Soluble major histocompatibility complex class I-related chain B molecules are increased and correlate with clinical outcomes during rhinovirus infection in healthy subjects

BACKGROUND: Surface major histocompatibility complex class I-related chain (MIC) A and B molecules are increased by IL-15 and have a role in the activation of natural killer group 2 member D-positive natural killer and CD8 T cells. MICA and MICB also exist in soluble forms (sMICA and sMICB). Rhinoviruses (RVs) are the major cause of asthma exacerbations, and IL-15 levels are decreased in the airways of subjects with asthma. The role of MIC molecules in immune responses in the lung has not been studied. Here, we determine the relationship between MICA and MICB and RV infection in vitro in respiratory epithelial cells and in vivo in healthy subjects and subjects with asthma. METHODS: Surface MICA and MICB, as well as sMICA and sMICB, in respiratory epithelial cells were measured in vitro in response to RV infection and exposure to IL-15. Levels of sMICA and sMICB in serum, sputum, and BAL were measured and correlated with blood and bronchoalveolar immune cells in healthy subjects and subjects with asthma before and during RV infection. RESULTS: RV increased MICA and MICB in vitro in epithelial cells. Exogenous IL-15 upregulated sMICB levels in RV-infected epithelial cells. Levels of sMICB molecules in serum were increased in healthy subjects compared with subjects with stable asthma. Following RV infection, airway levels of sMIC are upregulated, and there are positive correlations between sputum MICB levels and the percentage of bronchoalveolar natural killer cells in healthy subjects but not subjects with asthma. CONCLUSIONS: RV infection induces MIC molecules in respiratory epithelial cells in vitro and in vivo. Induction of MICB molecules is impaired in subjects with asthma, suggesting these molecules may have a role in the antiviral immune response to RV infections

CXC chemokines and antimicrobial peptides in rhinovirus-induced experimental asthma exacerbations

RATIONALE: Rhinoviruses (RVs) are the major triggers of asthma exacerbations. We have shown previously that lower respiratory tract symptoms, airflow obstruction, and neutrophilic airway inflammation were increased in experimental RV-induced asthma exacerbations. OBJECTIVES: We hypothesized that neutrophil-related CXC chemokines and antimicrobial peptides are increased and related to clinical, virologic, and pathologic outcomes in RV-induced exacerbations of asthma. METHODS: Protein levels of antimicrobial peptides (SLPI, HNP 1–3, elafin, and LL-37) and neutrophil chemokines (CXCL1/GRO-α, CXCL2/GRO-β, CXCL5/ENA-78, CXCL6/GCP-2, CXCL7/NAP-2, and CXCL8/IL-8) were determined in bronchoalveolar lavage (BAL) fluid of 10 asthmatics and 15 normal controls taken before, at day four during and 6 weeks post-experimental infection. RESULTS: BAL HNP 1–3 and Elafin were higher, CXCL7/NAP-2 was lower in asthmatics compared with controls at day 4 (P = 0.035, P = 0.048, and P = 0.025, respectively). BAL HNP 1–3 and CXCL8/IL-8 were increased during infection (P = 0.003 and P = 0.011, respectively). There was a trend to increased BAL neutrophils at day 4 compared with baseline (P = 0.076). BAL HNP 1–3 was positively correlated with BAL neutrophil numbers at day 4. There were no correlations between clinical parameters and HNP1–3 or IL-8 levels. CONCLUSIONS: We propose that RV infection in asthma leads to increased release of CXCL8/IL-8, attracting neutrophils into the airways where they release HNP 1–3, which further enhances airway neutrophilia. Strategies to inhibit CXCL8/IL-8 may be useful in treatment of virus-induced asthma exacerbations

The Role of IL-15 Deficiency in the Pathogenesis of Virus-Induced Asthma Exacerbations

Rhinovirus infections are the major cause of asthma exacerbations. We hypothesised that IL-15, a cytokine implicated in innate and acquired antiviral immunity, may be deficient in asthma and important in the pathogenesis of asthma exacerbations. We investigated regulation of IL-15 induction by rhinovirus in human macrophages in vitro, IL-15 levels in bronchoalveolar lavage (BAL) fluid and IL-15 induction by rhinovirus in BAL macrophages from asthmatic and control subjects, and related these to outcomes of infection in vivo. Rhinovirus induced IL-15 in macrophages was replication-, NF-κB- and α/β interferon-dependent. BAL macrophage IL-15 induction by rhinovirus was impaired in asthmatics and inversely related to lower respiratory symptom severity during experimental rhinovirus infection. IL-15 levels in BAL fluid were also decreased in asthmatics and inversely related with airway hyperresponsiveness and with virus load during in vivo rhinovirus infection. Deficient IL-15 production in asthma may be important in the pathogenesis of asthma exacerbations

