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.

List of scientific papers

I. Svedin E, Utorova R, Huhn MH, Larsson PG, Stone VM, Garimella M, Lind K, Hägglöf T, Pincikova T, Laitinen OH, McInerney GM, Scholte B, Hjelte L, Karlsson MCI, Flodström-Tullberg M. A Link Between a Common Mutation in CFTR and Impaired Innate and Adaptive Viral Defense. Journal of Infectious Diseases. 2017;216(10):1308-1317.
https://doi.org/10.1093/infdis/jix474

II. Virginia Stone, Renata Utorova, Marta Butrym, Amirbabak Sioofy-Khojine, Minna M. Hankaniemi, Emma Ringqvist, Anirudra Parajuli, Terezia Pincikova, Björn Fischler, Ferenc Karpati, Vesa P. Hytönen, Heikki Hyöty, Lena Hjelte, Malin Flodström-Tullberg. Coxsackie B virus infections are common in cystic fibrosis and can be prevented by vaccination. [Manuscript]

III. Renata Utorova, Amirbabak Sioofy Khojine, Terezia Pincikova, Jussi Lehtonen, Sami Oikarinen, Lena Hjelte, Noel G. Morgan, Sara J. Richardson, Heikki Hyöty, Malin Flodström-Tullberg. Investigating the role for enterovirus infections in cystic fibrosis-related diabetes. [Manuscript]