor de Transcripción STAT2/metabolismo , Sobreinfección/inmunología , Animales , Trasplante de Médula Ósea , Embrión de Pollo , Modelos Animales de Enfermedad , Femenino , Humanos , Subtipo H1N1 del Virus de la Influenza A/inmunología , Gripe Humana/diagnóstico , Gripe Humana/microbiología , Gripe Humana/mortalidad , Activación de Macrófagos/inmunología , Macrófagos Alveolares/metabolismo , Masculino , Células Madre Mesenquimatosas , Staphylococcus aureus Resistente a Meticilina/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neumonía Estafilocócica/diagnóstico , Neumonía Estafilocócica/microbiología , Neumonía Estafilocócica/mortalidad , Cultivo Primario de Células , Factor de Transcripción STAT2/genética , Factor de Transcripción STAT2/inmunología , Índice de Severidad de la Enfermedad , Transducción de Señal/inmunología , Sobreinfección/diagnóstico , Sobreinfección/microbiología , Sobreinfección/mortalidad , Quimera por Trasplante
3.
J Breath Res ; 12(2): 026015, 2018 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-29199638

RESUMEN

Volatile metabolites are currently under investigation as potential biomarkers for the detection and identification of pathogenic microorganisms, including bacteria, fungi, and viruses. Unlike bacteria and fungi, which produce distinct volatile metabolic signatures associated with innate differences in both primary and secondary metabolic processes, viruses are wholly reliant on the metabolic machinery of infected cells for replication and propagation. In the present study, the ability of volatile metabolites to discriminate between respiratory cells infected and uninfected with virus, in vitro, was investigated. Two important respiratory viruses, namely respiratory syncytial virus (RSV) and influenza A virus (IAV), were evaluated. Data were analyzed using three different machine learning algorithms (random forest (RF), linear support vector machines (linear SVM), and partial least squares-discriminant analysis (PLS-DA)), with volatile metabolites identified from a training set used to predict sample classifications in a validation set. The discriminatory performances of RF, linear SVM, and PLS-DA were comparable for the comparison of IAV-infected versus uninfected cells, with area under the receiver operating characteristic curves (AUROCs) between 0.78 and 0.82, while RF and linear SVM demonstrated superior performance in the classification of RSV-infected versus uninfected cells (AUROCs between 0.80 and 0.84) relative to PLS-DA (0.61). A subset of discriminatory features were assigned putative compound identifications, with an overabundance of hydrocarbons observed in both RSV- and IAV-infected cell cultures relative to uninfected controls. This finding is consistent with increased oxidative stress, a process associated with viral infection of respiratory cells.


Asunto(s)
Técnicas de Cultivo de Célula , Metabolómica/métodos , Virus Sincitiales Respiratorios/metabolismo , Compuestos Orgánicos Volátiles/análisis , Animales , Línea Celular , Análisis Discriminante , Humanos , Virus de la Influenza A/fisiología , Análisis de los Mínimos Cuadrados , Metaboloma , Ratones , Infecciones por Virus Sincitial Respiratorio/metabolismo
4.
J Leukoc Biol ; 98(3): 423-34, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26019295

RESUMEN

Elevated levels of solTNFR2 are observed in a variety of human pathophysiological conditions but regulation of TNFR2 levels during disease is not well understood. We found that solTNFR2 levels were increased following influenza infection or live-attenuated influenza virus challenge in mice and humans, respectively. As influenza-specific CD8(+) T cells up-regulated expression of TNFR2 after infection in mice, we hypothesized that CD8(+) T cells contributed, in part, to solTNFR2 production after influenza infection and were interested in the mechanisms by which CD8(+) T cells regulate TNFR2 shedding. Activation of these cells by TCR stimulation resulted in enhanced shedding of TNFR2 that required actin remodeling and lipid raft formation and was dependent on MAPK/ERK signaling. Furthermore, we identified ADAM17 as the protease responsible for TNFR2 shedding by CD8(+) T cells, with ADAM17 and TNFR2 required in "cis" for shedding to occur. We observed similar activation thresholds for TNF-α expression and TNFR2 shedding, suggesting that solTNFR2 functioned, in part, to regulate solTNF-α levels. Production of solTNFR2 by activated CD8(+) T cells reduced the availability of solTNF-α released by these cells, and TNFR2 blockade during influenza infection in mice enhanced the levels of solTNF-α, supporting this hypothesis. Taken together, this study identifies critical cellular mechanisms regulating TNFR2 shedding on CD8(+) T cells and demonstrates that TNFR2 contributes, in part, to the regulation of TNF-α levels during infection.


