Chronic obstructive lung diseases (COLD), such as asthma and COPD are major health issues, especially in modernized countries, and for which there are currently no curative therapies. Respiratory viral infections have been implicated in both development and exacerbation of COLD. Utilizing a mouse model of paramyxoviral infection, we have shown that infection with Sendai virus (SeV) leads to a long-lasting post-viral COLD with airway hyperreactivity and mucous cell metaplasia. This post-viral disease is dependent upon production of the chemokine CCL28 from lung dendritic cells. CCL28 has two receptors, CCR3 and CCR10, although it is not known through which of these receptors it exerts its effects in the SeV model. Blocking the effect of CCL28 in this model would be expected to prevent the development of the post-viral disease. We have recently developed a structure-based strategy to identify specific small molecule chemokine inhibitors, based on sulfotyrosine recognition pocket binding, that work by preventing receptor activation by the specific chemokine. We hypothesize that lung-specific CCL28 production is critical to the development of post-viral asthma, and that this process can be ablated by direct inhibition of CCL28's function. To test this hypothesis, we propose three specific aims: 1) Test the hypothesis that CCL28 activation of CCR10 leads to airway hyperresponsiveness and mucous cell metaplasia in a mouse model of obstructive lung disease. 2) Solve the 3D structure of CCL28 and identify important receptor recognition sites by NMR and mutagenesis. 3) Identify small molecule ligands that inhibit CCL28 activity in vitro and test their ability to prevent post-viral asthma in vivo. Upon completion of this project, we will have identified the chemokine receptor through which CCL28 mediates its action in the SeV model. Further, we will have developed at least one small molecule that inhibits CCL28 activity in both in vitro and in vivo assays. In the future, thee small molecule CCL28 antagonists could be further studied for potential use as a means to treat and/or prevent chronic obstructive lung disease in humans.

Public Health Relevance

Asthma and chronic obstructive pulmonary disease (COPD) form the spectrum of COLD for which there are no available curative therapies. The risk of developing asthma is greatly increased if the person has had a severe viral respiratory infection. However, we found that blocking the action of a specific inflammatory protein called CCL28 can prevent the symptoms of viral-induced COLD. We propose to search for CCL28 inhibitors using an innovative strategy that we devised to target proteins in this family. The development of a novel inhibitor of CCL28 activity will advance our understanding of airway diseases and address an unmet need for diagnosis and treatment of a public health problem.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI120655-01
Application #
8986907
Study Section
Special Emphasis Panel (ZRG1-CVRS-H (02))
Program Officer
Minnicozzi, Michael
Project Start
2015-06-15
Project End
2019-07-31
Budget Start
2015-06-15
Budget End
2016-07-31
Support Year
1
Fiscal Year
2015
Total Cost
$384,791
Indirect Cost
$134,791
Name
Medical College of Wisconsin
Department
Biochemistry
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Grayson, Mitchell H; Camarda, Lauren E; Hussain, Syed-Rehan A et al. (2018) Intestinal Microbiota Disruption Reduces Regulatory T Cells and Increases Respiratory Viral Infection Mortality Through Increased IFN? Production. Front Immunol 9:1587
Thomas, Monica A; Kleist, Andrew B; Volkman, Brian F (2018) Decoding the chemotactic signal. J Leukoc Biol 104:359-374
Scherzer, Rebecca; Grayson, Mitchell H (2018) Heterogeneity and the origins of asthma. Ann Allergy Asthma Immunol 121:400-405
Hussain, Syed-Rehan A; Mejias, Asuncion; Ramilo, Octavio et al. (2018) Post-viral atopic airway disease: pathogenesis and potential avenues for intervention. Expert Rev Clin Immunol :1-10
Thomas, Monica A; He, Jie; Peterson, Francis C et al. (2018) The Solution Structure of CCL28 Reveals Structural Lability that Does Not Constrain Antifungal Activity. J Mol Biol 430:3266-3282
Martorano, Lisa M; Grayson, Mitchell H (2018) Respiratory viral infections and atopic development: From possible mechanisms to advances in treatment. Eur J Immunol 48:407-414
Egner, John M; Jensen, Davin R; Olp, Michael D et al. (2018) Development and Validation of 2D Difference Intensity Analysis for Chemical Library Screening by Protein-Detected NMR Spectroscopy. Chembiochem 19:448-458
Tam, Jonathan S; Grayson, Mitchell H (2017) IgE and antiviral immune response in asthma. J Allergy Clin Immunol 139:1717