Severe asthma remains a debilitating and difficult to control disease. Notwithstanding the basic understanding that asthma is initiated and perpetuated by a strong inflammatory component, in many patients, the disease manifests in a severe form that is unresponsive to treatment by corticosteroids (CS). However, asthma in milder forms generally responds to standard steroid therapy. Our preliminary data presented in two human- based projects suggest that severe asthma cannot be explained simply by an overzealous Th2 response and eosinophilic airway inflammation. The overall hypothesis for this P01 application is that the pathophysiology of steroid refractory severe asthma involves cooperativity between a heightened Th1 (IFN-?) immune response often accompanied by increased IL-27 levels, residual Type 2 responses plus a deficient IL-10 response. This atypical immune response, not appreciated heretofore, induces specific downstream effects on airway epithelial cells such as profound nitro-oxidative stress, which perpetuate the inflammatory response resulting in chronic disease. Our hypothesis will be addressed in 2 Projects. Project 1 will establish the atypical immune fingerprint of CS-refractory severe asthma (SA) as compared to milder asthma using immunological and RNA-sequencing (RNA-Seq) approaches. A newly established mouse model of SA will be used to understand the role of immune pathways in inducing airway oxidative stress. The mechanisms by which the combination of IL- 27 and IFN-? causes glucocorticoid receptor (GR) dysfunction will be elucidated. RNA-sequencing (RNA-seq) approaches in conjunction with bioinformatic tools will be used to derive a gene interactome of SA. Project 2 will identify the molecular phenotypes induced by the intersection of Type 1 and 2 immune pathways, and IL-27 on primary airway epithelial cells using biased and unbiased (RNA-Seq) approaches. The role of nitro-oxidative stress in inducing these phenotypes will be determined. Also, whether these cytokine combinations induce CS- unresponsiveness in epithelial cells will be studied along with the possibility of improving the response by IL-10. Importantly both projects will examine the heightened STAT1 activation with low/no STAT3 activation observed in immune and epithelial cells, this altered balance being detrimental for both immune regulation and epithelial cell function. Synergistic interactions among projects will be afforded by support from the Administrative Core, to coordinate the activities of the P01 at all levels, the Human Biological Sampling and Immunocytometry Core and, the RNA-Seq and Bioinformatics Core. Thus, using cutting edge immunological, cellular and RNA sequencing techniques, the proposal will establish a new paradigm for severe asthma based on which novel therapeutics could be developed in the future.

Public Health Relevance

The goal of this application is to understand the aberrant immune response in severe asthma that is poorly responsive to standard therapy for asthma. A better understanding of interactions between the immune cells and their mediators and airway epithelial cells, as proposed in the study, will identify targets for the development of novel futue therapies. Project 1 Immune Pathway Interactions in Steroid Refractory Severe Asthma (Description as provided by applicant) Severe asthma belongs to a different category of asthma for the simple reason that unlike the milder form of the disease it is difficult to control by corticosteroids (CS). This general differetial response to therapy between mild and severe asthmatics suggests a difference in the nature of the immune in the two subclasses of asthmatics. In studies of human samples performed in collaboration with Dr. Sally Wenzel, we have observed that the majority (70-75%) of severe asthmatics harbor a prominent Th1 (IFN-?) adaptive immune response both at RNA and protein levels in their airways and 50% show a IFN-?hiIL-27hi response. The Th1 signature in SA is also accompanied by, a low but detectable, Th2 and Th17 presence. These findings are also corroborated by an unbiased RNA-sequencing (RNA-Seq) method. In addition, we have noted a severe deficiency in IL-10 production by T cells in bronchoalveolar lavage (BAL) fluid or in peripheral blood of all severe asthmatics. These results support our contention that SA cannot be explained solely as being mediated by Th2 effector cells, which dominate Th2hi mild asthma. Taking cues from the human studies, we have been successful in establishing a mouse model of SA that displays an immune profile similar to what we observe in human disease and one that is also largely CS-unresponsive. Collectively, our data lead us to hypothesize that: 1) In a majority of severe asthmatics, the aberrant airway immune response is distinct from that in milder asthma characterized by a IFN-?hi profile which is a key contributor to the severe asthma (SA) phenotype. Patients with the most severe form of disease have an IL-27hIFN-?hi profile in their BAL cells. 2) A second immune response that characterizes SA is deficient IL-10 production from T cells for which one underlying mechanism is increased STAT1 activation. 3) In combination, IFN-? and IL-27 induce insensitivity to CS in SA. To address these hypotheses we will: Aim 1. Establish that the immune response in the majority of severe asthmatics is distinct from that in milder asthmatics displaying an IFN-?hiIL-10lo profile in airway cells witha subset also being IL-27hi. Aim 2. Determine mechanisms underlying defective IL-10 production in severe asthma. Aim 3. Determine the role of IL-27 plus IFN-? in CS-unresponsiveness using peripheral blood mononuclear cells (PBMCs). Synergy between Projects 1 and 2, the latter focused on understanding the deleterious consequences of the immune effectors on airway epithelial cells, will identify novel targets for therapy for severe asthma which is currently an unmet medical need.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
1P01AI106684-01A1
Application #
8853009
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Davidson, Wendy F
Project Start
2015-06-01
Project End
2020-05-31
Budget Start
2015-06-01
Budget End
2016-05-31
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Oriss, Timothy B; Raundhal, Mahesh; Morse, Christina et al. (2017) IRF5 distinguishes severe asthma in humans and drives Th1 phenotype and airway hyperreactivity in mice. JCI Insight 2:
Das, Sudipta; Raundhal, Mahesh; Chen, Jie et al. (2017) Respiratory syncytial virus infection of newborn CX3CR1-deficent mice induces a pathogenic pulmonary innate immune response. JCI Insight 2:
Gauthier, Marc; Chakraborty, Krishnendu; Oriss, Timothy B et al. (2017) Severe asthma in humans and mouse model suggests a CXCL10 signature underlies corticosteroid-resistant Th1 bias. JCI Insight 2:
Modena, Brian D; Bleecker, Eugene R; Busse, William W et al. (2017) Gene Expression Correlated with Severe Asthma Characteristics Reveals Heterogeneous Mechanisms of Severe Disease. Am J Respir Crit Care Med 195:1449-1463
Ray, Anuradha; Kolls, Jay K (2017) Neutrophilic Inflammation in Asthma and Association with Disease Severity. Trends Immunol 38:942-954
Wenzel, Sally E; Tyurina, Yulia Y; Zhao, Jinming et al. (2017) PEBP1 Wardens Ferroptosis by Enabling Lipoxygenase Generation of Lipid Death Signals. Cell 171:628-641.e26
Trejo Bittar, Humberto E; Doberer, Daniel; Mehrad, Mitra et al. (2017) Histologic Findings of Severe/Therapy-Resistant Asthma From Video-assisted Thoracoscopic Surgery Biopsies. Am J Surg Pathol 41:182-188
Eddens, Taylor; Campfield, Brian T; Serody, Katelin et al. (2016) A Novel CD4+ T Cell-Dependent Murine Model of Pneumocystis-driven Asthma-like Pathology. Am J Respir Crit Care Med 194:807-820
Ray, Anuradha; Raundhal, Mahesh; Oriss, Timothy B et al. (2016) Current concepts of severe asthma. J Clin Invest 126:2394-403
Chen, Kong; Campfield, Brian T; Wenzel, Sally E et al. (2016) Antiinflammatory effects of bromodomain and extraterminal domain inhibition in cystic fibrosis lung inflammation. JCI Insight 1:

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