Asunto(s)
Proteínas ADAM/metabolismo , Linfocitos T CD8-positivos/inmunología , Gripe Humana/inmunología , Gripe Humana/virología , Infecciones por Orthomyxoviridae/inmunología , Receptores Tipo II del Factor de Necrosis Tumoral/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Proteína ADAM17 , Animales , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Vacunas contra la Influenza/inmunología , Ratones Endogámicos C57BL , Infecciones por Orthomyxoviridae/virología , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal , Solubilidad , Vacunas Atenuadas/inmunología
5.
Am J Physiol Lung Cell Mol Physiol ; 309(2): L158-67, 2015 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-26001778

RESUMEN

Suppression of type 17 immunity by type I interferon (IFN) during influenza A infection has been shown to enhance susceptibility to secondary bacterial pneumonia. Although this mechanism has been described in coinfection with gram-positive bacteria, it is unclear whether similar mechanisms may impair lung defense against gram-negative infections. Furthermore, precise delineation of the duration of type I IFN-associated susceptibility to bacterial infection remains underexplored. Therefore, we investigated the effects of preceding influenza A virus infection on subsequent challenge with the gram-negative bacteria Escherichia coli or Pseudomonas aeruginosa and the temporal association between IFN expression with susceptibility to Staphylococcus aureus challenge in a mouse model of influenza and bacterial coinfection. Here we demonstrate that preceding influenza A virus led to increased lung E. coli and P. aeruginosa bacterial burden, which was associated with suppression of type 17 immunity and attenuation of antimicrobial peptide expression. Enhanced susceptibility to S. aureus coinfection ceased at day 14 of influenza infection, when influenza-associated type I IFN levels had returned to baseline levels, further suggesting a key role for type I IFN in coinfection pathogenesis. These findings further implicate type I IFN-associated suppression of type 17 immunity and antimicrobial peptide production as a conserved mechanism for enhanced susceptibility to both gram-positive and gram-negative bacterial coinfection during influenza infection.


Asunto(s)
Infecciones por Escherichia coli/microbiología , Virus de la Influenza A/patogenicidad , Infecciones por Orthomyxoviridae/microbiología , Neumonía Bacteriana/microbiología , Neumonía/microbiología , Receptor de Interferón alfa y beta/fisiología , Infecciones Estafilocócicas/microbiología , Animales , Péptidos Catiónicos Antimicrobianos/metabolismo , Coinfección/inmunología , Coinfección/microbiología , Coinfección/virología , Susceptibilidad a Enfermedades , Escherichia coli/inmunología , Escherichia coli/patogenicidad , Infecciones por Escherichia coli/inmunología , Infecciones por Escherichia coli/virología , Virus de la Influenza A/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/virología , Neumonía/inmunología , Neumonía/virología , Neumonía Bacteriana/inmunología , Neumonía Bacteriana/virología , Infecciones Estafilocócicas/inmunología , Infecciones Estafilocócicas/virología , Staphylococcus aureus/inmunología , Staphylococcus aureus/patogenicidad
6.
Respir Res ; 16: 10, 2015 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-25651926

RESUMEN

BACKGROUND: Influenza is a common respiratory virus and Staphylococcus aureus frequently causes secondary pneumonia during influenza infection, leading to increased morbidity and mortality. Influenza has been found to attenuate subsequent Type 17 immunity, enhancing susceptibility to secondary bacterial infections. IL-27 is known to inhibit Type 17 immunity, suggesting a potential critical role for IL-27 in viral and bacterial co-infection. METHODS: A murine model of influenza and Staphylococcus aureus infection was used to mimic human viral, bacterial co-infection. C57BL/6 wild-type, IL-27 receptor α knock-out, and IL-10 knock-out mice were infected with Influenza H1N1 (A/PR/8/34) or vehicle for 6 days followed by challenge with Staphylococcus aureus or vehicle for 24 hours. Lung inflammation, bacterial burden, gene expression, and cytokine production were determined. RESULTS: IL-27 receptor α knock-out mice challenged with influenza A had increased morbidity compared to controls, but no change in viral burden. IL-27 receptor α knock-out mice infected with influenza displayed significantly decreased IL-10 production compared to wild-type. IL-27 receptor α knock-out mice co-infected with influenza and S. aureus had improved bacterial clearance compared to wild-type controls. Importantly, there were significantly increased Type 17 responses and decreased IL-10 production in IL-27 receptor α knock-out mice. Dual infected IL-10-/- mice had significantly less bacterial burden compared to dual infected WT mice. CONCLUSIONS: These data reveal that IL-27 regulates enhanced susceptibility to S. aureus pneumonia following influenza infection, potentially through the induction of IL-10 and suppression of IL-17.


Asunto(s)
Coinfección , Subtipo H1N1 del Virus de la Influenza A/inmunología , Interleucinas/inmunología , Pulmón/inmunología , Infecciones por Orthomyxoviridae/inmunología , Neumonía Estafilocócica/inmunología , Staphylococcus aureus/inmunología , Animales , Carga Bacteriana , Modelos Animales de Enfermedad , Interacciones Huésped-Patógeno , Inmunidad Celular , Subtipo H1N1 del Virus de la Influenza A/patogenicidad , Interleucina-10/deficiencia , Interleucina-10/genética , Interleucina-17/inmunología , Pulmón/microbiología , Pulmón/virología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Infecciones por Orthomyxoviridae/virología , Neumonía Estafilocócica/genética , Neumonía Estafilocócica/microbiología , Receptores de Citocinas/deficiencia , Receptores de Citocinas/genética , Receptores de Interleucina , Staphylococcus aureus/patogenicidad , Células Th17/inmunología , Células Th17/microbiología , Células Th17/virología , Factores de Tiempo , Carga Viral
7.
Am J Physiol Lung Cell Mol Physiol ; 308(7): L650-7, 2015 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-25617378

