Pathogenic resistance and tolerance as mechanisms of allergic airway inflammation and COPD

Asthma and chronic obstructive pulmonary disease (COPD) are the most common inflammatory lung diseases. There is a large subgroup in both asthma and COPD patients that have a higher frequency of episodes of severe worsening of the disease (exacerbations) that now lack efficient treatment options. Up to 80 percent of all exacerbations are triggered by respiratory viral infections. The mechanisms leading to lower airway respiratory infections in chronic inflammatory lung diseases are poorly understood. Deficient production of antiviral type-I and type –III interferons is a favoured explanatory factor, suggesting a defect in pathogen resistance. Additional to a reduced antiviral response in patients with chronic lung inflammation is an exaggerated injurious immune response towards pathogens, suggesting also involvement of a dysfunctional tolerance mechanism as a factor of developing severe exacerbations.

Viral-induced exacerbations have been characterized by occurrence of necrotic cells. These necrotic cells might cause pathogenic effects in the lungs since they are highly immunogenic due to release of inflammatory mediators (DAMPs). One of our current observations suggests involvement of type-I interferons in driving regulated cell necrosis (necroptosis). Hence, aberrant cell death pathways due to defects in anti-viral response could be one potential mechanism linking a defective pathogenic resistance to a dysfunctional tolerance mechanism. Currently little is known what cell types that are prone to undergo necrosis and how different cell death pathways are involved in exacerbations. One of the parts of this project aims to establish a rhinovirus-induced exacerbation model in mice with key aspects of human disease. This model will be used to validate which cell types undergoing necrosis, study the mechanism of necrosis and finally the effects of lytic eosinophils in inflammation. Eosinophils are an important cell type involved in the pathophysiology of asthma. Hence eosinophils from atopic patients will also be isolated from blood to develop an improved model for studying immunoreactivity. Furthermore we will use human bronchial biopsies from asthmatic and COPD patients to explore an association between the necroptosis effector molecule MLKL and IL-1-beta previously observed in our mouse model. The results from this project will help us understand why certain groups of asthmatic and COPD patients are more prone to develop severe exacerbations. It also helps us appreciate how much of pathogenic resistance versus tolerance mechanism are involved in asthma exacerbations. This could ultimately lead to better treatment strategy for viral-induced exacerbations.