Interferon lambda induces antiviral response to HSV-1 in epithelial cells.
Katarína Lopušná 1
Peter Kabát 1,2
Ingeborg Režuchová 2
1 Department of Microbiology and Virology, Comenius University Bratislava, Slovak Republic 2 Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovak Republic
|Section:||Cellular metabolism, physiology, molecular biology and genetics|
Human herpesvirus-1 (HSV-1) is a common neurotropic virus widespread around the world. Lytic infection present mainly in epithelial cells is followed by virion transport into neurons, microglia or astrocytes and the latency establishment. Depending on various factors, including the host immune status, the reactivation of HSV-1 from latency may lead to recurrent lytic infection in epithelial and neuronal cells causing herpes labialis, keratoconjunctivitis or herpetic encephalitis. Currently used antiviral therapy is struggling with an increasing number of resistance and accompanied by serious side effects including neurotoxicity and renal function problems as well. Therefore, potential clinical application of type III interferons (IFNs) is the subject of intensive investigations nowadays. Type III IFNs are crucial regulators of molecular networks, which control the expression of more than hundred of cellular proteins characterized by having antiviral activities (e. g. ISG). Although four subtypes of type III IFNs (IFN-λ1, IFN-λ2, IFN-λ3 and IFN-λ4) have been defined at gene and protein level, the full spectrum of their biological activities has not been sufficiently characterized.
The aim of this study was to evaluate IFN-λ induced antiviral activity against multi-cycle replication of two medically important strains of HSV-1 variant in pathogenicity and cytopathic effect, highly pathogenic ANGpath (syn+) and moderate pathogenic KOS (nonsyn). To compare the differences in activation of signalling pathways, we used two cell types, Vero and Vero E6 cells. Although Vero cells are unable to express IFNs, they exert functional pathways leading to expression of ISGs. On the other hand, Vero E6 cells are inherent to respond to viral infection by endogenous expression of IFN-λ. To determine the best choice of IFN-λ1 concentration to be used in following experiments studying the stimulation of Vero cells, as the first we tested different concentrations of IFN-λ1. We identified the strongest antiviral activity against either ANGpath or KOS in concentration 35 ng/ml IFN-λ1. To determine the IFN-λ1 induced antiviral activity against herpesvirus progeny, Vero E6 cells and also Vero cells, pretreated with IFN-λ1 at this concentration, were infected with ANGpath or KOS at MOI of 0.01. Our results confirmed that IFN-λ1 exerts antiviral activity against ANGpath when virus titer declined from 14 to 32 hpi in Vero cells. In Vero E6 cells, we found some inhibition effect on replication of ANGpath, but none on that of KOS at 32 hpi and later. These results may indicate an important role of stronger activity of HSV-1 KOS vhs protein known to mediate the rapid degradation of cellular mRNA including IFNs and ISG transcripts. Following studies are in the progress to reveal new aspects regarding the characteristics of antiviral activity shown here to be inducible by novel cytokine IFN-λ1 against HSV-1 as well as the role of IFN-λ1 in virus-host interactions.