Rhinovirus Infection Induces Degradation of Antimicrobial Peptides and Secondary Bacterial Infection in Chronic Obstructive Pulmonary Disease

Mallia, Patrick; Footitt, Joseph; Sorrentino, Rosa; Jepson, Annette; Contoli, Marco; Trujillo-Torralbo, Maria-Belen; Kebadze, Tatiana; Aniscenko, Julia; Oleszkiewicz, Gregory; Gray, Katrina; Message, Simon D.; Ito, Kazuhiro; Barnes, Peter J.; Adcock, Ian M.; Papi, Alberto; Stanciu, Luminita A.; Elkin, Sarah; Kon, Onn Min; Johnson, Malcolm; Johnston, Sebastian L.

doi:10.1164/rccm.201205-0806oc

Cited by 239 publications

(276 citation statements)

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“…Subjects with COPD had a postbronchodilator FEV 1 between 50 and 80% of predicted and an FEV 1 /FVC ratio less than 70%. The subjects were inoculated intranasally with low-dose rhinovirus-16 (10 TCID 50 ), using an atomizer as previously described (15). Induced sputum was collected at baseline before RV inoculation (Day 0) and again on Days 5, 15, and 42 after rhinovirus infection (17).…”

Section: Subjects and Samplingmentioning

confidence: 99%

“…We have developed a human model of COPD exacerbation that uses experimental rhinovirus infection and induces the clinical, physiological, and inflammatory features typical of COPD exacerbations (14). In 60% of patients with COPD, rhinovirus infection is followed by positive sputum bacterial cultures (15), but it remains unclear whether these represent de novo infections or an increase in load of preexisting organisms from the lower airways. The aim of this study, therefore, was to investigate the effect of rhinovirus infection on the respiratory microbiome in COPD.…”

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confidence: 99%

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Outgrowth of the Bacterial Airway Microbiome after Rhinovirus Exacerbation of Chronic Obstructive Pulmonary Disease

Molyneaux

Mallia

Cox

et al. 2013

Am J Respir Crit Care Med

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341

271

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Rationale: Rhinovirus infection is followed by significantly increased frequencies of positive, potentially pathogenic sputum cultures in chronic obstructive pulmonary disease (COPD). However, it remains unclear whether these represent de novo infections or an increased load of organisms from the complex microbial communities (microbiome) in the lower airways. Objectives: To investigate the effect of rhinovirus infection on the airway bacterial microbiome. Methods: Subjects with COPD (n ¼ 14) and healthy control subjects with normal lung function (n ¼ 17) were infected with rhinovirus. Induced sputum was collected at baseline before rhinovirus inoculation and again on Days 5, 15, and 42 after rhinovirus infection and DNA was extracted. The V3-V5 region of the bacterial 16S ribosomal RNA gene was amplified and pyrosequenced, resulting in 370,849 high-quality reads from 112 of the possible 124 time points. Measurements and Main Results: At 15 days after rhinovirus infection, there was a sixfold increase in 16S copy number (P ¼ 0.007) and a 16% rise in numbers of proteobacterial sequences, most notably in potentially pathogenic Haemophilus influenzae (P ¼ 2.7 3 10 -20 ), from a preexisting community. These changes occurred only in the sputum microbiome of subjects with COPD and were still evident 42 days after infection. This was in contrast to the temporal stability demonstrated in the microbiome of healthy smokers and nonsmokers. Conclusions: After rhinovirus infection, there is a rise in bacterial burden and a significant outgrowth of Haemophilus influenzae from the existing microbiota of subjects with COPD. This is not observed in healthy individuals. Our findings suggest that rhinovirus infection in COPD alters the respiratory microbiome and may precipitate secondary bacterial infections.Keywords: rhinovirus; chronic obstructive pulmonary disease; bacteria; microbiome Chronic obstructive pulmonary disease (COPD) is a growing global health epidemic, predicted to be the fourth leading cause of mortality worldwide by 2030 (1). Despite the chronic nature of COPD, acute exacerbations are the major cause of mortality, accounting for almost 70% of health care costs and accelerating the progressive decline in lung function (2). The great majority of exacerbations are caused by respiratory infections with bacteria and viruses, each of which has been detected in about 50% of cases, with coinfection common (3). The concurrent presence of bacteria and viruses during exacerbations of COPD has been shown to be associated with a greater decline in lung function and prolonged hospital stay (3, 4).Current understanding of the interactions between viruses and bacteria in exacerbations of obstructive airway disease is based predominantly upon classical microbial culture techniques. These have suggested that the lower airways are sterile , has therefore supplied the information regarding J.F.'s contribution to the manuscript and his competing interests, and it is correct to the best of her knowledge.The funders had no role in stu...

