Rhinovirus (RV) infection accounts for a large fraction of asthma exacerbations. Airway neutrophils and IL-8 levels are increased in RV-induced exacerbations, suggesting that RV stimulates exacerbations by inducing epithelial cell expression of (El_R)+ C-X-C chemokines, leading to an exaggerated inflammatory response. In pilot studies, we have shown that RV39 induces IL-8, ENA-78 and GRO-ct expression in primary, mu- cociliary-differentiated human tracheal epithelial cells. In 16HBE14o- cells, RV39 infection activates Src, PI 3-kinase, Akt and ERK minutes after infection, and activation of these kinases is required for IL-8 expression. RV increases C-X-C chemokine expression induced by two pro-asthmatic cytokines, IL-13 and TNFa. Fi- nally, RV1B infection of C57/BL6 mice increases airway neutrophils and levels of MIP-2, a murine ELR(+) C- X-C chemokine. Wetherefore hypothesize that RV is sufficient to activate biochemical signalingpathways involved in the asthmatic response, providing a mechanism for RV-induced asthma exacerbations.
Specific Aim 1 : Characterize upstream activators and downstream effectors of PI 3-kinase required for RV-induced ELR(+) C-X-C chemokine expression. We hypothesize that: 1) RV colocalizes with Src, PI 3- kinase, Akt and Grb2 in lipid rafts;2) Src is required for activation of the PI 3-kinase/Akt pathway;3) Class IA, II and III PI 3-kinases are required for maximal RV-induced expression of IL-8, ENA-78 and GROot;and 4) maximal NF-KB activation requires PI 3-kinase-dependent activation of NADPH oxidase.
Specific Aim 2 : Determine the biochemical signaling mechanisms responsible for cooperative effects of RV and pro-asthmatic cytokines on airway epithelial cell IL-8 expression. We hypothesize that: 1) ERKand JNK regulate IL-8 expression via activation of the AP-1 promoter site, which functions as a basal level en- hancer;2) additive effects of RV39 and TNFa are mediated by increased p65 RelA phosphorylation and NF- transactivation;3) synergistic effects of RV39 and IL-13 are mediated by increased AP-1 transactivation.
Specific Aim 3 : Determine the steps in the viral life cycle required or sufficient for RV-induced signaling and chemokine responses and, conversely, determine the requirement of host cell signal transduction for viralinfection. We hypothesize that: 1) ICAM1 ligation is required and sufficient for activation of Src, PI 3- kinase, Akt, ERK and JNK;2) viral replication is not required for activation of these signaling intermediates; and 3) PI 3-kinase activation is required for RV39 internalization.
Specific Aim 4 : Determine the requirements of PI 3-kinase signaling and ELR(+) C-X-C chemokines for RV-inducedresponses in vivo. We hypothesize that: 1) RV1B infection is sufficient for airway inflammation and epithelial cell signaling in vivo;2) PI 3-kinase is required for RV1B-induced airway inflammation in vivo; and 3) C-X-C chemokine receptor (CXCR)-2 regulates RV1B-induced airway inflammation in vivo. Understandina RV-induced asthma exacerbations will lead to improvements in the treatment of this disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL081420-05
Application #
7783827
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Noel, Patricia
Project Start
2006-04-15
Project End
2010-12-12
Budget Start
2010-04-01
Budget End
2010-12-12
Support Year
5
Fiscal Year
2010
Total Cost
$368,980
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pediatrics
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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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