Host-Virus Interactions in Asthma and COPD

Sammanfattning: Asthma and chronic obstructive pulmonary disease (COPD) are associated with periods of worsened symptoms, known as exacerbations. Severe exac-erbations can result in hospitalisation, irreversible decline of the disease and sometimes death. Thus, exacerbations are a major cause of morbidity, mortality and healthcare cost. Treatment or prevention of exacerbations is an area of unmet medical need as the current standard of care has insuffi-cient impact on exacerbation frequency and severity. Respiratory viral infections are hypothesized to be important triggers of exacerbations. It has been shown that 41-95% of asthma exacerbations and 22-57% of COPD exacerbations are associated with a respiratory virus in-fection, the most common agent being human rhinovirus (RV). Other vi-ruses frequently associated with exacerbations include respiratory syncytial virus and influenza. Prevention or attenuation of respiratory virus infec-tions could therefore have significant impact on exacerbation frequency and severity. The mechanisms by which viruses trigger exacerbations are poorly un-derstood, although there is evidence for defective anti-viral interferon (IFN) responses in cells from patients with asthma and COPD. Further investiga-tion of host-virus interactions and their impact on underlying airway dis-ease, may lead to novel therapeutic targets for the prevention of exacerba-tions. We investigated host-virus interactions in asthma and COPD through a multi-faceted approach. First, we performed an in vitro functional ge-nomics screen using RNA interference (RNAi), to identify targets that are essential for RV replication in primary normal human bronchial epithelial cells. Second, we evaluated the efficacy of inhaled IFNβ-1a for the preven-tion of severe asthma exacerbations in a Phase 2 trial. Finally, we per-formed an observational, longitudinal study in COPD patients to investi-gate the relationship between exacerbations, viral and bacterial infections, air pollution and anti-microbial peptides (AMPs). In the first study, we identified lanosterol synthase (LSS) as a potential therapeutic target which, when inhibited, blocks RV replication and en-hances the RV-induced IFNβ response. We discovered that the mechanism of this effect was related to the induction of a regulatory sterol, 24(S),25 epoxycholesterol. In our phase 2 trial (INEXAS), we found that inhaled IFNβ-1a did not prevent the occurrence of severe asthma exacerbations, but improved peak expiratory flow (PEF). In an exploratory analysis, we also identified poten-tial responder subgroups, based on blood eosinophil counts or serum inter-leukin (IL)-18 levels. In our COPD cohort, we found that both viral infections and increases in ambient air pollution were associated with exacerbations. Viral exacerba-tions were strongly associated with upregulation of the IFN response bi-omarkers, CXCL10, CXCL11 and IFNγ. We went on to discover that the levels of beta-defensin 2 (hBD-2), an AMP expressed by the lung epitheli-um, is reduced in the sputum of patients who experienced exacerbations, and further found an association between low hBD-2 levels at exacerbation and the presence of a respiratory virus. The studies presented in this thesis have identified and evaluated key components of host-virus interactions and applied those to the context of asthma and COPD. In all cases, we found the IFN response to be central, not only to the events that occur inside the virus-infected cell, but also to the downstream consequences of infection at the tissue and organ level, likely playing a key role in both anti-bacterial and anti-viral host defense. Despite the extraordinary complexity of the interaction between the virus and its host, this thesis demonstrates that key drivers of this interplay can be identified, manipulated and, hopefully, developed into future medicines for the prevention of asthma and COPD exacerbations.