RESUMEN

Influenza infection results in considerable pulmonary pathology, a significant component of which is mediated by CD8(+) T cell effector functions. To isolate the specific contribution of CD8(+) T cells to lung immunopathology, we utilized a nonviral murine model in which alveolar epithelial cells express an influenza antigen and injury is initiated by adoptive transfer of influenza-specific CD8(+) T cells. We report that IFN-γ production by adoptively transferred influenza-specific CD8(+) T cells is a significant contributor to acute lung injury following influenza antigen recognition, in isolation from its impact on viral clearance. CD8(+) T cell production of IFN-γ enhanced lung epithelial cell expression of chemokines and the subsequent recruitment of inflammatory cells into the airways. Surprisingly, Stat1 deficiency in the adoptive-transfer recipients exacerbated the lung injury that was mediated by the transferred influenza-specific CD8(+) T cells but was still dependent on IFN-γ production by these cells. Loss of Stat1 resulted in sustained activation of Stat3 signaling, dysregulated chemokine expression, and increased infiltration of the airways by inflammatory cells. Taken together, these data identify important roles for IFN-γ signaling and Stat1-independent IFN-γ signaling in regulating CD8(+) T cell-mediated acute lung injury. This is the first study to demonstrate an anti-inflammatory effect of Stat1 on CD8(+) T cell-mediated lung immunopathology without the complication of differences in viral load.


Asunto(s)
Lesión Pulmonar Aguda/inmunología , Linfocitos T CD8-positivos/inmunología , Interferón gamma/fisiología , Factor de Transcripción STAT1/metabolismo , Lesión Pulmonar Aguda/virología , Animales , Linfocitos T CD8-positivos/metabolismo , Células Cultivadas , Ratones Endogámicos BALB C , Ratones Noqueados , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/metabolismo , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT3/metabolismo , Transducción de Señal
8.
PLoS One ; 9(9): e108385, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25251060

RESUMEN

Virus infection triggers a CD8(+) T cell response that aids in virus clearance, but also expresses effector functions that may result in tissue injury. CD8(+) T cells express a variety of activating and inhibiting ligands, though regulation of the expression of inhibitory receptors is not well understood. The ligand for the inhibitory receptor, NKG2A, is the non-classical MHC-I molecule Qa1(b), which may also serve as a putative restricting element for the T cell receptors of purported regulatory CD8(+) T cells. We have previously shown that Qa1(b)-null mice suffer considerably enhanced immunopathologic lung injury in the context of CD8(+) T cell-mediated clearance of influenza infection, as well as evidence in a non-viral system that failure to ligate NKG2A on CD8(+) effector T cells may represent an important component of this process. In this report, we examine the requirements for induction of NKG2A expression, and show that NKG2A expression by CD8(+) T cells occurs as a result of migration from the MLN to the inflammatory lung environment, irrespective of peripheral antigen recognition. Further, we confirmed that NKG2A is a mediator in limiting immunopathology in virus infection using mice with a targeted deletion of NKG2A, and infecting the mutants with two different viruses, influenza and adenovirus. In neither infection is virus clearance altered. In influenza infection, the enhanced lung injury was associated with increased chemoattractant production, increased infiltration of inflammatory cells, and significantly enhanced alveolar hemorrhage. The primary mechanism of enhanced injury was the loss of negative regulation of CD8(+) T cell effector function. A similar effect was observed in the livers of mutant mice infected intravenously with adenovirus. These results demonstrate the immunoregulatory role of CD8(+) NKG2A expression in virus infection, which negatively regulates T cell effector functions and contributes to protection of tissue integrity during virus clearance.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Lesión Pulmonar/patología , Subfamília C de Receptores Similares a Lectina de Células NK/genética , Subfamília C de Receptores Similares a Lectina de Células NK/metabolismo , Infecciones por Orthomyxoviridae/inmunología , Adenoviridae/patogenicidad , Infecciones por Adenoviridae/inmunología , Infecciones por Adenoviridae/patología , Infecciones por Adenoviridae/veterinaria , Traslado Adoptivo , Animales , Técnicas de Inactivación de Genes , Virus de la Influenza A/patogenicidad , Lesión Pulmonar/inmunología , Lesión Pulmonar/virología , Ratones , Infecciones por Orthomyxoviridae/patología , Infecciones por Orthomyxoviridae/veterinaria
9.
J Immunol ; 192(12): 5839-51, 2014 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-24790150

