IL-15-Mediated IL-6Ra Effector Memory CD8+ T Cells in Dysfunctional Lung Responses During Cigarette Smoke Exposure and Influenza Viral Infections
Abstract
The burden of medical and social resources slated for tobacco smoke-related diseases is predicted to be $47 trillion by 2030 and is especially relevant for the military Veteran population with high incidence of smokers. Viral infections have more severe consequences in individuals who have been exposed to cigarette smoke (CS) than in those who are not. The mechanisms that underlie the exaggerated virus-induced pathological lung responses in CS-exposed individuals have not been adequately addressed. We and others have demonstrated that respiratory viruses cause increased levels of inflammation, tissue destruction, and fibrosis in CS-exposed mice. Influenza (flu) infections are more severe, with more cough, phlegm production, and breathlessness in smokers. CS exposure was an important risk factor in the 1978 H1N1 influenza epidemic in healthy young military recruits. Chronic obstructive pulmonary disease (COPD) is a composite entity that includes chronic bronchitis and emphysema. It is the third leading cause of death in the US. Approximately 15 million people in the US have COPD, with another 10 million undiagnosed, costing $5.7 billion. COPD affects large numbers of Veterans. Unfortunately, the prevalence of tobacco use among the Veterans (39%) is staggeringly higher than the general population (19.8%). Even though it is clear that CS is the major cause of COPD, only 10%-15% of the patients who smoke develop COPD, suggesting that CS alone is not enough. Additional events are needed to induce the disease process. It is also clear that not all COPD are the same. Therefore, the management and treatment approaches for these patients should not be the same, and we provide a mechanistic approach towards this disease and possible targeted and therapeutic options for our patients. Some COPD patients have more of a bronchitic phenotype characterized by persistent airway inflammation with sputum production. Others develop oxygen dependency with emphysema as a result of irreversible and progressive airflow limitation and tissue destruction. Pulmonary fibrotic changes can also occur with airway fibrosis and with parenchymal fibrosis as combined pulmonary fibrosis and emphysema (CPFE). There is also a subset of COPD patients who have frequent flares or exacerbation of their COPD, which results with increased rate of disease progression and loss of lung function. Acute exacerbations due to viruses are more severe, last longer, and are associated with heightened responses than exacerbations due to other non-viral causes. However, the mechanisms that mediate the exacerbations and their effects on lung tissue inflammation, injury, repair, and remodeling are only beginning to be understood. This grant will investigate the cellular and molecular mechanisms by which viruses interact with CS to regulate injury and fibrotic responses in the lung. There is no known cure for COPD and new drugs are very much needed to reduce morbidity and mortality. Our group has been studying the synergistic interaction of cigarette smoke exposure and viral infections in the lung and the cytokine interleukin-15 (IL-15) is important in this process. Circulating IL-15 is elevated in CS-exposed and COPD patients with respiratory viral infections and excessive IL-15 in response to viral infection results in increased persistent lung inflammation and fibrotic responses. Using the mouse modeling system and human samples from patients, we have identified important immune pathways that may contribute to the increased pathology of viral infections in smokers and patients with COPD. We will explore the interface of IL-15 (thus macrophages, which are major secretors) and IL-6Ralphahigh effector memory (EM) CD8+ T cells as a significant contributor in the development of pathological hyperinflammatory and fibrotic responses in the smokers and COPD subjects during influenza infection. The overall goal of the studies is to characterize the IL-15 reg
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910377
Entities
People
- Charles S Dela Cruz
Organizations
- United States Army
- Yale University