Antagonistic antiviral activity between IFN-lambda and IFN-alpha against lethal Crimean-Congo hemorrhagic fever virus in vitro

Crimean Congo Hemorrhagic fever virus (CCHFV) is the causative agent of Crimean-Congo hemorrhagic fever, a severe disease with a mortality rate of around 30% in humans. Previous studies demonstrate that pre-treatment with type I IFNs have an antiviral effect against CCHFV, while established CCHFV infection is almost insensitive to subsequent IFN-α treatment. No data concerning type III IFNs antiviral activity against CCHFV are available so far. The aim of the present study was to explore the capability of IFN-λ1 to inhibit the replication of CCHFV and the possible synergism/antagonism between IFN-α and IFN-λ1 both in the inhibition of CCHFV replication and in the activation of intracellular pathways of IFN response. Human A549 and HuH7 cells were treated with increasing amounts of IFN-λ1, or IFN-α or a combination of them, infected with CCHF; the extent of virus yield inhibition and the induction of MxA and 2'-5'OAS mRNA was measured. Our study pointed out that type III IFN possess an antiviral activity against CCHFV, even if lower than type I IFN. Moreover, a clear antagonism between IFN-λ and IFN-α was observed in both cell lines (A549 and HuH7 cells), in terms of antiviral effect and activation of pivotal ISGs, i.e. MxA and 2'-5'OAS. Elucidating the interplay between type I and III IFNs will help to better understand innate defence mechanisms against viral infections and may provide novel scientific evidence for a more rational planning of available and future treatments, particularly against human diseases caused by high concern viruses.