RESUMEN

TNF-α is a pleotropic cytokine that has both proinflammatory and anti-inflammatory functions during influenza infection. TNF-α is first expressed as a transmembrane protein that is proteolytically processed to release a soluble form. Transmembrane TNF-α (memTNF-α) and soluble TNF-α (solTNF-α) have been shown to exert distinct tissue-protective or tissue-pathologic effects in several disease models. However, the relative contributions of memTNF-α or solTNF-α in regulating pulmonary immunopathology following influenza infection are unclear. Therefore, we performed intranasal influenza infection in mice exclusively expressing noncleavable memTNF-α or lacking TNF-α entirely and examined the outcomes. We found that solTNF-α, but not memTNF-α, was required to limit the size of the immune response and the extent of injury. In the absence of solTNF-α, there was a significant increase in the CD8(+) T cell response, including virus-specific CD8(+) T cells, which was due in part to an increased resistance to activation-induced cell death. We found that solTNF-α mediates these immunoregulatory effects primarily through TNFR1, because mice deficient in TNFR1, but not TNFR2, exhibited dysregulated immune responses and exacerbated injury similar to that observed in mice lacking solTNF-α. We also found that solTNF-α expression was required early during infection to regulate the magnitude of the CD8(+) T cell response, indicating that early inflammatory events are critical for the regulation of the effector phase. Taken together, these findings suggest that processing of memTNF-α to release solTNF-α is a critical event regulating the immune response during influenza infection.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Membrana Celular/inmunología , Subtipo H1N1 del Virus de la Influenza A/inmunología , Infecciones por Orthomyxoviridae/inmunología , Receptores Tipo I de Factores de Necrosis Tumoral/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Animales , Linfocitos T CD8-positivos/patología , Muerte Celular/genética , Muerte Celular/inmunología , Membrana Celular/genética , Membrana Celular/patología , Subtipo H1N1 del Virus de la Influenza A/genética , Ratones , Ratones Noqueados , Infecciones por Orthomyxoviridae/genética , Infecciones por Orthomyxoviridae/patología , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Receptores Tipo II del Factor de Necrosis Tumoral/genética , Receptores Tipo II del Factor de Necrosis Tumoral/inmunología , Solubilidad , Factor de Necrosis Tumoral alfa/genética
10.
J Biol Chem ; 289(1): 152-62, 2014 Jan 03.
Artículo en Inglés | MEDLINE | ID: mdl-24247241

RESUMEN

Cif (PA2934), a bacterial virulence factor secreted in outer membrane vesicles by Pseudomonas aeruginosa, increases the ubiquitination and lysosomal degradation of some, but not all, plasma membrane ATP-binding cassette transporters (ABC), including the cystic fibrosis transmembrane conductance regulator and P-glycoprotein. The goal of this study was to determine whether Cif enhances the ubiquitination and degradation of the transporter associated with antigen processing (TAP1 and TAP2), members of the ABC transporter family that play an essential role in antigen presentation and intracellular pathogen clearance. Cif selectively increased the amount of ubiquitinated TAP1 and increased its degradation in the proteasome of human airway epithelial cells. This effect of Cif was mediated by reducing USP10 deubiquitinating activity, resulting in increased polyubiquitination and proteasomal degradation of TAP1. The reduction in TAP1 abundance decreased peptide antigen translocation into the endoplasmic reticulum, an effect that resulted in reduced antigen available to MHC class I molecules for presentation at the plasma membrane of airway epithelial cells and recognition by CD8(+) T cells. Cif is the first bacterial factor identified that inhibits TAP function and MHC class I antigen presentation.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/metabolismo , Presentación de Antígeno , Proteínas Bacterianas/metabolismo , Antígenos de Histocompatibilidad Clase I/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Pseudomonas aeruginosa/metabolismo , Ubiquitinación , Factores de Virulencia/metabolismo , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/inmunología , Proteínas Bacterianas/genética , Proteínas Bacterianas/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Retículo Endoplásmico/genética , Retículo Endoplásmico/inmunología , Retículo Endoplásmico/metabolismo , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/inmunología , Complejo de la Endopetidasa Proteasomal/genética , Complejo de la Endopetidasa Proteasomal/inmunología , Transporte de Proteínas/genética , Transporte de Proteínas/inmunología , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/inmunología , Pseudomonas aeruginosa/patogenicidad , Ubiquitina Tiolesterasa/genética , Ubiquitina Tiolesterasa/inmunología , Ubiquitina Tiolesterasa/metabolismo , Factores de Virulencia/genética , Factores de Virulencia/inmunología
11.
J Infect Dis ; 209(6): 865-75, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24072844

RESUMEN

Influenza A represents a significant cause of morbidity and mortality worldwide. Bacterial complications of influenza A confer the greatest risk to patients. TH17 pathway inhibition has been implicated as a mechanism by which influenza A alters bacterial host defense. Here we show that preceding influenza causes persistent Staphylococcus aureus infection and suppression of TH17 pathway activation in mice. Influenza does not inhibit S. aureus binding and uptake by phagocytic cells but instead attenuates S. aureus induced TH17 related antimicrobial peptides necessary for bacterial clearance in the lung. Importantly, exogenous lipocalin 2 rescued viral exacerbation of S. aureus infection and decreased free iron levels in the bronchoalveolar lavage from mice coinfected with S. aureus and influenza. These findings indicate a novel mechanism by which influenza A inhibits TH17 immunity and increases susceptibility to secondary bacterial pneumonia. Identification of new mechanisms in the pathogenesis of bacterial pneumonia could lead to future therapeutic targets.


