BTX-A51 treatment modulates host innate immune responses via NF-κB and β-catenin signaling during Rift Valley fever virus infection in vitro
- 1Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, Virginia, USA
- 2Center for Emerging, Zoonotic and Arthropod-borne Pathogens, Virginia Tech, Blacksburg, Virginia, USA
Abstract
Rift Valley fever virus (RVFV) is a zoonotic and mosquito-borne hemorrhagic pathogen of high pandemic potential, endemic to most countries in Africa. It most severely causes disease in small domestic ruminants and is transmitted to humans. RVFV has been declared a priority pathogen by the World Health Organization for vaccine and therapeutic development. Outbreaks of this virus are known to cause great disturbances to the economy, agriculture, food availability, and healthcare system of local communities. No U.S. FDA-approved vaccines or therapeutics exist for the prevention or treatment of RVFV. Here, we used BTX-A51, an anticancer drug and casein kinase-1 (CK1) inhibitor, as a pharmacological tool to investigate the role of CK1 in regulating innate immune signaling during RVFV infection. The results show that CK1 inhibition via BTX-A51 dampened NF-κB-mediated signaling by blocking different steps in the cascade that require CK1 phosphorylation for signal progression. Consequently, this reduced translocation of p65 to the nucleus and transcriptional activation of pro-inflammatory cytokines and enzymes. Additionally, BTX-A51 treatment influenced the β-catenin pathway, resulting in a significant increase in β-catenin protein levels and β-catenin colocalization with p65. Delayed BTX-A51 treatment retained its impact on cytokine gene expression and partially rescued cells from RVFV-induced cell death. Our data suggest that CK1 inhibition influences both RVFV replication and host innate immune signaling, suggesting a relationship between the NF-κB and β-catenin pathways during RVFV infection. These findings identify CK1-mediated signaling as a potential target for host-directed therapeutic strategies aimed at limiting excessive virus-induced inflammation.
IMPORTANCE: Rift Valley fever virus (RVFV) is a zoonotic and mosquito-borne pathogen of high pandemic risk, affecting ruminants and humans. Disease outbreaks cause great health and economic disruptions to communities across the African continent, being famously known for its “abortion storms.” Casein kinase 1 (CK1) is a host kinase ubiquitously present in eukaryotic cells and involved in multiple pathways, such as NF-κB-mediated inflammation and β-catenin signaling. Both NF-κB and β-catenin signaling are altered in RVFV-infected cells. This manuscript tests the ability of BTX-A51, a CK1 inhibitor, to limit viral replication and inflammatory signaling. BTX-A51 acted concomitantly on the NF-κB and β-catenin pathways to reduce proinflammatory signaling in RVFV-infected cells. Due to many mechanisms of infection being conserved across the Bunyavirales order, these findings also create the potential for BTX-A51 treatment to be tested against different viruses as a tool for pandemic preparedness.
Related
- Catenin Alpha-Like 1 (CTNNAL1) Modulates Cancer Stem Cell-Associated Properties and Epithelial-Mesenchymal Transition (EMT)-Associated Phenotypes in MDA-MB-231 Breast Cancer Cells.
- PLPP1 inhibits Wnt/β-catenin signaling via enhancing Caveolin-1/β-catenin interaction and is negatively regulated by c-Myc in osteosarcoma
- 838 ETV6 rearrangements impair T cell infiltration via activating β-Catenin signaling in triple-negative breast cancer
- VGLL4 Suppresses Malignant Phenotypes of Clear Cell Renal Cell Carcinoma Cells Through Modulation of Hippo/YAP and Wnt/β-Catenin Signaling Pathways
- Bile acid sequestration reveals microbiome remodeling that dominates FXR signaling to shape host responses to enteric infection
BibTeX
@article{flor2026btxa51,
title = {{BTX-A51 treatment modulates host innate immune responses via NF-κB and β-catenin signaling during Rift Valley fever virus infection in vitro}},
author = {Rafaela Flor and Timothy Stocker and Kaylee Petraccione and Maryna Akhrymuk and Brittany N. Heath and Ivan Akhrymuk and Caitlin M. Woodson and Kylene Kehn-Hall},
journal = {Journal of Virology},
year = {2026},
month = sep,
doi = {10.1128/jvi.01042-26},
url = {https://doi.org/10.1128/jvi.01042-26},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - BTX-A51 treatment modulates host innate immune responses via NF-κB and β-catenin signaling during Rift Valley fever virus infection in vitro
AU - Rafaela Flor
AU - Timothy Stocker
AU - Kaylee Petraccione
AU - Maryna Akhrymuk
AU - Brittany N. Heath
AU - Ivan Akhrymuk
AU - Caitlin M. Woodson
AU - Kylene Kehn-Hall
PY - 2026
DA - 2026/09/09
JO - Journal of Virology
DO - 10.1128/jvi.01042-26
UR - https://doi.org/10.1128/jvi.01042-26
AB - Rift Valley fever virus (RVFV) is a zoonotic and mosquito-borne hemorrhagic pathogen of high pandemic potential, endemic to most countries in Africa. It most severely causes disease in small domestic ruminants and is transmitted to humans. RVFV has been declared a priority pathogen by the World Health Organization for vaccine and therapeutic development. Outbreaks of this virus are known to cause great disturbances to the economy, agriculture, food availability, and healthcare system of local communities. No U.S. FDA-approved vaccines or therapeutics exist for the prevention or treatment of RVFV. Here, we used BTX-A51, an anticancer drug and casein kinase-1 (CK1) inhibitor, as a pharmacological tool to investigate the role of CK1 in regulating innate immune signaling during RVFV infection. The results show that CK1 inhibition via BTX-A51 dampened NF-κB-mediated signaling by blocking different steps in the cascade that require CK1 phosphorylation for signal progression. Consequently, this reduced translocation of p65 to the nucleus and transcriptional activation of pro-inflammatory cytokines and enzymes. Additionally, BTX-A51 treatment influenced the β-catenin pathway, resulting in a significant increase in β-catenin protein levels and β-catenin colocalization with p65. Delayed BTX-A51 treatment retained its impact on cytokine gene expression and partially rescued cells from RVFV-induced cell death. Our data suggest that CK1 inhibition influences both RVFV replication and host innate immune signaling, suggesting a relationship between the NF-κB and β-catenin pathways during RVFV infection. These findings identify CK1-mediated signaling as a potential target for host-directed therapeutic strategies aimed at limiting excessive virus-induced inflammation. IMPORTANCE: Rift Valley fever virus (RVFV) is a zoonotic and mosquito-borne pathogen of high pandemic risk, affecting ruminants and humans. Disease outbreaks cause great health and economic disruptions to communities across the African continent, being famously known for its “abortion storms.” Casein kinase 1 (CK1) is a host kinase ubiquitously present in eukaryotic cells and involved in multiple pathways, such as NF-κB-mediated inflammation and β-catenin signaling. Both NF-κB and β-catenin signaling are altered in RVFV-infected cells. This manuscript tests the ability of BTX-A51, a CK1 inhibitor, to limit viral replication and inflammatory signaling. BTX-A51 acted concomitantly on the NF-κB and β-catenin pathways to reduce proinflammatory signaling in RVFV-infected cells. Due to many mechanisms of infection being conserved across the Bunyavirales order, these findings also create the potential for BTX-A51 treatment to be tested against different viruses as a tool for pandemic preparedness.
SN - 0022-538X
SN - 1098-5514
ER -