– Important Insights for the Development of Antiviral Therapies
A research team led by the Paul-Ehrlich-Institut examined the interaction between the Zika virus and the antiviral restriction factor tetherin.
The scientists discovered that although infected cells increase their production of the antiviral tetherin protein in response to the virus infection, the Zika virus is able to mediate the rapid breakdown of tetherin and thus successfully subvert the immune system. These findings are important for the development of antiviral therapies against many other viruses as well. The Journal of Virology reported on the results in its online edition from 22 December 2021.
The Zika virus (ZIKV) is a flavivirus that is mainly transmitted by the Aedes mosquito (also known as the yellow fever mosquito, dengue mosquito or Egyptian tiger mosquito). The virus attracted international attention in 2015 when a Zika virus epidemic struck the South Pacific as well as South and North America. Zika virus infections occur worldwide, but are especially prevalent in the tropics and subtropics. The Asian tiger mosquito, another potential carrier, is also found sporadically in Germany. The first Zika virus transmissions by mosquitoes in Europe were reported in southern France in the autumn of 2019.
Zika virus infections are mild in most cases. However, a Zika virus infection is of major concern for pregnant women, especially in the first trimester of pregnancy, because it can lead to microcephaly (undersized skull) and other brain malformations in the foetus. In addition, Zika virus infections have been linked to Guillain-Barré Syndrome. To date, there is no vaccine or specific therapy for treating a Zika virus infection.
Researchers at the Paul-Ehrlich-Institut, the Federal Institute for Drugs and Medical Devices (BfArM), the Aachen University Clinic, and the German Centre for Infection Research (DZIF) in Braunschweig, under the direction of Professor Eberhard Hildt, head of the Virology Division of the Paul-Ehrlich-Institut, are studying the interactions between the Zika virus and its human hosts. A particular focus of their research is on the interactions between the Zika virus and the restriction factor tetherin. Tetherin is an interferon-inducible cellular protein with antiviral properties against a wide range of enveloped viruses. It inhibits their release by attaching the viruses to each other and to the cell membrane. Tetherin is therefore an important part of the innate immune response, but viruses have developed different strategies to escape tetherin.
The research group investigated the effects of the Zika virus on the expression (formation) of tetherin messenger RNA (messenger ribonucleic acid, mRNA) using cell cultures with different cell types (HaCat, A549, Vero and HT-1080 cells) as well as with two different Zika virus strains (French Polynesia H / PF2013 and Uganda 976). Increased expression of mRNA usually means increased protein formation. Conversely, the scientists also investigated the influence of tetherin on the Zika virus release.
The team found that a Zika virus infection of the cells does indeed lead to increased tetherin mRNA expression (formation). However, this increased expression did not lead to an increased tetherin protein concentration in the cells, which would be expected given the observed increased transcription of the gene. Rather, the tetherin concentration actually decreased as a result of the reduced half-life (the length of time that passes before the protein concentration is halved).
The experimental data suggests that lysosomal degradation of tetherin occurs in cells infected with ZIKV. Lysosomes are enclosed cell organelles (vesicles) in cells of higher organisms in which endogenous and foreign substances are broken down. By contrast, when the breakdown of tetherin in cells was prevented experimentally, tetherin was quite able to prevent the release and reproduction of the Zika virus. The inhibition of the tetherin degradation was achieved by depletion of the ESCRT-0 protein HRS. The ESCRT complex plays an important role in various cellular processes, such as the sorting of membrane proteins for lysosomal degradation or viral coating. The ability of the Zika virus to cause an increased breakdown of tetherin in infected cells is therefore an effective viral escape strategy.
What is the significance of these results? The development of antiviral treatment strategies that can be used for as many different virus types as possible is crucial, especially when considering currently emerging viruses and viruses that are spreading rapidly around the world in times of globalisation and global warming. This objective can be achieved with therapeutic approaches that enable people to bypass a virus’s immune escape strategies and thereby successfully fight it off. Inhibitors of fibroblast growth factor (FGF) are one of the recently discussed options for combating viral infections. FGF affects the interferon response, which in turn is an important pillar in defence against infection. However, current results point to the discrepancy between increased gene stimulation (increased mRNA transcription) and downstream functionality. Hence, an antiviral approach could be the targeted inhibition of the breakdown of these interferon-induced proteins in order to enable their antiviral effectiveness. Inhibiting the previously mentioned HRS protein could be another antiviral strategy.
Herrlein ML, Schmanke P, Elgner F, Sabino C, Akhras S, Bender D, Glitscher M, Tabari D, Scholl C, Stingl J, Hildt E (2021): Catch me if you can – the crosstalk of ZIKV and the restriction factor Tetherin.