Functional Studies of Flavivirus-Host Cell Interactions

NS5 is a central protein in the flavivirus life cycle, functioning both as an RNA-dependent RNA polymerase and a virulence factor. We have shown that TBE virus NS5 interacts with host proteins to block type I interferon signaling via the JAK–STAT pathway (Werme et al., 2008). Additionally, we mapped NS5 interactions with PDZ domain-containing proteins such as Scribble, ZO‑1, and RIMS2, affecting cell polarity and neural development processes (Ellencrona et al., 2009; Wigerius et al., 2010).

In collaboration with Travis Taylor’s group at the University of Toledo, we recently identified TRIM21 and TRIM14 as antiviral factors. TRIM14 interacts with both NS5 and NS3 – a multifunctional flaviviral enzyme with protease and helicase activities – thereby influencing viral replication and the host innate immune response (Tran P. et al., 2025).

We have also investigated how the host’s Lunapark protein affects flavivirus replication and cellular membrane organization, particularly in relation to neurological effects during infection (Tran P. et al., 2021).

Our studies utilize infectious clones and replicon systems for TBEV, Langat virus, and Zika virus, in combination with reverse genetics tools, to functionally map NS3 and NS5 activity. The goal is to understand how molecular virus–host interactions drive pathogenesis and to identify novel antiviral targets.

Selected References: 
Werme K, Wigerius M, Johansson M. Tick-Borne Encephalitis Virus NS5 associates with membrane protein Scribble and impairs interferon-stimulated JAK–STAT signaling. Cellular Microbiology. 2008;10(3):696–712.

Ellencrona K, Syed A, Johansson M. Flavivirus NS5 Associates with Host-Cell Proteins Zonula Occludens-1 and the Regulating Synaptic Membrane Exocytosis-2 Via an Internal PDZ Binding Mechanism. Biological Chemistry. 2009;390(3):319–323.

Wigerius M, Melik W, Elväng A, Johansson M. Rac1 and Scribble are targets in arrest of neurite outgrowth by TBE virus NS5. Molecular and Cellular Neuroscience. 2010;45(1):260–271.

Tran P, Asghar N, Taylor RT, Johansson M. Identification of TRIM21 and TRIM14 as Antiviral Factors Against Tick-Borne Flaviviruses. Viruses. 2025;17(5):644.

Tran P, Hartman L, Johansson M. Roles of the Endogenous Lunapark Protein during Flavivirus Replication. Viruses. 2021;13(9):1865.