Asunto(s)
Péptidos Catiónicos Antimicrobianos/metabolismo , Virus de la Influenza A/inmunología , Infecciones por Orthomyxoviridae/microbiología , Neumonía Estafilocócica/microbiología , Staphylococcus aureus/inmunología , Análisis de Varianza , Animales , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/microbiología , Líquido del Lavado Bronquioalveolar/virología , Coinfección/microbiología , Coinfección/virología , Interacciones Huésped-Patógeno/inmunología , Virus de la Influenza A/patogenicidad , Macrófagos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Neutrófilos/inmunología , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/virología , Neumonía Estafilocócica/inmunología , Neumonía Estafilocócica/virología , Staphylococcus aureus/patogenicidad , Células Th17
12.
PLoS One ; 8(11): e79340, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24223177

RESUMEN

Influenza infection in humans evokes a potent CD8(+) T-cell response, which is important for clearance of the virus but may also exacerbate pulmonary pathology. We have previously shown in mice that CD8(+) T-cell expression of TNF-α is required for severe and lethal lung injury following recognition of an influenza antigen expressed by alveolar epithelial cells. Since TNF-α is first expressed as a transmembrane protein that is then proteolytically processed to release a soluble form, we sought to characterize the role of TNF-α processing in CD8(+) T-cell-mediated injury. In this study we observed that inhibition of ADAM17-mediated processing of TNF-α by CD8(+) T cells significantly attenuated the diffuse alveolar damage that occurs after T-cell transfer, resulting in enhanced survival. This was due in part to diminished chemokine expression, as TNF-α processing was required for lung epithelial cell expression of CXCL2 and the subsequent inflammatory infiltration. We confirmed the importance of CXCL2 expression in acute lung injury by transferring influenza-specific CD8(+) T cells into transgenic mice lacking CXCR2. These mice exhibited reduced airway infiltration, attenuated lung injury, and enhanced survival. Theses studies describe a critical role for TNF-α processing by CD8(+) T cells in the initiation and severity of acute lung injury, which may have important implications for limiting immunopathology during influenza infection and other human infectious or inflammatory diseases.


Asunto(s)
Proteínas ADAM/metabolismo , Linfocitos T CD8-positivos/inmunología , Regulación de la Expresión Génica , Lesión Pulmonar/inmunología , Lesión Pulmonar/virología , Proteolisis , Factor de Necrosis Tumoral alfa/metabolismo , Proteínas ADAM/deficiencia , Proteína ADAM17 , Animales , Células Epiteliales/metabolismo , Células Epiteliales/patología , Femenino , Humanos , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Pulmón/virología , Lesión Pulmonar/metabolismo , Lesión Pulmonar/patología , Macrófagos/inmunología , Ratones , Infiltración Neutrófila , Receptores de Interleucina-8B/metabolismo , Transducción de Señal , Solubilidad , Factor de Necrosis Tumoral alfa/química
13.
J Immunol ; 191(10): 5153-9, 2013 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-24089191

RESUMEN

Pneumonia is a leading cause of death worldwide. Staphylococcal aureus can be a cause of severe pneumonia alone or a common pathogen in secondary pneumonia following influenza. Recently, we reported that preceding influenza attenuated the Type 17 pathway, increasing the lung's susceptibility to secondary infection. IL-1ß is known to regulate host defense, including playing a role in Th17 polarization. We examined whether IL-1ß signaling is required for S. aureus host defense and whether influenza infection impacted S. aureus-induced IL-1ß production and subsequent Type 17 pathway activation. Mice were challenged with S. aureus (USA 300), with or without preceding Influenza A/PR/8/34 H1N1 infection. IL-1R1(-/-) mice had significantly higher S. aureus burden, increased mortality, and decreased Type 17 pathway activation following S. aureus challenge. Coinfected mice had significantly decreased IL-1ß production versus S. aureus infection alone at early time points following bacterial challenge. Preceding influenza did not attenuate S. aureus-induced inflammasome activation, but there was early suppression of NF-κB activation, suggesting an inhibition of NF-κB-dependent transcription of pro-IL-1ß. Furthermore, overexpression of IL-1ß in influenza and S. aureus-coinfected mice rescued the induction of IL-17 and IL-22 by S. aureus and improved bacterial clearance. Finally, exogenous IL-1ß did not significantly rescue S. aureus host defense during coinfection in IL-17RA(-/-) mice or in mice in which IL-17 and IL-22 activity were blocked. These data reveal a novel mechanism by which Influenza A inhibits S. aureus-induced IL-1ß production, resulting in attenuation of Type 17 immunity and increased susceptibility to bacterial infection.


