Tretinoin, a Vitamin A derivative, exerts antiviral effects against Chikungunya virus infection through the nuclear retinoid receptor signaling pathways

  1. Soumyajit Ghosh
  2. Chandan Mahish
  3. Archana Mahapatra
  4. Tathagata Mukherjee
  5. Pratima Kumari
  6. Bijita Bhowmick
  7. Saikat De
  8. Udvas Ghorai
  9. Rajshree Rajmohan Jena
  10. Seema Pradhan
  11. Subhasis Chattopadhyay
  12. Soma Chattopadhyay

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Abstract

Chikungunya virus (CHIKV) has reemerged as a global pathogen causing serious public health threat and socio-economic damage, particularly due to the absence of specific antivirals. Retinoids have been reported to exhibit antiviral potentials against multiple viral infections. In the present study, Tretinoin (TR) or all-trans retinoic acid (ATRA) was evaluated for its anti-CHIKV activity using in vitro , in vivo , and ex vivo models. TR was able to impede CHIKV infection efficiently in Vero and physiologically relevant muscle cells, C2C12, with drastic reduction in the viral RNA, proteins and progeny formation. The IC 50 of TR against CHIKV was estimated to be 20.05 µM and 19.71 µM in Vero and C2C12 cells, respectively. In addition, the inhibition was effective during entry as well as in the early stages of post CHIKV-infection. Notably, TR showed remarkable virucidal activity. Next, global transcriptome profile demonstrated that the signaling by Retinoic acid pathway was highly upregulated after CHIKV infection and Retinoic acid receptors (RAR), specifically RAR-β are the key mediators for the anti-CHIKV effect of TR. Further, the drug was also capable to modulate CHIKV-induced inflammatory responses by reducing the phosphorylated MAPKs, NF-κB and proinflammatory cytokines. Interestingly, TR protected C57BL/6 mice from CHIKV challenge by diminishing viral burden leading to reduced clinical scores and better survival. Similar observation was also noticed in the ex vivo model of CHIKV-infected hPBMC-derived monocyte-macrophage populations. In conclusion, this work demonstrated the repurposing potential of TR against CHIKV infection for the first time, encouraging its clinical validation towards future therapeutics.

IMPORTANCE

CHIKV is an arbovirus causing Chikungunya Fever (CHIKF) leading to debilitating arthralgia and myalgia. The unavailability of licensed antivirals or potent vaccines against CHIKV encourages extensive research to find a therapeutic cure. Retinoids, the derivatives of vitamin A, have been repurposed as antiviral agents against a broad range of viruses; however, their efficacy against alphaviruses remains unexplored. Accordingly, Tretinoin (TR), also known as all-trans retinoic acid (ATRA), was validated for anti-CHIKV efficacy in this investigation. Significant perturbation of CHIKV titer through the modulation of Retinoic acid receptors (RAR) was observed upon drug-treatment. Further, TR reduced major inflammatory markers (MAPKs and proinflammatory cytokines) supporting its anti-inflammatory effect. Further, its anti-CHIKV potential was validated in the mouse model and hPBMC-derived monocyte-macrophage cells, indicating the pre-clinical efficacy. Finally, this is the first study to report the anti-CHIKV property of Tretinoin using in vitro , in vivo , and ex vivo approaches suggesting its repurposing potential.

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  1. PREreview

    This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/17497216.

    This preprint explores the antiviral effects of tretinoin, a Vitamin A derivative, against Chikungunya, which currently lacks antiviral treatments. Tretnoin acts as a ligand for retinoic acid receptors (RARs), which regulate gene expression related to cell growth and immune responses. While chikungunya is not new, it has been showing a global reemergence recently, and thus, the paper is quite timely. 

    Some major issues that struck me as odd included the ambiguity of the proper peer reviewer. This paper covers a lot of methods, from RT-qPCR to in vivo titer tests. Most peer reviewers will not have expertise in all the methods, since they cover a broad range, but it's good that the data is being validated in different forms.

    Tretinoin is typically administered topically or at low dosages because of its potential toxicity. If the observed antiviral activity occurs outside of the recommended concentrations, the clinical translation of tretinoin might be limited. The main in vivo data were derived from CHIKV-infected mice, not humans. The way in which the immune and metabolic systems in mice respond to the drug is different from that of humans, so the results might not translate exactly to human outcomes.  Tretinoin, as a retinoid, can induce side effects, including cytotoxicity, oxidative stress, and immune modulation, which suppresses pro-inflammatory cytokines and can impair the host's own mechanisms for clearing the infection. There is limited evidence regarding the ex vivo human-derived macrophage assays, as only one immune cell population type was evaluated, without comparing responses amongst other CHIKV target cells like T cells, dendritic cells, and endothelial cells.

    Competing interests

    The author declares that they have no competing interests.

    Use of Artificial Intelligence (AI)

    The author declares that they used generative AI to come up with new ideas for their review.

  2. Version published to 10.1101/2025.09.29.679315 on bioRxiv