RESUMEN
BACKGROUND: Cell-surface mucins are expressed in apical epithelial cells of the respiratory tract, and contribute a crucial part of the innate immune system. Despite anti-inflammatory or antiviral functions being revealed for certain cell-surface mucins such as MUC1, the roles of other mucins are still poorly understood, especially in viral infections. METHODS: To further identify mucins significant in influenza infection, we screened the expression of mucins in human nasal epithelial cells infected by H3N2 influenza A virus. RESULTS: We found that the expression of MUC15 was significantly upregulated upon infection, and specific only to active infection. While MUC15 did not interact with virus particles or reduce viral replication directly, positive correlations were observed between MUC15 and inflammatory factors in response to viral infection. Given that the upregulation of MUC15 was only triggered late into infection when immune factors (including cytokines, chemokines, EGFR and phosphorylated ERK) started to peak and plateau, MUC15 may potentially serve an immunomodulatory function later during influenza viral infection. CONCLUSIONS: Our study revealed that MUC15 was one of the few cell-surface mucins induced during influenza infection. While MUC15 did not interact directly with influenza virus, we showed that its increase coincides with the peak of immune activation and thus MUC15 may serve an immunomodulatory role during influenza infection.
Asunto(s)
Subtipo H3N2 del Virus de la Influenza A/fisiología , Gripe Humana/patología , Mucinas/metabolismo , Animales , Células Cultivadas , Quimiocinas/metabolismo , Citocinas/metabolismo , Perros , Células Epiteliales/clasificación , Células Epiteliales/metabolismo , Receptores ErbB/metabolismo , Humanos , Gripe Humana/metabolismo , Células de Riñón Canino Madin Darby , Mucinas/antagonistas & inhibidores , Mucinas/genética , Cavidad Nasal/citología , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/aislamiento & purificación , Proteínas Recombinantes/farmacología , Regulación hacia Arriba , Replicación Viral/efectos de los fármacosRESUMEN
Tight junctions (TJs) alteration is commonly seen in airway inflammatory diseases. Oncostatin M (OSM) is an inflammatory mediator associated with chronic rhinosinusitis with nasal polyps (CRSwNP). We have previously shown that human nasal epithelial cells (hNECs) are highly permissive cells for influenza A virus (IAV). However, its role in TJs alteration and the effects of IAV on inducing OSM expression in nasal epithelium remains to be further investigated. In this study, OSM and TJs expression was measured and compared between inferior turbinate from healthy controls and nasal polyps from CRSwNP. Additionally, hNECs cultured at air-liquid interface (ALI) were infected with H3N2 influenza virus to study the role of influenza virus in inducing epithelial OSM expression as a possible means of exacerbation. The expression of ZO-1, claudin-1, and occludin was markedly decreased and correlated negatively with that of OSM in CRSwNP. By using the in vitro hNEC model, H3N2 infection resulted in significantly increased OSM expression (2.2-, 4.7- and 3.9-fold higher at 8, 24, and 48â¯h post-infection vs. mock infection). Furthermore, OSM is found to co-localize with ciliated and goblet cells in hNECs infected with H3N2 influenza virus. Our findings demonstrated that increased OSM expression is implicated in CRSwNP as a possible mechanism of TJs' impairment, which can be further augmented following influenza infection via epithelial OSM expression, possibly contributing to exacerbations.
Asunto(s)
Subtipo H3N2 del Virus de la Influenza A/genética , Gripe Humana/genética , Mucosa Nasal/metabolismo , Pólipos Nasales/genética , Oncostatina M/genética , Rinitis/genética , Sinusitis/genética , Adulto , Estudios de Casos y Controles , Diferenciación Celular , Enfermedad Crónica , Claudina-1/genética , Claudina-1/metabolismo , Células Epiteliales/metabolismo , Células Epiteliales/patología , Células Epiteliales/virología , Femenino , Regulación de la Expresión Génica , Interacciones Huésped-Patógeno/genética , Humanos , Subtipo H3N2 del Virus de la Influenza A/crecimiento & desarrollo , Subtipo H3N2 del Virus de la Influenza A/metabolismo , Gripe Humana/metabolismo , Gripe Humana/patología , Gripe Humana/virología , Masculino , Persona de Mediana Edad , Mucosa Nasal/patología , Mucosa Nasal/virología , Pólipos Nasales/metabolismo , Pólipos Nasales/patología , Pólipos Nasales/virología , Ocludina/genética , Ocludina/metabolismo , Oncostatina M/metabolismo , Cultivo Primario de Células , Rinitis/metabolismo , Rinitis/patología , Rinitis/virología , Transducción de Señal , Sinusitis/metabolismo , Sinusitis/patología , Sinusitis/virología , Uniones Estrechas/metabolismo , Uniones Estrechas/patología , Uniones Estrechas/virología , Proteína de la Zonula Occludens-1/genética , Proteína de la Zonula Occludens-1/metabolismoRESUMEN
Human rhinoviruses (HRVs) are the commonest cause of the common cold. While HRV is less pathogenic than other respiratory viruses, it is frequently associated with exacerbation of chronic respiratory diseases such as rhinosinusitis and asthma. Nasal epithelial cells are the first sites of viral contact, immune initiation, and airway interconnectivity, but there are limited studies on HRV infection of nasal epithelial cells. Hence, we established a model of HRV infection of in vitro-differentiated human nasal epithelial cells (hNECs) derived from multiple individuals. Through HRV infection of hNECs, we found that HRV mainly targeted ciliated cells and preferentially induced type I and III interferon antiviral pathways. Quantitative polymerase chain reaction analysis of inflammatory genes suggested predominant type 1 immunity signaling and recruitment, with secreted CXCL9, IP-10, CXCL11, and RANTES as likely initiators of airway inflammatory responses. Additionally, we further explored HRV bidirectional release from the hNECs and identified 11 associated genes. Other HRV interactions were also identified through a systematic comparison with influenza A virus infection of hNECs. Overall, this in vitro hNEC HRV infection model provides a platform for repeatable and controlled studies of different individuals, thus providing novel insights into the roles of human nasal epithelium in HRV interaction and immune initiation.
Asunto(s)
Células Epiteliales/inmunología , Células Epiteliales/virología , Mucosa Nasal/citología , Rhinovirus/fisiología , Adulto , Diferenciación Celular , Células Cultivadas , Proteína 58 DEAD Box/genética , Proteína 58 DEAD Box/metabolismo , Regulación de la Expresión Génica , Humanos , Interferón Tipo I/genética , Interferón Tipo I/metabolismo , Interferones/genética , Interferones/metabolismo , Persona de Mediana Edad , Receptores Inmunológicos , Receptor Toll-Like 7/genética , Receptor Toll-Like 7/metabolismo , Replicación Viral , Adulto Joven , Interferón lambdaRESUMEN
In this study, we evaluated the effects of targeted sinonasal surgery on nasal and maxillary sinus airflow patterns. A patient, who underwent right balloon sinuplasty and left uncinectomy for recurrent maxillary sinus barometric pressure, and concomitant septoplasty and bilateral inferior turbinate reduction for deviated nasal septum and inferior turbinate hypertrophy, was selected. Two 3D models representing both pre- and post-operative sinonasal morphology were constructed. The models were then used to evaluate nasal and maxillary sinus airflow patterns during respiration at ventilation rates of 7.5 L/min, 15 L/min and 30 L/min using computational fluid dynamics. The results showed that septoplasty and inferior turbinate reduction increased the nasal volume by 13.6%. The airflow patterns in the nasal cavity showed reasonably decreased resistance and slightly more even flow partitioning after the operation. Maxillary sinus ventilation significantly increased during inspiration in the left sinus after uncinectomy, and during expiration in right sinus after balloon sinuplasty. This study demonstrates computational fluid dynamics simulation is a tool in the investigation of outcomes after targeted, minimally invasive sinonasal surgery.