Background

Recent evidence indicates that Staphylococcus aureus, one of the most important human pathogens, secretes vesicles into the extracellular milieu.



Objective

To evaluate whether inhalation of S. aureus-derived extracellular vesicles (EV) is causally related to the pathogenesis of inflammatory pulmonary diseases.



Methods

Staphylococcus aureus EV were prepared by sequential ultrafiltration and ultracentrifugation. The innate immune response was evaluated in vitro after the application of EV to airway epithelial cells and alveolar macrophages. In vivo innate and adaptive immune responses were evaluated after airway exposure to EV. Adjuvant effects of EV on the development of hypersensitivity to inhaled allergens were also evaluated after airway sensitization with S. aureus EV and ovalbumin (OVA).



Results

Staphylococcus aureus and S. aureus EV were detected in house dust. Alveolar macrophages produced both tumor necrosis α (TNF-α) and interleukin 6 (IL-6) after in vitro stimulation with S. aureus EV, whereas airway epithelial cells produced only IL-6. Repeated airway exposure to S. aureus EV induced both Th1 and Th17 cell responses and neutrophilic pulmonary inflammation, mainly via a Toll-like receptor 2 (TLR2)-dependent mechanism. In terms of adjuvant effects, airway sensitization with S. aureus EV and OVA resulted in neutrophilic pulmonary inflammation after OVA challenge alone. This phenotype was partly reversed by the absence of interferon γ (IFN-γ) or IL-17.



Conclusion

Staphylococcus aureus EV can induce Th1 and Th17 neutrophilic pulmonary inflammation, mainly in a TLR2-dependent manner. Additionally, S. aureus EV enhance the development of airway hypersensitivity to inhaled allergens.

Staphylococcus aureus‐derived extracellular vesicles induce neutrophilic pulmonary inflammation via both Th1 and Th17 cell responses

Chronic obstructive respiratory disorders such as asthma and chronic obstructive pulmonary disease often originate early in life. In addition to a genetic predisposition, prenatal and early-life environmental exposures have a persistent impact on respiratory health. Acting during a critical phase of lung development, these factors may change lung structure and metabolism, and may induce maladaptive responses to harmful agents, which will affect the whole lifespan. Some environmental factors, such as exposure to cigarette smoke, type of childbirth and diet, may be modifiable, but it is more difficult to influence other factors, such as preterm birth and early exposure to viruses or allergens. Here, we bring together recent literature to analyse the critical aspects involved in the early stages of lung development, going back to prenatal and perinatal events, and we discuss the mechanisms by which noxious factors encountered early on may have a lifelong impact on respiratory health. We briefly comment on the need for early disease biomarkers and on the possible role of "-omic" technologies in identifying risk profiles predictive of chronic respiratory conditions. Such profiles could guide the ideation of effective preventive strategies and/or targeted early lifestyle or therapeutic interventions.

https://erj.ersjournals.com/content/erj/44/6/1682.full.pdf

Early-life origins of chronic respiratory diseases: understanding and promoting healthy ageing.

SummaryBackground
Many bacterial components in indoor dust can evoke inflammatory pulmonary diseases. Bacteria secrete nanometre-sized vesicles into the extracellular milieu, but it remains to be determined whether bacteria-derived extracellular vesicles in indoor dust are pathophysiologically related to inflammatory pulmonary diseases.

Objective
To evaluate whether extracellular vesicles (EV) in indoor air are related to the pathogenesis of pulmonary inflammation and/or asthma.

Methods
Indoor dust was collected from a bed mattress in an apartment. EV were prepared by sequential ultrafiltration and ultracentrifugation. Innate and adaptive immune responses were evaluated after airway exposure of EV.

Results
Repeated intranasal application of indoor-dust-induced neutrophilic pulmonary inflammation accompanied by lung infiltration of both Th1 and Th17 cells. EV 50–200 nm in diameter were present (102.5 μg protein concentration/g dust) in indoor dust. These vesicles were internalized by airway epithelial cells and alveolar macrophages, and this process was blocked by treatment of polymyxin B (an antagonist of lipopolysaccharide, an outer-membrane component of Gram-negative bacteria). Intranasal application of 0.1 or 1 μg of these vesicles for 4 weeks elicited neutrophilic pulmonary inflammation. This phenotype was accompanied by lung infiltration of both Th1 and Th17 cells, which were reversed by treatment of polymyxin B. Serum dust EV-reactive IgG1 levels were significantly higher in atopic children with asthma than in atopic healthy children and those with rhinitis or dermatitis.

