Acute exacerbations are the major cause of morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD). Rhinovirus, which causes acute exacerbations may also accelerate progression of lung disease in these patients. Current therapies reduces the respiratory symptoms and does not treat the root cause of exacerbations effectively. We hypothesized that quercetin, a potent antioxidant and anti-inflammatory agent with antiviral properties may be useful in treating rhinovirus-induced changes in COPD. Mice with COPD phenotype maintained on control or quercetin diet and normal mice were infected with sham or rhinovirus, and after 14 days mice were examined for changes in lung mechanics and lung inflammation. Rhinovirus-infected normal mice showed no changes in lung mechanics or histology. In contrast, rhinovirus-infected mice with COPD phenotype showed reduction in elastic recoiling and increase in lung inflammation, goblet cell metaplasia, and airways cholinergic responsiveness compared to sham-infected mice. Interestingly, rhinovirus-infected mice with COPD phenotype also showed accumulation of neutrophils, CD11b+/CD11c+ macrophages and CD8+ T cells in the lungs. Quercetin supplementation attenuated rhinovirus-induced all the pathologic changes in mice with COPD phenotype. Together these results indicate that quercetin effectively mitigates rhinovirus-induced progression of lung disease in a mouse model of COPD. Therefore, quercetin may be beneficial in the treatment of rhinovirus-associated exacerbations and preventing progression of lung disease in COPD.

Airway epithelial cells are the major target for rhinovirus (RV) infection and express pro-inflammatory chemokines and antiviral cytokines that play a role in innate immunity. Previously, we demonstrated that RV interaction with TLR2 causes IRAK-1 depletion in both airway epithelial cells and macrophages. Further, IRAK-1 degradation caused by TLR2 activation was shown to inhibit single stranded RNA-induced interferons (IFN) expression in dendritic cells. Therefore, in this study, we examined the role of TLR2 and IRAK-1 in RV-induced IFN-β, IFN- λ1 and CXCL-10, which require signaling by viral RNA. In airway epithelial cells, blocking TLR2 enhanced RV-induced expression of IFNs and CXCL-10. By contrast, IRAK-1 inhibition abrogated RV-induced expression of CXCL-10, but not IFNs in these cells Neutralization of IL-33 or its receptor, ST2, which requires IRAK-1 for signaling inhibited RV-stimulated CXCL-10 expression. Additionally, RV induced expression of both ST2 and IL-33 in airway epithelial cells. In macrophages, however, RV-stimulated CXCL-10 expression was primarily dependent on TLR2/IL-1 receptor. Interestingly, in a mouse model of rhinovirus infection, blocking ST2 not only attenuated RV-induced CXCL-10, but also lung inflammation. Finally, influenza and respiratory syncytial virus-induced CXCL-10 was also found to be partially dependent on IL-33/ST2/IRAK-1 signaling in airway epithelial cells. Together our results indicate that RV-stimulates CXCL-10 expression via IL-33/ST2 signaling axis, and that TLR2 signaling limits RV-induced CXCL-10 via IRAK-1 depletion at least in airway epithelial cells. To our knowledge, this is the first report to demonstrate the role of respiratory virus induced IL-33 in the induction of CXCL-10 in airway epithelial cells.

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We have demonstrated that intranasal immunotherapy with allergens formulated in a nanoemulsion (NE) mucosal adjuvant suppresses Th2/IgE-mediated allergic responses and protects from allergen challenge in murine food allergy models. Protection conferred by this therapy is associated with strong suppression of allergen specific Th2 cellular immunity and increased Th1 cytokines. Here we extend these studies to examine the effect of NE-allergen immunization in mice sensitized to multiple foods. Mice were sensitized to both egg and peanut and then received NE vaccine formulated with either one or both of these allergens. The animals were then subjected to oral challenges with either egg or peanut to assess reactivity. Immunization with NE formulations containing both egg and peanut markedly reduced reactivity after oral allergen challenge with either allergen. Interestingly, mice that received the vaccine containing only peanut also had reduced reactivity to challenge with egg. Protection from oral allergen challenge was achieved despite the persistence of allergen-specific IgE and was associated with strong suppression of both Th2-polarized immune responses, alarmins and type 2 innate lymphoid cells (ILC2). NE-induced bystander suppression of reactivity required IFN-γ and the presence of an allergen in the NE vaccine. These results demonstrate that anaphylactic reactions to food allergens can be suppressed using allergen-specific immunotherapy without having to eliminate allergen-specific IgE and suggests that modulation of Th2 immunity towards one allergen may induce bystander effects that suppress reactivity to other allergens through the induction of IFN-γ and suppression of alarmins in the intestine. In addition, these data suggest that a NE vaccine for a single food allergen may lead to a global suppression of allergic responses to multiple foods.

Rhinovirus (RV), which is associated with acute exacerbations, also causes persistent lung inflammation in patients with chronic obstructive pulmonary disease (COPD), but the underlying mechanisms are not well-known. Recently, we demonstrated that RV causes persistent lung inflammation with accumulation of a subset of macrophages (CD11b+/CD11c+), and CD8+ T cells, and progression of emphysema. In the present study, we examined the mechanisms underlying the RV-induced persistent inflammation and progression of emphysema in mice with COPD phenotype. Our results demonstrate that at 14 days post-RV infection, in addition to sustained increase in CCL3, CXCL-10 and IFN-γ expression as previously observed, levels of interleukin-33 (IL-33), a ligand for ST2 receptor, and matrix metalloproteinase (MMP)12 are also elevated in mice with COPD phenotype, but not in normal mice. Further, MMP12 was primarily expressed in CD11b+/CD11c+ macrophages. Neutralization of ST2, reduced the expression of CXCL-10 and IFN-γ and attenuated accumulation of CD11b+/CD11c+ macrophages, neutrophils and CD8+ T cells in COPD mice. Neutralization of IFN-γ, or ST2 attenuated MMP12 expression and prevented progression of emphysema in these mice. Taken together, our results indicate that RV may stimulate expression of CXCL-10 and IFN-γ via activation of ST2/IL-33 signaling axis, which in turn promote accumulation of CD11b+/CD11c+ macrophages and CD8+ T cells. Furthermore, RV-induced IFN-γ stimulates MMP12 expression particularly in CD11b+/CD11c+ macrophages, which may degrade alveolar walls thus leading to progression of emphysema in these mice. In conclusion, our data suggest an important role for ST2/IL-33 signaling axis in RV-induced pathological changes in COPD mice.

The present study was aimed at evaluating the effectiveness of amoxicillin-bearing HSA (human serum albumin) and PLGA [poly(lactic-co-glycolic acid)] microparticles in combating Listeria monocytogenes infection in Swiss albino mice. Amoxicillin-bearing HSA microspheres were prepared by chemical cross-linking of a drug/albumin mixture with glutaraldehyde, and PLGA microspheres were prepared by the W/O/W (water-in-oil-in-water) emulsion technique. The microspheres were characterized for their size, ζ potential and entrapment efficiency using SEM (scanning electron microscopy) and a Zetasizer. Release kinetics was performed in a phosphate buffer (pH 7.4) at 37°C simulating physiological conditions. Bacterial burden in various vital organs and survival data established enhanced efficacy of PLGA and HSA microspheres as compared with free drug. Among the two delivery systems, PLGA microspheres, when compared with HSA microspheres, imparted better efficacy in terms of reduction in bacterial load as well as increase in survival. The results of the present study clearly demonstrate that microparticles successfully target the infected macrophages and the approach could be well exploited for targeting the intracellular pathogens as well.