Impaired innate interferon induction in severe therapy resistant atopic asthmatic children

Deficient type I interferon-β and type III interferon-λ induction by rhinoviruses has previously been reported in mild/moderate atopic asthmatic adults. No studies have yet investigated if this occurs in severe therapy resistant asthma (STRA). Here, we show that compared with non-allergic healthy control children, bronchial epithelial cells cultured ex vivo from severe therapy resistant atopic asthmatic children have profoundly impaired interferon-β and interferon-λ mRNA and protein in response to rhinovirus (RV) and polyIC stimulation. Severe treatment resistant asthmatics also exhibited increased virus load, which negatively correlated with interferon mRNA levels. Furthermore, uninfected cells from severe therapy resistant asthmatic children showed lower levels of Toll-like receptor-3 mRNA and reduced retinoic acid inducible gene and melanoma differentiation-associated gene 5 mRNA after RV stimulation. These data expand on the original work, suggesting that the innate anti-viral response to RVs is impaired in asthmatic tissues and demonstrate that this is a feature of STRA

Viruses exacerbating chronic pulmonary disease: the role of immune modulation

Chronic pulmonary diseases are a major cause of morbidity and mortality and their impact is expected to increase in the future. Respiratory viruses are the most common cause of acute respiratory infections and it is increasingly recognized that respiratory viruses are a major cause of acute exacerbations of chronic pulmonary diseases such as asthma, chronic obstructive pulmonary disease and cystic fibrosis. There is now increasing evidence that the host response to virus infection is dysregulated in these diseases and a better understanding of the mechanisms of abnormal immune responses has the potential to lead to the development of new therapies for virus-induced exacerbations. The aim of this article is to review the current knowledge regarding the role of viruses and immune modulation in chronic pulmonary diseases and discuss avenues for future research and therapeutic implications

Neutrophil adhesion molecules in experimental rhinovirus infection in COPD

Background COPD exacerbations are associated with neutrophilic airway inflammation. Adhesion molecules on the surface of neutrophils may play a key role in their movement from blood to the airways. We analysed adhesion molecule expression on blood and sputum neutrophils from COPD subjects and non-obstructed smokers during experimental rhinovirus infections. Methods Blood and sputum were collected from 9 COPD subjects and 10 smoking and age-matched control subjects at baseline, and neutrophil expression of the adhesion molecules and activation markers measured using flow cytometry. The markers examined were CD62L and CD162 (mediating initial steps of neutrophil rolling and capture), CD11a and CD11b (required for firm neutrophil adhesion), CD31 and CD54 (involved in neutrophil transmigration through the endothelial monolayer) and CD63 and CD66b (neutrophil activation markers). Subjects were then experimentally infected with rhinovirus-16 and repeat samples collected for neutrophil analysis at post-infection time points. Results At baseline there were no differences in adhesion molecule expression between the COPD and non-COPD subjects. Expression of CD11a, CD31, CD62L and CD162 was reduced on sputum neutrophils compared to blood neutrophils. Following rhinovirus infection expression of CD11a expression on blood neutrophils was significantly reduced in both subject groups. CD11b, CD62L and CD162 expression was significantly reduced only in the COPD subjects. Blood neutrophil CD11b expression correlated inversely with inflammatory markers and symptom scores in COPD subjects. Conclusion Following rhinovirus infection neutrophils with higher surface expression of adhesion molecules are likely preferentially recruited to the lungs. CD11b may be a key molecule involved in neutrophil trafficking in COPD exacerbations

Expression of programmed death-1 ligand (PD-L) 1, PD-L2, B7-H3, and inducible costimulator ligand on human respiratory tract epithelial cells and regulation by respiratory syncytial virus and type 1 and 2 cytokines

