ORIGINAL RESEARCH article
Front. Immunol.
Sec. Viral Immunology
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1630116
This article is part of the Research TopicImmunology of Vector-borne Tropical Diseases of the AmericasView all 3 articles
Pharmacological inhibition of the RhoA pathway by melatonin reduces viral replication and proinflammatory response against ZIKV and DENV-4 neuroinfections
Provisionally accepted
Jose De Jesus Bravo Silva
Ricardo Jimenez-CamachoMagda L Benitez-VegaJonathan Hernandez-CastilloCarlos D Cordero-RiveraCarlos N Farfan-MoralesMarcos Perez-GarciaRaymundo Cruz
Rosa M Del Angel*- Center for Research and Advanced Studies, National Polytechnic Institute of Mexico (CINVESTAV), México City, Mexico
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Zika virus (ZIKV) and dengue virus (DENV) are members of the Flaviviridae family that currently lack specific treatments, significant public health threat in tropical regions. ZIKV infection is associated with Guillain-Barré syndrome and congenital Zika syndrome, while severe dengue can lead to encephalitis, meningitis, and stroke. Both viruses modulate the RhoA GTPase pathway, which plays a critical role in immune responses and cytoskeletal remodeling. Interestingly, melatonin, a hormone with immunomodulatory and antioxidant functions that regulates the sleep-wake cycle, has been previously shown to reduce Japanese encephalitis virus (JEV) replication by attenuating RhoA activation. In this study, we demonstrate that the inhibition of the RhoA pathway by melatonin exerts an antiviral effect against ZIKV and DENV-4. Melatonin also decreased the inflammatory response induced by both viruses in U87-MG cells. Quantitative RT-PCR analysis revealed decreased expression of interferon-stimulated genes (MX1, IFI44L, and IFN-β) and proinflammatory cytokines (IL-1β and TNF-α). Immunodeficient AG129 mice treated with melatonin exhibited higher survival rates and milder clinical signs, particularly during DENV-4 infection, reduced viral genome copies of ZIKV and DENV-4. In neonatal immunocompetent CD1 mice, melatonin significantly reduced viral genome copies of ZIKV and DENV-4 in the brain, suppressed inflammatory gene expression, microglial *Corresponding author: activation, and polarization shift between M1 and M2 phenotypes. Together, these findings suggest that melatonin could be a potential therapeutic agent for limiting ZIKV and DENV-4 infections both in vitro and in vivo, highlighting its promise for the treatment of pan-Flaviviridae neuroinfections.
Keywords: Inflammation, Melatonin, Brain, Cerebellum, viral infection, ZIKV, DENV-4
Received: 16 May 2025; Accepted: 16 Jul 2025.
Copyright: © 2025 Bravo Silva, Jimenez-Camacho, Benitez-Vega, Hernandez-Castillo, Cordero-Rivera, Farfan-Morales, Perez-Garcia, Cruz and Del Angel. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Rosa M Del Angel, Center for Research and Advanced Studies, National Polytechnic Institute of Mexico (CINVESTAV), México City, Mexico
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