Asunto(s)
Subtipo H1N1 del Virus de la Influenza A/inmunología , Interleucina-1beta/metabolismo , Infecciones por Orthomyxoviridae/inmunología , Neumonía Estafilocócica/inmunología , Staphylococcus aureus/inmunología , Animales , Carga Bacteriana/genética , Carga Bacteriana/inmunología , Coinfección/inmunología , Coinfección/microbiología , Coinfección/virología , Activación Enzimática/inmunología , Inflamasomas/inmunología , Interleucina-17/biosíntesis , Interleucina-1beta/biosíntesis , Interleucinas/biosíntesis , Pulmón/inmunología , Pulmón/microbiología , Pulmón/virología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , FN-kappa B/metabolismo , Receptores Tipo I de Interleucina-1/deficiencia , Receptores Tipo I de Interleucina-1/genética , Transducción de Señal , Interleucina-22
14.
Am J Pathol ; 182(4): 1286-96, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23490254

RESUMEN

Influenza infection is widespread in the United States and the world. Despite low mortality rates due to infection, morbidity is common and little is known about the molecular events involved in recovery. Influenza infection results in persistent distal lung remodeling, and the mechanism(s) involved are poorly understood. Recently IL-22 has been found to mediate epithelial repair. We propose that IL-22 is critical for recovery of normal lung function and architecture after influenza infection. Wild-type and IL-22(-/-) mice were infected with influenza A PR8/34 H1N1 and were followed up for up to 21 days post infection. IL-22 receptor was localized to the airway epithelium in naive mice but was expressed at the sites of parenchymal lung remodeling induced by influenza infection. IL-22(-/-) mice displayed exacerbated lung injury compared with wild-type mice, which correlated with decreased lung function 21 days post infection. Epithelial metaplasia was observed in wild-type mice but was not evident in IL-22(-/-) animals that were characterized with an increased fibrotic phenotype. Gene expression analysis revealed aberrant expression of epithelial genes involved in repair processes, among changes in several other biological processes. These data indicate that IL-22 is required for normal lung repair after influenza infection. IL-22 represents a novel pathway involved in interstitial lung disease.


Asunto(s)
Epitelio/patología , Epitelio/virología , Interleucinas/metabolismo , Pulmón/patología , Pulmón/virología , Infecciones por Orthomyxoviridae/patología , Cicatrización de Heridas , Animales , Membrana Basal/metabolismo , Membrana Basal/patología , Colágeno/metabolismo , Células Epiteliales/metabolismo , Células Epiteliales/patología , Células Epiteliales/virología , Epitelio/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Interleucinas/deficiencia , Pulmón/fisiopatología , Metaplasia , Ratones , Ratones Endogámicos C57BL , Infecciones por Orthomyxoviridae/genética , Infecciones por Orthomyxoviridae/fisiopatología , Infecciones por Orthomyxoviridae/virología , Receptores de Interleucina/metabolismo , Pruebas de Función Respiratoria , Transducción de Señal/genética , Interleucina-22
15.
PLoS One ; 7(10): e46581, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23056353

RESUMEN

Influenza A virus (IAV) is a leading cause of respiratory tract disease worldwide. Anti-viral CD8(+) T lymphocytes responding to IAV infection are believed to eliminate virally infected cells by direct cytolysis but may also contribute to pulmonary inflammation and tissue damage via the release of pro-inflammatory mediators following recognition of viral antigen displaying cells. We have previously demonstrated that IAV antigen expressing inflammatory cells of hematopoietic origin within the infected lung interstitium serve as antigen presenting cells (APC) for infiltrating effector CD8(+) T lymphocytes; however, the spectrum of inflammatory cell types capable of serving as APC was not determined. Here, we demonstrate that viral antigen displaying neutrophils infiltrating the IAV infected lungs are an important cell type capable of acting as APC for effector CD8(+) T lymphocytes in the infected lungs and that neutrophils expressing viral antigen as a result of direct infection by IAV exhibit the most potent APC activity. Our findings suggest that in addition to their suggested role in induction of the innate immune responses to IAV, virus clearance, and the development of pulmonary injury, neutrophils can serve as APCs to anti-viral effector CD8(+) T cells within the infected lung interstitium.


Asunto(s)
Células Presentadoras de Antígenos/inmunología , Linfocitos T CD8-positivos/inmunología , Pulmón/virología , Neutrófilos/virología , Orthomyxoviridae/inmunología , Humanos , Pulmón/inmunología , Neutrófilos/inmunología
16.
PLoS One ; 7(5): e38249, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22693606

RESUMEN

BACKGROUND: Arsenic (As) exposure is a significant worldwide environmental health concern. Chronic exposure via contaminated drinking water has been associated with an increased incidence of a number of diseases, including reproductive and developmental effects. The goal of this study was to identify adverse outcomes in a mouse model of early life exposure to low-dose drinking water As (10 ppb, current U.S. EPA Maximum Contaminant Level). METHODOLOGY AND FINDINGS: C57B6/J pups were exposed to 10 ppb As, via the dam in her drinking water, either in utero and/or during the postnatal period. Birth outcomes, the growth of the F1 offspring, and health of the dams were assessed by a variety of measurements. Birth outcomes including litter weight, number of pups, and gestational length were unaffected. However, exposure during the in utero and postnatal period resulted in significant growth deficits in the offspring after birth, which was principally a result of decreased nutrients in the dam's breast milk. Cross-fostering of the pups reversed the growth deficit. Arsenic exposed dams displayed altered liver and breast milk triglyceride levels and serum profiles during pregnancy and lactation. The growth deficits in the F1 offspring resolved following separation from the dam and cessation of exposure in male mice, but did not resolve in female mice up to six weeks of age. CONCLUSIONS/SIGNIFICANCE: Exposure to As at the current U.S. drinking water standard during critical windows of development induces a number of adverse health outcomes for both the dam and offspring. Such effects may contribute to the increased disease risks observed in human populations.


Asunto(s)
Arsénico/farmacología , Agua Potable/química , Feto/efectos de los fármacos , Crecimiento y Desarrollo/efectos de los fármacos , Contaminantes Químicos del Agua/farmacología , Crianza de Animales Domésticos , Animales , Arsénico/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Lactancia/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Leche Humana/efectos de los fármacos , Leche Humana/metabolismo , Embarazo , Triglicéridos/metabolismo
17.
J Immunol ; 186(3): 1666-1674, 2011 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-21178015

RESUMEN

Staphylococcus aureus is a significant cause of hospital and community acquired pneumonia and causes secondary infection after influenza A. Recently, patients with hyper-IgE syndrome, who often present with S. aureus infections of the lung and skin, were found to have mutations in STAT3, required for Th17 immunity, suggesting a potential critical role for Th17 cells in S. aureus pneumonia. Indeed, IL-17R(-/-) and IL-22(-/-) mice displayed impaired bacterial clearance of S. aureus compared with that of wild-type mice. Mice challenged with influenza A PR/8/34 H1N1 and subsequently with S. aureus had increased inflammation and decreased clearance of both virus and bacteria. Coinfection resulted in greater type I and II IFN production in the lung compared with that with virus infection alone. Importantly, influenza A coinfection resulted in substantially decreased IL-17, IL-22, and IL-23 production after S. aureus infection. The decrease in S. aureus-induced IL-17, IL-22, and IL-23 was independent of type II IFN but required type I IFN production in influenza A-infected mice. Furthermore, overexpression of IL-23 in influenza A, S. aureus-coinfected mice rescued the induction of IL-17 and IL-22 and markedly improved bacterial clearance. These data indicate a novel mechanism by which influenza A-induced type I IFNs inhibit Th17 immunity and increase susceptibility to secondary bacterial pneumonia.


Asunto(s)
Subtipo H1N1 del Virus de la Influenza A/inmunología , Interleucina-17/antagonistas & inhibidores , Interleucina-17/fisiología , Infecciones por Orthomyxoviridae/inmunología , Neumonía Bacteriana/inmunología , Infecciones Estafilocócicas/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Células Cultivadas , Predisposición Genética a la Enfermedad , Humanos , Interferón Tipo I/administración & dosificación , Interferón Tipo I/biosíntesis , Interleucina-17/deficiencia , Interleucina-23/antagonistas & inhibidores , Interleucinas/antagonistas & inhibidores , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Infecciones por Orthomyxoviridae/genética , Infecciones por Orthomyxoviridae/microbiología , Neumonía Bacteriana/genética , Neumonía Bacteriana/virología , Transducción de Señal/genética , Transducción de Señal/inmunología , Infecciones Estafilocócicas/genética , Infecciones Estafilocócicas/virología , Staphylococcus aureus/inmunología , Linfocitos T Colaboradores-Inductores/metabolismo , Linfocitos T Colaboradores-Inductores/virología , Interleucina-22
18.
Viral Immunol ; 23(6): 639-45, 2010 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21142450

RESUMEN

CD8(+) T-cell-mediated pulmonary immunopathology in respiratory virus infection is mediated in large part by antigen-specific TNF-α expression by antiviral effector T cells, which results in epithelial chemokine expression and inflammatory infiltration of the lung. To further define the signaling events leading to lung epithelial chemokine production in response to CD8(+) T-cell antigen recognition, we expressed the adenoviral 14.7K protein, a putative inhibitor of TNF-α signaling, in the distal lung epithelium, and analyzed the functional consequences. Distal airway epithelial expression of 14.7K resulted in a significant reduction in lung injury resulting from severe influenza pneumonia. In vitro analysis demonstrated a significant reduction in the expression of an important mediator of injury, CCL2, in response to CD8(+) T-cell recognition, or to TNF-α. The inhibitory effect of 14.7K on CCL2 expression resulted from attenuation of NF-κB activity, which was independent of Iκ-Bα degradation or nuclear translocation of the p65 subunit. Furthermore, epithelial 14.7K expression inhibited serine phosphorylation of Akt, GSK-3ß, and the p65 subunit of NF-κB, as well as recruitment of NF-κB for DNA binding in vivo. These results provide insight into the mechanism of 14.7K inhibition of NF-κB activity, as well as further elucidate the mechanisms involved in the induction of T-cell-mediated immunopathology in respiratory virus infection.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Lesión Pulmonar/patología , Infecciones por Orthomyxoviridae/inmunología , Mucosa Respiratoria/inmunología , Transducción de Señal/inmunología , Linfocitos T Citotóxicos/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Proteínas E3 de Adenovirus/inmunología , Animales , Quimiocina CCL2/inmunología , Quimiocinas/inmunología , Virus de la Influenza A/inmunología , Lesión Pulmonar/inmunología , Ratones , Ratones Endogámicos BALB C , FN-kappa B/inmunología
19.
Mol Immunol ; 47(2-3): 623-31, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19786304

