Viral infections, most commonly by human rhinovirus (HRV), are the most frequent cause of asthma attacks. In theory, chemokine production by HRV-infected epithelial cells induces the recruitment of inflammatory cells to the airways, which in turn elaborate cytokines and mediators capable of increasing airway responses. This paradigm, however, fails to explain why asthmatics experience manifestations of lower airways disease following colds while normals do not. This proposal tests the novel hypothesis that pre-existing airways disease, either allergic or non-allergic, modifies the polarization state of airway macrophages, leading to an altered response to rhinovirus infection. Consistent with this, our pilot data indicate that allergen sensitization and challenge with ovalbumin (OVA) alters the response to HRV infection from a neutrophilic response to a Th2-dominant, combined neutrophilic and eosinophilic response that is mediated in part by macrophage production of eotaxin-1/CCL11 and MCP-1/CCL2. HRV-infected macrophages produce eotaxin-1 and MCP-1 in vivo and ex vivo, and macrophage depletion attenuates HRV-enhanced airway eosinophilic inflammation and hyperresponsiveness. Finally, macrophages from OVA-treated mice show increased expression of the alternative activation markers Arg-1, Ym-1 and MGL-2. The overall airway response to HRV infection depends not only on pro-inflammatory pathways but also the antiviral response. It has been hypothesized that asthmatics are prone to HRV-induced exacerbations due to deficient interferon (IFN) production. However, reduced IFN production may be accompanied by attenuated inflammatory responses, which would tend to protect against asthma exacerbation. Indeed, our pilot data show that HRV1B-infected Toll-like receptor-3 -/- mice with lower IFN responses show reduced airways inflammation and responsiveness. In this application, we will examine the signaling intermediates required for HRV-induced IFN expression in vivo, and test whether impaired IFN production leads to increased HRV-induced airway inflammation. We propose the following Specific Aims:
Specific Aim 1. Determine the effects of preexisting airways disease on HRV responses.
Specific Aim 2. Determine the role of the macrophage in HRV-induced exacerbations of pre- existing airways disease in mice.
Specific Aim 3. Determine the effect of impaired IFN production on viral load and airway inflammation in vivo. Completion of this work, which includes both animal and human studies, will provide a new paradigm for poorly-understood viral-induced asthma attacks, identify molecular targets for therapeutic intervention, introduce a device for detection of respiratory viruses, and directly test the hypothesis that impaired IFN production leads to more severe asthma exacerbations.
Viral infections, most commonly caused by rhinovirus, are the most frequent cause of asthma attacks. This application seeks to understand the cellular and biochemical mechanisms underlying rhinovirus-induced asthma exacerbations. It proposes a new paradigm in which rhinovirus infects alternatively polarized macrophages, resulting in exaggerated pro-inflammatory responses. Insight provided from the proposed studies may lead to new treatments for asthma and other chronic airways diseases.
|Han, Mingyuan; Hong, Jun Young; Jaipalli, Suraj et al. (2017) IFN-? Blocks Development of an Asthma Phenotype in Rhinovirus-Infected Baby Mice by Inhibiting Type 2 Innate Lymphoid Cells. Am J Respir Cell Mol Biol 56:242-251|
|Han, Mingyuan; Chung, Yutein; Young Hong, Jun et al. (2016) Toll-like receptor 2-expressing macrophages are required and sufficient for rhinovirus-induced airway inflammation. J Allergy Clin Immunol 138:1619-1630|
|Faris, Andrea N; Ganesan, Shyamala; Chattoraj, Asamanja et al. (2016) Rhinovirus Delays Cell Repolarization in a Model of Injured/Regenerating Human Airway Epithelium. Am J Respir Cell Mol Biol 55:487-499|
|Chung, Yutein; Hong, Jun Young; Lei, Jing et al. (2015) Rhinovirus infection induces interleukin-13 production from CD11b-positive, M2-polarized exudative macrophages. Am J Respir Cell Mol Biol 52:205-16|
|Feldman, Amy S; He, Yuan; Moore, Martin L et al. (2015) Toward primary prevention of asthma. Reviewing the evidence for early-life respiratory viral infections as modifiable risk factors to prevent childhood asthma. Am J Respir Crit Care Med 191:34-44|
|Hong, Jun Young; Chung, Yutein; Steenrod, Jessica et al. (2014) Macrophage activation state determines the response to rhinovirus infection in a mouse model of allergic asthma. Respir Res 15:63|
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|Saba, Thomas G; Chung, Yutein; Hong, Jun Young et al. (2014) Rhinovirus-induced macrophage cytokine expression does not require endocytosis or replication. Am J Respir Cell Mol Biol 50:974-84|
|Hong, Jun Young; Bentley, J Kelley; Chung, Yutein et al. (2014) Neonatal rhinovirus induces mucous metaplasia and airways hyperresponsiveness through IL-25 and type 2 innate lymphoid cells. J Allergy Clin Immunol 134:429-39|
|Bentley, J Kelley; Sajjan, Uma S; Dzaman, Marta B et al. (2013) Rhinovirus colocalizes with CD68- and CD11b-positive macrophages following experimental infection in humans. J Allergy Clin Immunol 132:758-761.e3|
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