BACKGROUND: Respiratory syncytial virus (RSV) is associated with wheezing illness, and infections can occur repeatedly throughout life. We hypothesized that RSV infection of respiratory tract epithelial cells up-regulates B7 molecules that regulate memory immune responses and that type 1 and 2 cytokines differentially modulate this induction. METHODS: We used flow-cytometric analysis to investigate programmed death-1 ligand (PD-L) 1, PD-L2, B7-H3, and inducible costimulatory ligand (ICOS-L) expression on tracheal (NCI-H292), bronchial (BEAS-2B), and alveolar (A549) epithelial cells; regulation of this expression by RSV, interferon (IFN)- gamma , and interleukin (IL)-4; and the effects of IFN-gamma and IL-4 on RSV-induced expression of these molecules. RESULTS: B7-H3 was strongly expressed, PD-L1 and ICOS-L were moderately expressed, and PD-L2 was weakly expressed on unstimulated tracheal, bronchial, and alveolar epithelial cells. RSV infection up-regulated PD-L1, PD-L2, and B7-H3 expression on all cells and ICOS-L expression on bronchial and alveolar epithelial cells. IL-4 treatment alone had no effect, whereas IFN-gamma treatment alone increased PD-L1 and PD-L2 expression on all cells and decreased B7-H3 expression on bronchial and alveolar epithelial cells. On RSV-infected alevolar epithelial cells, IFN-gamma treatment increased PD-L1 and PD-L2 expression and decreased B7-H3 and ICOS-L expression, and IL-4 treatment increased PD-L2 and B7-H3 expression and decreased ICOS-L expression. CONCLUSIONS: Respiratory tract epithelial cells express a wide range of B7 molecules. RSV infection increases their expression, and this expression is differentially regulated by IFN-gamma and IL-4. These processes may be involved in decreasing T cell antiviral immune responses to RSV and in RSV-associated wheezing

Rapid communications A cluster of Listeria monocytogenes infections in

Hospital-acquired listeriosis cases are not commonly reported but remain a significant public health problem. We report on three cases in patients with underlying conditions occurring during one week in February 2011. The cases had common exposure to pre-packed sandwiches and salads manufactured in compliance with regulations. Breaches in cold chain and shelf life controls at hospital level were identified as key contributing factors. Rigorous hospital food management systems remain important for patient safety. Case description and clinical diagnosis Listeria monocytogenes bacteraemia was confirmed in three patients admitted on 4, 5, and 6 February 2011 to a hospital in the Midlands region of England. Two were male and one was female. All lived in the same city served by the hospital but did not have any social links. Two cases were in the age range 50-59 years and one was older, over 80 years. All the three cases had underlying conditions which included malignancies and inflammatory bowel disease. Cases were admitted in February 2011 to the same hospital where they had been hospitalised previously between 22 and 31 January 2011. Onset of symptoms leading to readmission of all three patients, ranged fro

Vitamin D increases the antiviral activity of bronchial epithelial cells in vitro

BACKGROUND: By modulating the antiviral immune response via vitamin D receptor, the active form of vitamin D (1,25-dihydroxyvitamin D, calcitriol) could play a central role in protection against respiratory virus infections. This in vitro study tested the hypothesis that respiratory viruses modulate vitamin D receptor expression in human bronchial epithelial cells and this modulation affects the antiviral response to exogenous vitamin D. METHODS: Human primary bronchial epithelial cells were infected with rhinoviruses and respiratory syncytial virus in the presence or absence of vitamin D. Expression of vitamin D receptor, 1α-hydroxylase (1α(OH)ase), 24-hydroxylase (24(OH)ase), innate interferons, interferon stimulated genes and cathelicidin were measured by quantitative polymerase chain reaction. The antiviral effect of vitamin D on rhinovirus replication was determined by measurement of virus load. A direct inactivation assay was used to determine the antiviral activity of cathelicidin. RESULTS: Both RV and RSV decreased vitamin D receptor and 24(OH)ase and, in addition, RSV increased 1α(OH)ase expression in epithelial cells. Vitamin D decreased rhinovirus replication and release, and increased rhinovirus-induced interferon stimulated genes and cathelicidin. Furthermore, cathelicidin had direct anti-rhinovirus activity. CONCLUSIONS: Despite lower vitamin D receptor levels in rhinovirus-infected epithelial cells, exogenous vitamin D increased antiviral defences most likely via cathelicidin and innate interferon pathways