Activation of the innate immune system to treat (+)RNA virus infections

EUVIRNA ER-1
Project completed.

Summary

Combination drug therapies are more successful in the treatment of (+)RNA virus infection than single drug administration. This is partly due to the high mutation frequency of these viruses by which they can develop resistance against antiviral drugs. At Janssen infectious Diseases, we currently investigate novel strategies to stimulate intracellular innate immune pathways, in combination with direct acting anti-viral drugs (DAAs), to improve upon known drug combinations for suppressing viral replication.

Activation of viral innate immune receptors results amongst all in the expression of interferons (IFNs), which are cytokines that are important in the antiviral immune response. IFNs form a family that is divided into type I, II and III IFNs. Type I IFNs include twelve subtypes of IFN-α, IFN-β and IFN-ω. IFN subtypes differ in their downstream effects and clinical studies have demonstrated differences in efficacy towards multiple clinical indications and in occurrence of adverse effects upon treatment with different types of recombinant IFNs.

It is known for viral hepatitis that IFNs play an important role in disease progression and response to treatment. While most research on IFNs has been carried out with IFN-α2 and IFN-β, which are both used in the clinics, other IFN subtypes have been less studied. To better understand the role of the different IFN subtypes in liver immune responses, we investigated the transcriptional responses induced in human primary hepatocytes upon stimulation with different IFN subtypes by microarray. We observed a high similarity in gene expression profiles among the different IFN subtypes. For IFN-α1, IFN-λ1, IFN-λ2 and IFN-λ3 however, the number of genes up-and downregulated upon treatment, was lower compared to other IFN subtypes. For IFN-α1, this may be attributed to a difference in receptor affinity among IFN-alphas. By ANOVA analysis, 135 genes were identified that are differentially expressed among treatment with the different IFN subtypes and the functions of their respective proteins in different cell processes was further investigated.

Activation and inactivation of proteins in innate immune pathways is dependent on post-translational modification events that include both phosphorylation and ubiquitylation. Viruses have evolved mechanisms to modulate the host ubiquitin system and express proteins with deubiquitylating activity whereby they can inhibit activation of innate immune pathways. These enzymes may form a novel enzymatic class of drug targets, which we evaluated by the writing of a review in collaboration with the lab of prof. Eric Snijder.

Host institute
Janssen Infectious Diseases-Diagnostics, Beerse , Belgium
Antiviral Drug Development
Supervisor: Dr. Gregory Fanning