RESUMEN

Influenza infection of the distal airways results in severe lung injury, a considerable portion of which is immunopathologic and attributable to the host responses. We have used a mouse model to specifically investigate the role of antiviral CD8(+) T cells in this injury, and have found that the critical effector molecule is TNF-alpha expressed by the T cells upon antigen recognition. Interestingly, the immunopathology which ensues is characterized by significant accumulation of host inflammatory cells, recruited by chemokines expressed by the target alveolar epithelial cells. In this study we analyzed the mechanisms involved in the induction of epithelial chemokine expression triggered by antigen-specific CD8(+) T cell recognition, and demonstrate that the early growth response-1 (Egr-1) transcription factor is rapidly induced in epithelial cells, both in vitro and ex vivo, and that this is a critical regulator of a host of inflammatory chemokines. Genetic deficiency of Egr-1 significantly abrogates both the chemokine expression and the immunopathologic injury associated with T cell recognition, and it directly regulates transcriptional activity of a model CXC chemokine, MIP-2. We further demonstrate that Egr-1 induction is triggered by TNF-alpha-dependent ERK activation, and inhibition of this pathway ablates Egr-1 expression. These findings suggest that Egr-1 may represent an important target in mitigating the immunopathology of severe influenza infection.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Proteína 1 de la Respuesta de Crecimiento Precoz/inmunología , Células Epiteliales/inmunología , Enfermedades Pulmonares/inmunología , Enfermedades Pulmonares/patología , Alveolos Pulmonares/inmunología , Alveolos Pulmonares/patología , Traslado Adoptivo , Animales , Linfocitos T CD8-positivos/efectos de los fármacos , Quimiocina CXCL2/biosíntesis , Quimiocina CXCL2/genética , Quimiocinas/inmunología , Activación Enzimática/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Células Epiteliales/enzimología , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Perfilación de la Expresión Génica , Enfermedades Pulmonares/enzimología , Ratones , FN-kappa B/metabolismo , Regiones Promotoras Genéticas/genética , Unión Proteica/efectos de los fármacos , Alveolos Pulmonares/efectos de los fármacos , Alveolos Pulmonares/enzimología , Factor de Necrosis Tumoral alfa/farmacología
20.
J Immunol ; 183(8): 5301-10, 2009 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-19783685

RESUMEN

Acute lung injury due to influenza infection is associated with high mortality, an increase in neutrophils in the airspace, and increases in tissue myeloperoxidase (MPO). Because IL-17A and IL-17F, ligands for IL-17 receptor antagonist (IL-17RA), have been shown to mediate neutrophil migration into the lung in response to LPS or Gram-negative bacterial pneumonia, we hypothesized that IL-17RA signaling was critical for acute lung injury in response to pulmonary influenza infection. IL-17RA was critical for weight loss and both neutrophil migration and increases in tissue myeloperoxidase (MPO) after influenza infection. However, IL-17RA was dispensable for the recruitment of CD8(+) T cells specific for influenza hemagglutinin or nucleocapsid protein. Consistent with this, IL-17RA was not required for viral clearance. However, in the setting of influenza infection, IL-17RA(-/-) mice showed significantly reduced levels of oxidized phospholipids, which have previously been shown to be an important mediator in several models of acute lung injury, including influenza infection and gastric acid aspiration. Taken together, these data support targeting IL-17 or IL-17RA in acute lung injury due to acute viral infection.


Asunto(s)
Lesión Pulmonar Aguda/virología , Subtipo H1N1 del Virus de la Influenza A , Gripe Humana/complicaciones , Neutrófilos/inmunología , Receptores de Interleucina-17/metabolismo , Lesión Pulmonar Aguda/inmunología , Animales , Líquido del Lavado Bronquioalveolar/inmunología , Líquido del Lavado Bronquioalveolar/virología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/virología , Movimiento Celular/inmunología , Modelos Animales de Enfermedad , Humanos , Gripe Humana/inmunología , Interleucina-17/inmunología , Interleucina-17/metabolismo , Interleucina-6/inmunología , Interleucina-6/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Neutrófilos/metabolismo , Neutrófilos/virología , Peroxidasa/inmunología , Peroxidasa/metabolismo , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/inmunología , Transducción de Señal/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismo
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