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Section: Subjects and Samplingmentioning

confidence: 99%

mentioning

confidence: 99%

Outgrowth of the Bacterial Airway Microbiome after Rhinovirus Exacerbation of Chronic Obstructive Pulmonary Disease

Molyneaux

Mallia

Cox

et al. 2013

Am J Respir Crit Care Med

Self Cite

341

271

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“…Expression of some AMPs can be induced by infectious and inflammatory stimuli, which prompted researchers to investigate their role in secondary infections. Experimental infection of COPD patients with rhinovirus significantly increased the incidence of bacterial infections (Mallia et al, 2012). In those COPD patients who also developed a secondary bacterial infection, sputum levels of the protease inhibitors SLPI (serine leukocyte peptidase inhibitor) and elafin were decreased.…”

Section: Antimicrobial Peptidesmentioning

confidence: 99%

Viral–bacterial interactions in the respiratory tract

Bellinghausen

Rohde

Savelkoul

et al. 2016

Journal of General Virology

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“…In this case, bacterial infection of the lower airways is often associated with COPD exacerbation and progression (2), but more sensitive PCR-based technology detects respiratory viruses in the airway with high frequency as well (3)(4)(5)(6)(7). Moreover, viral challenge shows that viral infection alone is sufficient to induce COPD exacerbation and to lead to secondary bacterial infection with exacerbation (8,9). Despite these associations, a primary cause-and-effect relationship between viral infection and the pathogenesis of COPD remains to be fully established.…”

Section: Introductionmentioning

confidence: 99%

Long-term IL-33–producing epithelial progenitor cells in chronic obstructive lung disease

Byers

Alexander‐Brett²,

Patel³

et al. 2013

J. Clin. Invest.

280

255

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Chronic obstructive lung disease is characterized by persistent abnormalities in epithelial and immune cell function that are driven, at least in part, by infection. Analysis of parainfluenza virus infection in mice revealed an unexpected role for innate immune cells in IL-13-dependent chronic lung disease, but the upstream driver for the immune axis in this model and in humans with similar disease was undefined. We demonstrate here that lung levels of IL-33 are selectively increased in postviral mice with chronic obstructive lung disease and in humans with very severe chronic obstructive pulmonary disease (COPD). In the mouse model, IL-33/IL-33 receptor signaling was required for Il13 and mucin gene expression, and Il33 gene expression was localized to a virus-induced subset of airway serous cells and a constitutive subset of alveolar type 2 cells that are both linked conventionally to progenitor function. In humans with COPD, IL33 gene expression was also associated with IL13 and mucin gene expression, and IL33 induction was traceable to a subset of airway basal cells with increased capacities for pluripotency and ATP-regulated release of IL-33. Together, these findings provide a paradigm for the role of the innate immune system in chronic disease based on the influence of long-term epithelial progenitor cells programmed for excess IL-33 production.

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Rhinovirus Infection Induces Degradation of Antimicrobial Peptides and Secondary Bacterial Infection in Chronic Obstructive Pulmonary Disease

Cited by 239 publications

References 34 publications

Outgrowth of the Bacterial Airway Microbiome after Rhinovirus Exacerbation of Chronic Obstructive Pulmonary Disease

Outgrowth of the Bacterial Airway Microbiome after Rhinovirus Exacerbation of Chronic Obstructive Pulmonary Disease

Viral–bacterial interactions in the respiratory tract

Long-term IL-33–producing epithelial progenitor cells in chronic obstructive lung disease

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