Tick-Borne Flaviviruses Depress AKT Activity during Acute Infection by Modulating AKT1/2

Abstract

Tick-borne flaviviruses (TBFVs) are reemerging public health threats. To develop therapeutics against these pathogens, increased understanding of their interactions with the mammalian host is required. The PI3K-AKT pathway has been implicated in TBFV persistence, but its role during acute virus infection remains poorly understood. Previously, we showed that Langat virus (LGTV)-infected HEK 293T cells undergo a lytic crisis with a few surviving cells that become persistently infected. We also observed that AKT2 mRNA is upregulated in cells persistently infected with TBFV. Here, we investigated the virus-induced effects on AKT expression over the course of acute LGTV infection and found that total phosphorylated AKT (pAKT), AKT1, and AKT2 decrease over time, but AKT3 increases dramatically. Furthermore, cells lacking AKT1 or AKT2 were more resistant to LGTV-induced cell death than wild-type cells because they expressed higher levels of pAKT and antiapoptotic proteins, such as XIAP and survivin. The differential modulation of AKT by LGTV may be a mechanism by which viral persistence is initiated, and our results demonstrate a complicated manipulation of host pathways by TBFVs.

Identification of Host Factors Differentially Induced by Clinically Diverse Strains of Tick-Borne Encephalitis Virus

“…To investigate whether immune sensing mediates the differences observed between Hypr and Vs strains in mammalian cells, the expression of key host defense markers were compared between cells expressing Hypr and Vs replicons. These included TIAR, TIA-1, and G3BP1, markers of stress granule formation that have previously been shown to bind to the TBEV genome ( 56 , 57 ); phosphorylated AKT, a prosurvival kinase activated in TBEV-infected cells ( 58 , 59 ); IRF-3, the canonical interferon response factor previously shown to be induced by TBEV NS5 ( 28 ); and caspase-8 and -3, inducer and executioner caspases of the apoptosis cascade ( 25 , 60 , 61 ), respectively. Upon analysis, stress granule (SG) formation was more extensive in Vs compared to Hypr replicon cells ( Fig.…”

Dengue Virus Dysregulates Master Transcription Factors and PI3K/AKT/mTOR Signaling Pathway in Megakaryocytes

“…On the contrary, Japanese Encephalitis Virus and DENV have been shown to enhance the phosphorylation of AKT in a mouse neuroblastoma cell line (N18). However, reduction in both pan-AKT and phospho-AKT has been shown by Tick-borne flavivirus infection in HEK-293 cells (Kirsch et al, 2020). PI3K, an upstream signalling molecule of AKT, and AKT forms a key signaling nexus along with mTOR, which regulates cell survival, metabolism, and differentiation (Jean and Kiger, 2014).…”

In human astrocytes neurotropic flaviviruses increase autophagy, yet their replication is autophagy-independent

“…These effects could be related to higher infectivity and faster production of infectious TBEV in human astrocytes compared with WNV and/or could be attributed to distinct regulation of autophagy by respective viruses. Infection with TBEV has been shown to deplete AKT levels, which induces autophagy by inhibiting the AKT-mTOR pathway [ 105 ]. On the other hand, the observed delay in augmentation of autophagy upon WNV infection could be due to indirect mechanisms of autophagy activation.…”