Common respiratory virus infections in cystic fibrosis : from immunity to vaccine

Cystic fibrosis is the most common lethal monogenetic disease in Caucasians. It is caused by mutations in the cystic fibrosis transmembrane conductance regulator protein which is responsible for appropriate ion and water transport across epithelial cell membranes. The main clinical problems in cystic fibrosis are lung disease, pancreatic insufficiency and cystic fibrosisrelated diabetes. Respiratory virus infections predispose individuals with cystic fibrosis to bacterial infections and chronic colonization of the airway which exacerbate lung disease. The mechanisms behind this are poorly understood but the immune system is evidently involved. In this thesis, we studied common cold-causing enteroviruses, the Coxsackieviruses, in cystic fibrosis. In Paper I, we showed that a part of adaptive immune response towards Coxsackieviruses, namely production of neutralizing antibodies, is impaired in an experimental mouse model for cystic fibrosis (carrying the delF508 mutation). In Paper II, we elaborated on this finding and studied whether the delF508 mice could be protected from Coxsackievirus infection by vaccination and showed that vaccination was safe and efficient. We found that the production of virus-neutralizing antibodies upon vaccination in the delF508 mice was initially weak but improved upon a booster dose. We studied the frequency of Coxsackievirus infections in individuals with cystic fibrosis and found that they are common in this patient group. We conclude that common respiratory virus infections in cystic fibrosis can be successfully prevented by vaccination, which could potentially contribute to better lung function. Disease mortality is increased six-fold in individuals with cystic fibrosis-related diabetes, the pathogenesis of which is largely unknown. An autopsy study, where pancreatic tissue from cystic fibrosis patients was used as control, discovered presence of enterovirus in islets of cystic fibrosis patients with diabetes. In Paper III, we studied pancreas autopsy material from another cohort of cystic fibrosis patients with diabetes and found that 80% were positive for enterovirus in the islets compared to 40% in non-diabetic controls without cystic fibrosis. We also searched for serological evidence of a link between previous enterovirus infections and the development of cystic fibrosis-related diabetes but found no such relationship. A low-grade infection which does not induce antibody response, or a long-term persistent infection might be an explanation to this. We conclude that the role for enteroviruses in development of cystic fibrosis-related diabetes should not be excluded. In conclusion, this thesis contributes to the field of cystic fibrosis by revealing a potential immune defect in response to viral infections. It also demonstrates that common respiratory virus infections can potentially be targets for preventive treatments in cystic fibrosis. In addition, the potential role of enterovirus involvement in the pathogenesis of cystic fibrosisrelated diabetes has been presented, motivating for further studies

Coxsackievirus B infections are common in Cystic Fibrosis and experimental evidence supports protection by vaccination

Viral respiratory tract infections exacerbate airway disease and facilitate life-threatening bacterial colonization in cystic fibrosis (CF). Annual influenza vaccination is recommended and vaccines against other common respiratory viruses may further reduce pulmonary morbidity risk. Enteroviruses have been found in nasopharyngeal samples from CF patients experiencing pulmonary exacerbations. Using serology tests, we found that infections by a group of enteroviruses, Coxsackievirus Bs (CVBs), are prevalent in CF. We next showed that a CVB vaccine, currently undergoing clinical development, prevents infection and CVB-instigated lung damage in a murine model of CF. Finally, we demonstrate that individuals with CF have normal vaccine responses to a similar, commonly used enterovirus vaccine (inactivated poliovirus vaccine). Our study demonstrates that CVB infections are common in CF and provides experimental evidence indicating that CVB vaccines could be efficacious in the CF population. The role of CVB infections in contributing to pulmonary exacerbations in CF should be further studied.publishedVersionPeer reviewe

A Link Between a Common Mutation in CFTR and Impaired Innate and Adaptive Viral Defense

textabstractAcute respiratory virus infections predispose the cystic fibrosis (CF) lung to chronic bacterial colonization, which contributes to high mortality. For reasons unknown, respiratory virus infections have a prolonged duration in CF. Here, we demonstrate that mice carrying the most frequent cystic fibrosis transmembrane conductance regulator (CFTR) mutation in humans, ΔF508, show increased morbidity and mortality following infection with a common human enterovirus. ΔF508 mice demonstrated impaired viral clearance, a slower type I interferon response and delayed production of virus-neutralizing antibodies. While the ΔF508 mice had a normal immune cell repertoire, unchanged serum immunoglobulin concentrations and an intact immune response to a T-cell-independent antigen, their response to a T-cell-dependent antigen was significantly delayed. Our studies reveal a novel function for CFTR in antiviral immunity and demonstrate that the ΔF508 mutation in cftr is coupled to an impaired adaptive immune response. This important insight could open up new approaches for patient care and treatment