Development of a mouse model mimicking key aspects of a viral asthma exacerbation

Abstract

Viral respiratory tract infections are known triggers of asthma exacerbations in both adults and children. The current standard of care, inhaled CS (corticosteroids) and LABAs (long-acting β2-adrenoceptor agonists), fails to prevent the loss of control that manifests as an exacerbation. In order to better understand the mechanisms underlying viral asthma exacerbations we established an in vivo model using the clinically relevant aeroallergen HDM (house dust mite) and the viral mimetic/TLR3 (Toll-like receptor 3) agonist poly(I:C). Poly(I:C) alone induced a similar neutrophilic inflammatory profile in the BAL (bronchoalveolar lavage) to that of HRV1b (human rhinovirus 1b) alone, accompanied by both elevated BAL KC (keratinocyte-derived chemokine) and IL-1β (interleukin-1β). When mice allergic to HDM were also challenged with poly(I:C) the neutrophilic inflammatory profile was exacerbated. Increased CD8(+) T-cell numbers, increased CD4(+) and CD8(+) cell activation and elevated KC and IL-1β were observed. No increases in Th2 cytokines or the eosinophil chemoattractant CCL11 [chemokine (C-C motif) ligand 11], above those induced by HDM alone, were observed. The poly(I:C)-exacerbated neutrophilia did not translate into changes in AHR (airways hyper-responsiveness), indicating that in this model inflammation and AHR are two mechanistically independent events. To test the clinical relevance of this model CS sensitivity was assessed using prednisone, a synthetic oral CS used to manage exacerbations in asthmatic patients already on maximal doses of inhaled CS. The increased neutrophils, and accompanying cytokines/chemokines KC and IL-1β induced by poly(I:C) challenge of HDM-sensitized and challenged mice were insensitive to oral prednisone therapy. In summary we have described a CS-resistant mouse model mimicking the key aspects of viral asthma exacerbation using the clinically relevant aeroallergen HDM and the viral mimic poly(I:C). This model may provide better understanding of disease mechanisms underlying viral exacerbations and could be used to build early confidence in novel therapeutic axes targeting viral asthma exacerbations in Th2 asthmatics.

Mouse models of severe asthma: Understanding the mechanisms of steroid resistance, tissue remodelling and disease exacerbation

“…After chronic HDM challenge, dsRNA administration increased neutrophil and T-cell recruitment and induced steroid-resistant inflammatory cytokine production. 88 Early-life infection with pneumonia virus of mice (PVM) (a mouse model of RSV infection) in conjunction with allergen sensitization/challenge promoted eosinophilic inflammation, allergen-specific IgE and IgG and production of T H 2 cytokines (IL-4, IL-5 and IL-13). 89 Furthermore, neonatal PVM infection induced AHR and mucus cell hyperplasia, regardless of allergen sensitization/challenge.…”

Versican Deficiency Significantly Reduces Lung Inflammatory Response Induced by Polyinosine-Polycytidylic Acid Stimulation

“…Viral lung infection is one of the exacerbating factors contributing to chronic lung diseases, such as asthma (1)(2)(3)(4)(5)(6). During acute lung inflammation, extracellular matrix (ECM) 6 around blood vessels and airways remodels to allow for infiltration of leukocytes.…”

“…During acute lung inflammation, extracellular matrix (ECM) 6 around blood vessels and airways remodels to allow for infiltration of leukocytes. This "provisional" ECM involves accumulation of the hygroscopic molecules hyaluronan (HA) and the chondroitin sulfate (CS) proteoglycan (PG) versican, which together create a loose and hydrated space necessary for leukocyte ingress and additionally for migration and expansion of resident stromal cells.…”

Poly(inosinic-cytidylic) Acid–Triggered Exacerbation of Experimental Asthma Depends on IL-17A Produced by NK Cells

“…In turn, such dsRNA motifs can be sensed by the immune system via TLR3 or retinoic acid-inducible gene-I (8,9), suggesting a central role of this receptors in the pathogenesis of acute asthma exacerbations. This hypothesis is supported by mouse experiments demonstrating that not only rhinovirus infection but also local application of viral dsRNA or poly(inosinic-cytidylic) acid (pIC) alone triggers exacerbation of experimental asthma in mice (10)(11)(12). However, the underlying mechanisms of this disease pattern remain completely unclear.…”