Conclusion & Clinical Relevance
Indoor dust EV, especially derived from Gram-negative bacteria, is a possible causative agent of neutrophilic airway diseases.

Extracellular vesicles, especially derived from Gram-negative bacteria, in indoor dust induce neutrophilic pulmonary inflammation associated with both Th1 and Th17 cell responses

Airway remodeling is observed in the airways of patients with asthma, and differentiation of fibroblasts to myofibroblasts plays a critical role in the progress of airway remodeling. Viral infection induces not only the disease development and exacerbations but also airway remodeling. The aim of this study was to evaluate whether the activation of Toll-like receptor 3 (TLR3) can affect the differentiation of fibroblasts to myofibroblasts and the extracellular matrix (ECM) protein production. Human fetal lung fibroblasts (HFL-1) and adult lung fibroblasts were treated with a synthetic double-stranded RNA, polyinosine-polycytidylic acid (poly[I:C]) and the expression of alpha-smooth muscle actin (alpha-SMA), a marker of myofibroblast differentiation, was evaluated. The release of transforming growth factor-beta(1) (TGF-beta(1)) and ECM protein production were assessed. The effect of anti-TGF-beta antibody on the alpha-SMA and ECM production was also assessed. Poly(I:C) significantly augmented the alpha-SMA expression (P < 0.01) and release of TGF-beta(1) (P < 0.01) compared with control. Bafilomycin, an inhibitor of TLR3 signaling, diminished poly(I:C)-augmented TGF-beta(1) release. Anti-TGF-beta(1) antibody inhibited the poly(I:C)-augmented alpha-SMA expression. Poly(I:C) enhanced translocation of nuclear factor-kB (NF-kappaB) and interferon regulatory factor-3 (IRF-3) into the nucleus. Poly(I:C)-augmented TGF-beta(1) release was almost completely blocked by NF-kappaB inhibitors, but not by silencing IRF-3. The production of fibronectin and collagen I expression were significantly increased by poly(I:C) (P < 0.01) and they were inhibited by anti-TGF-beta antibody. These results suggest that activation of TLR3 can affect the differentiation to myofibroblasts and enhance ECM production via the NF-kappaB-TGF-beta(1)-dependent pathway.

Activation of Toll-Like Receptor 3 Augments Myofibroblast Differentiation

Respiratory infections exacerbate chronic lung diseases promoting airway inflammation and hyperreactivity. Toll-like receptor 3 (TLR3) recognizes viral double-stranded (ds) RNA such as polyinosinic...

TLR3 activation stimulates cytokine secretion without altering agonist-induced human small airway contraction or relaxation

Background Although respiratory viral infections in early childhood can enhance the development of airway allergen sensitization, the exact mechanisms of the effects of viral infections on the adaptive immune response to inhaled allergens are controversial. Objective We sought to evaluate the effects of double-stranded RNA (dsRNA) on airway sensitization to inhaled allergens. Methods Novel mouse models were created through simultaneous airway sensitization to an allergen and low or high doses of dsRNA. The mouse models were applied to Toll-like receptor 3–, IL-13–, IL-4–, signal transducer and activator of transcription (STAT) 6–, IFN-γ–, and T-box expressed in T cells (T-bet)–deficient mice to evaluate underlying pathophysiologic mechanisms in the development of allergic lung inflammation. Results We found that airway allergen sensitization with dsRNA induced lung inflammation that was not present in Toll-like receptor 3–deficient mice. Moreover, lung inflammation enhanced by low-dose dsRNA was impaired in IL-13–deficient mice, whereas lung inflammation by high-dose dsRNA was impaired in IFN-γ–deficient mice. The models also demonstrated that low-dose dsRNA enhanced IL-4 expression during allergen sensitization and that inflammation enhanced by low-dose dsRNA was not present in IL-4– or STAT6-deficient mice. In contrast, the present study showed that high-dose dsRNA enhanced IFN-γ expression during allergen sensitization and that the development of lung inflammation enhanced by high-dose dsRNA was impaired in T-bet–deficient mice. Conclusion These findings suggest that airway allergen exposure during respiratory viral infections might induce asthma induced by both T H 1 and T H 2 immune responses to inhaled allergens. Clinical implications Targeting both T H 1 and T H 2 lung inflammation might be important in the treatment of virus-associated asthma.

TH2 and TH1 lung inflammation induced by airway allergen sensitization with low and high doses of double-stranded RNA.

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TH2 and TH1 lung inflammation induced by airway allergen sensitization with low and high doses of double-stranded RNA.