Monday 30 June 2014
Induction and suppression of the innate antiviral responses by picornaviruses
Promotor: Prof. dr F.J.M. van Kuppeveld
Defence: 30 June 2014
On the front line of innate antiviral immune reactions is the type I interferon (IFN-α/β) system. IFN-α/β are small signaling molecules that can be produced by virtually all nucleated cells in our body upon virus infections, and induce a so-called “antiviral state” in neighboring cells by activating the production of hundreds of antiviral proteins. To mount an IFN-α/β response timely and correctly, cells employ specialized receptors that recognize “non-self” molecular motifs. RIG-I like receptors (RLRs), such as RIG-I and MDA5, recognize viral RNAs and induce IFN-α/β production via a number of signaling molecules (e.g. MAVS, TBK1 and IRF3).
However sophisticated our immune system may be, viruses, including picornaviruses, have evolved to actively suppress host antiviral responses to gain replication advantage. Picornaviruses are a large family of viruses and cause a variety of diseases in both humans (e.g. poliomyelitis, viral meningitis, the common cold and hepatitis A) as well as animals (e.g. foot-and-mouth disease). In this thesis project, we investigated the interaction between two important genera of picornaviruses, namely Enterovirus and Cardiovirus, and the IFN-α/β antiviral system. We provided the first experimental evidence on MDA5 activation during a normal virus infection. We showed that a double-stranded picornavirus RNA replication intermediate (the replicative form, RF), is a potent MDA5 activator both upon transfection as well as in infected cells. We also demonstrated a central role of a protease of enteroviruses (i.e. the 2A protease) in the antagonization of the MDA5-mediated ! IFN-α/β induction pathway, likely by cleaving MDA5 and MAVS, during infections of these viruses. Meanwhile, we provided new insights into the IFN-α/β-suppressing mechanism of cardioviruses, pinpointing it to a specific step in the MDA5 signaling pathway (namely between TBK1 phosphorylation and IRF3 activation).
Besides the IFN-α/β response, cellular stress response may also have antiviral activities. Under stressful conditions such as viral infections, cells make large aggregates of RNAs and proteins (stress granules), to temporarily store these molecules and halt protein production until the stress is released. . The antiviral functions of this stress response and their antiviral mechanisms are just beginning to be understood. Here we presented data on the antiviral activity of the stress response against picornaviruses, and tackled the relationship between the stress response and the RLR signaling pathway themselves. Lastly but not leastly, using an artificial small RNA ligand, we showed that RLR pathway activation may represent an opportunity for antiviral therapeutic interventions.
These new insights are valuable to future development of vaccines and antiviral therapies against the large family of picornaviruses.