Dataset Information

CCL7 and IRF-7 Mediate Hallmark Inflammatory and IFN Responses following Rhinovirus 1B Infection.

ABSTRACT: Rhinovirus (RV) infections are common and have the potential to exacerbate asthma. We have determined the lung transcriptome in RV strain 1B-infected naive BALB/c mice (nonallergic) and identified CCL7 and IFN regulatory factor (IRF)-7 among the most upregulated mRNA transcripts in the lung. To investigate their roles we employed anti-CCL7 Abs and an IRF-7-targeting small interfering RNA in vivo. Neutralizing CCL7 or inhibiting IRF-7 limited neutrophil and macrophage influx and IFN responses in nonallergic mice. Neutralizing CCL7 also reduced activation of NF-?B p65 and p50 subunits, as well as airway hyperreactivity (AHR) in nonallergic mice. However, neither NF-?B subunit activation nor AHR was abolished with infection of allergic mice after neutralizing CCL7, despite a reduction in the number of neutrophils, macrophages, and eosinophils. IRF-7 small interfering RNA primarily suppressed IFN-? and IFN-? levels during infection of allergic mice. Our data highlight a pivotal role of CCL7 and IRF-7 in RV-induced inflammation and IFN responses and link NF-?B signaling to the development of AHR.

SUBMITTER: Girkin J

PROVIDER: S-EPMC4417644 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

CCL7 and IRF-7 Mediate Hallmark Inflammatory and IFN Responses following Rhinovirus 1B Infection.

Girkin Jason J Hatchwell Luke L Foster Paul P Johnston Sebastian L SL Bartlett Nathan N Collison Adam A Mattes Joerg J

Journal of immunology (Baltimore, Md. : 1950) 20150406 10

Rhinovirus (RV) infections are common and have the potential to exacerbate asthma. We have determined the lung transcriptome in RV strain 1B-infected naive BALB/c mice (nonallergic) and identified CCL7 and IFN regulatory factor (IRF)-7 among the most upregulated mRNA transcripts in the lung. To investigate their roles we employed anti-CCL7 Abs and an IRF-7-targeting small interfering RNA in vivo. Neutralizing CCL7 or inhibiting IRF-7 limited neutrophil and macrophage influx and IFN responses in ...[more]

PMID: 25847975

Similar Datasets

Project description:Impaired interferon (IFN) production has been observed in various obstructive respiratory diseases. This contributes to enhanced sensitivity towards viral infections triggering acute exacerbations. To compensate for this impaired host IFN response, there is need to explore new therapeutic strategies, like exogenous administration of IFNs as prophylactic treatment. In the present study, we examined the protective potential of IFN-?1 and compared it with the previously established protecting effect of IFN-?. A549 cells and human primary bronchial epithelial cells were first treated with either IFN-? (500 IU/ml) or IFN-?1 (500 ng/ml) for 18 h. For infection, two approaches were adopted: i) Continuous scenario: after pre-treatment, cells were infected immediately for 24 h with human rhinovirus 1B (HRV1B) in IFN-containing medium, or were cultured for another 72 h in IFN-containing medium, and then infected for 24 h with HRV1B, ii) Pre-treatment scenario: IFN-containing medium was replaced after 18 h and cells were infected for 4 h either immediately after pre-treatment or after additional culturing for 72 h in IFN-free medium. The protective effect was evaluated in terms of reduction in the number of viral copies/infectious progeny, and enhanced expression of IFN-stimulated genes (ISGs). In both cell types and in both approaches, IFN-?1 and IFN-? treatment resulted in pronounced and long-lasting antiviral effects exemplified by significantly reduced viral copy numbers and diminished infectious progeny. This was associated with strong up-regulation of multiple ISGs. However, in contrast to the IFN-? induced expression of ISGs, which decreased over time, expression of ISGs induced by IFN-?1 was sustained or even increased over time. Here we demonstrate that the protective potential of IFN-?1 is comparable to IFN-?. Yet, the long-lasting induction of ISGs by IFN-?1 and most likely less incitement of side effects due to more localized expression of its receptors could make it an even more promising candidate for prophylactic treatment than IFN-?.

