The RLR-MAVS-IRF3 axis activates the IFN pathway to restrict Tonate virus infection
- 1Institut de Génétique Moléculaire de Montpellier (IGMM), Univ Montpellier, CNRS, Montpellier, France
- 2MIVEGEC, Univ Montpellier, CNRS, IRD, Montpellier, France
- 3Department of Medical Technology, LMI PRESTO, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
Abstract
Tonate virus (TONV) is a neglected mosquito-borne alphavirus of the Venezuelan equine encephalitis complex associated with febrile illness, encephalitis, and fetal central nervous system abnormalities. Yet, host pathways that sense TONV infection and restrict its replication remain poorly defined. Here, we investigated the interaction between TONV and the type I interferon (IFN-I) system in human T98G and A549 cells. We show that TONV infection led to the accumulation of cytosolic double-stranded RNA and a robust IFN response. RIG-I and MDA5 depletion as well as that of MAVS and IRF3 strongly reduced TONV-induced IFN response. Disruption of RIG-I, MDA5, MAVS, or IRF3 resulted in an increase of dsRNA-positive cells and a higher viral RNA accumulation. Finally, we found that treatment with exogenous IFN-I strongly inhibits TONV replication, reducing both viral RNA loads and infectious particle production. Thus, together, our results identify the RIG-I/MDA5-MAVS-IRF3 axis as a major pathway sensing TONV infection and establishing an IFN-I-dependent antiviral state, providing the first molecular characterization of TONV innate immune sensing in human cells. Author summary: Tonate virus is an understudied mosquito-borne virus that circulates in South America. Most recognized human infections resemble other mosquito-borne febrile illnesses, which may contribute to underdiagnosis, although severe cases including brain inflammation and fetal abnormalities have been reported. We investigated how human cells detect Tonate virus and mount an antiviral response. We found that infection activates key cellular sensors that signal through a common pathway to induce type I interferons. Disrupting components of this pathway reduced interferon production and allowed greater accumulation of viral RNA, demonstrating that this pathway contributes directly to controlling Tonate virus infection. Conversely, treating cells with type I interferon prior to infection strongly reduced viral replication and production of infectious particles. Together, our findings provide the first molecular description of how human cells sense and restrict Tonate virus. Our study provides a foundation for future work on Tonate virus pathogenesis, immune control, and potential antiviral interventions.
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BibTeX
@article{labadie2026rlrmavsirf3,
title = {{The RLR-MAVS-IRF3 axis activates the IFN pathway to restrict Tonate virus infection}},
author = {Thomas Labadie and Roger Eloiflin and Zoé Denis and Marie Motos and Joanna Re and Moritz Schüssler and Morgane Chemarin and Isabelle Moltini-Conclois and Valérie Courgnaud and Dorothée Missé and Nadine Laguette and Karim Majzoub},
journal = {PLOS Neglected Tropical Diseases},
year = {2026},
month = oct,
doi = {10.1371/journal.pntd.0014559},
url = {https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0014559},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The RLR-MAVS-IRF3 axis activates the IFN pathway to restrict Tonate virus infection
AU - Thomas Labadie
AU - Roger Eloiflin
AU - Zoé Denis
AU - Marie Motos
AU - Joanna Re
AU - Moritz Schüssler
AU - Morgane Chemarin
AU - Isabelle Moltini-Conclois
AU - Valérie Courgnaud
AU - Dorothée Missé
AU - Nadine Laguette
AU - Karim Majzoub
PY - 2026
DA - 2026/10/16
JO - PLOS Neglected Tropical Diseases
DO - 10.1371/journal.pntd.0014559
UR - https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0014559
AB - Tonate virus (TONV) is a neglected mosquito-borne alphavirus of the Venezuelan equine encephalitis complex associated with febrile illness, encephalitis, and fetal central nervous system abnormalities. Yet, host pathways that sense TONV infection and restrict its replication remain poorly defined. Here, we investigated the interaction between TONV and the type I interferon (IFN-I) system in human T98G and A549 cells. We show that TONV infection led to the accumulation of cytosolic double-stranded RNA and a robust IFN response. RIG-I and MDA5 depletion as well as that of MAVS and IRF3 strongly reduced TONV-induced IFN response. Disruption of RIG-I, MDA5, MAVS, or IRF3 resulted in an increase of dsRNA-positive cells and a higher viral RNA accumulation. Finally, we found that treatment with exogenous IFN-I strongly inhibits TONV replication, reducing both viral RNA loads and infectious particle production. Thus, together, our results identify the RIG-I/MDA5-MAVS-IRF3 axis as a major pathway sensing TONV infection and establishing an IFN-I-dependent antiviral state, providing the first molecular characterization of TONV innate immune sensing in human cells. Author summary: Tonate virus is an understudied mosquito-borne virus that circulates in South America. Most recognized human infections resemble other mosquito-borne febrile illnesses, which may contribute to underdiagnosis, although severe cases including brain inflammation and fetal abnormalities have been reported. We investigated how human cells detect Tonate virus and mount an antiviral response. We found that infection activates key cellular sensors that signal through a common pathway to induce type I interferons. Disrupting components of this pathway reduced interferon production and allowed greater accumulation of viral RNA, demonstrating that this pathway contributes directly to controlling Tonate virus infection. Conversely, treating cells with type I interferon prior to infection strongly reduced viral replication and production of infectious particles. Together, our findings provide the first molecular description of how human cells sense and restrict Tonate virus. Our study provides a foundation for future work on Tonate virus pathogenesis, immune control, and potential antiviral interventions.
SN - 1935-2735
SN - 1935-2727
ER -