Enterovirus infections in type 1 diabetes and cystic fibrosis : antiviral defence and viral immune evasion strategies

Sammanfattning: Enteroviruses are common viruses which cause infections in humans that usually result in mild flu-like symptoms before viral clearance. However, in some cases these infections can progress to more severe diseases such as myocarditis, pancreatitis and hepatitis. Coxsackievirus induced hepatitis in infants may become so severe that the outcome is fatal. In addition, infections with enteroviruses belonging to the group B Coxsackieviruses have been implicated in the etiology of type 1 diabetes. Enterovirus infections are also commonly observed in patients with cystic fibrosis, resulting in lung exacerbations and morbidity. Proper antiviral response mechanisms are crucial for the prevention of viral replication and spread, as well as the inhibition of virus induced cellular damage. Recently a novel group of interferons, called type III interferons, were discovered and shown to have antiviral properties predominantly in cells of epithelial origin. In Paper I we show that type III interferons protect primary human hepatocytes from Coxsackievirus infection. Given the importance of interferons in preventing early viral replication, many viruses have developed mechanisms to inhibit their induction. In Paper II, we showed that Coxsackieviruses inhibit the induction of type III interferons in infected cells. In addition, we demonstrated that this inhibition was caused by the proteolytic activity of the viral protease 2Apro. The exact role of enterovirus infections in type 1 diabetes development is still under speculation. Coxsackieviruses encodes several viral proteins that have been shown to interfere with cellular function and signaling pathways. In Paper III, we used primary human pancreatic islets and an insulin-secreting cell line to identify mechanisms by which Coxsackeiviruses can cause beta cell dysfunction. We found that the viral proteins 2Apro, 3A and 3Cpro could, independently of one other, affect exocytosis with 2Apro and 3Cpro targeting calcium influx while 3A inhibited exocytosis via a calcium independent mechanism. An impaired antimicrobial defense has been observed in patients with cystic fibrosis. This could explain why common respiratory infections are often prolonged and more severe in these patients. By using a mouse model for cystic fibrosis, we showed in Paper IV that the most common mutation resulting in cystic fibrosis, F508del, caused an impaired adaptive immune response with a delayed production of neutralizing antibodies to Coxsackievirus. In conclusion, the studies performed in this thesis add to our understanding of innate and adaptive immune response mechanisms during Coxackievirus infections. In addition they demonstrate a role for viral proteins in circumventing host antiviral immune responses, thus causing cellular damage, which could contribute to disease pathology. Increasing the knowledge of host-pathogen interactions may help to develop new treatments that could prevent severe Coxsackievirus infections.