Project description:Abstract Objectives Viral respiratory infections cause considerable morbidity and economic loss. While rhinoviruses (RV) typically cause little more than the common cold, they can produce severe infections and disease exacerbations in susceptible individuals, such as those with asthma. Variations in the regulation of key antiviral cytokines, particularly type I interferon (IFN‐α and IFN‐β), may contribute to RV susceptibility. To understand this variability, we compared the transcriptomes of high and low type I IFN producers. Methods Blood mononuclear cells from 238 individuals with or without asthma were cultured in the presence or absence of RV. Those samples demonstrating high or low RV‐stimulated IFN‐α production (N = 75) underwent RNA‐sequencing. Results Gene expression patterns were similar in samples from healthy participants and those with asthma. At baseline, the high IFN‐α producer group showed higher expression of genes associated with plasmacytoid dendritic cells, the innate immune response and vitamin D activation, but lower expression of oxidative stress pathways than the low IFN‐α producer group. After RV stimulation, the high IFN‐α producer group showed higher expression of genes found in immune response biological pathways and lower expression of genes linked to developmental and catabolic processes when compared to the low IFN‐α producer group. Conclusions These differences suggest that the high IFN‐α group has a higher level of immune system readiness, resulting in a more intense and perhaps more focussed pathogen‐specific immune response. These results contribute to a better understanding of the variability in type I IFN production between individuals. For this study on variation in IFN‐α production, samples from high and low IFN‐α producers were selected and their transcriptomes were compared before and after rhinovirus stimulation. Differential gene expression analysis revealed immunological differences at baseline prior to stimulus and differences in antiviral response and expression of genes related to cellular functions.

Project description:Prematurity and bronchopulmonary dysplasia (BPD) increase the risk of asthma later in life. Supplemental oxygen therapy is a risk factor for chronic respiratory symptoms in infants with BPD. Hyperoxia induces cell injury and release of damage-associated molecular patterns (DAMPs). Cytoskeletal filamentous actin (F-actin) is a DAMP which binds Clec9a, a C-type lectin selectively expressed on CD103+ dendritic cells (DCs). Co-stimulation of Clec9a and TLR3 induces maximal proinflammatory responses. We have shown that neonatal hyperoxia (a model of BPD) increases lung IL-12+Clec9a+CD103+ DCs, pro-inflammatory responses and airway hyperreactivity following rhinovirus (RV) infection. CD103+ DCs and Clec9a are required for these responses. Hyperoxia increases F-actin levels in bronchoalveolar lavage fluid (BALF). We hypothesized that the F-actin severing protein gelsolin attenuates neonatal hyperoxia-induced Clec9a+CD103+ DC-dependent pro-inflammatory responses to RV and preserves alveolarization. We exposed neonatal mice to hyperoxia and treated them with gelsolin intranasally. Subsequently we inoculated the mice with RV intranasally. Alternatively, we inoculated normoxic neonatal mice with BALF from hyperoxia-exposed mice (hyperoxic BALF), RV and gelsolin. We analyzed lung gene expression two days after RV infection. For in vitro studies, lung CD11c+ cells were isolated from C57BL/6J or Clec9agfp-/- mice and incubated with hyperoxic BALF and RV. Cells were analyzed by flow cytometry. In neonatal mice, gelsolin blocked hyperoxia-induced Il12p40, TNF-α and IFN-γ mRNA and protein expression in response to RV infection. Similar effects were observed when gelsolin was co-administered with hyperoxic BALF and RV. Gelsolin decreased F-actin levels in hyperoxic BALF in vitro and inhibited hyperoxia-induced D103lo DC expansion and inflammation in vivo. Gelsolin also attenuated hyperoxia-induced hypoalveolarization. Further, incubation of lung CD11c+ cells from WT and Clec9agfp-/- mice with hyperoxic BALF and RV, showed Clec9a is required for maximal hyperoxic BALF and RV induced IL-12 expression in CD103+ DCs. Finally, in tracheal aspirates from mechanically ventilated human preterm infants the F-actin to gelsolin ratio positively correlates with FiO2, and gelsolin levels decrease during the first two weeks of mechanical ventilation. Collectively, our findings demonstrate a promising role for gelsolin, administered by inhalation into the airway to treat RV-induced exacerbations of BPD and prevent chronic lung disease.

Dataset Information

CCL7 and IRF-7 Mediate Hallmark Inflammatory and IFN Responses following Rhinovirus 1B Infection.

Publications

CCL7 and IRF-7 Mediate Hallmark Inflammatory and IFN Responses following Rhinovirus 1B Infection.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets