Abstract
Respiratory syncytial virus (RSV) infection is still a major cause of hospitalization of young children and older adults. Despite recent significant advances, critical gaps remain in prevention strategies, particularly for older infants and underserved populations, and to date there is no specific treatment available. The aryl hydrocarbon receptor (AHR) is a transcription factor initially identified as mediator of the toxic effects of environmental pollutants that was later found to be also activated by ligands derived from food, the gut microbiome, and host metabolism. AHR activation by these naturally occurring, or nutritional, ligands has been associated with beneficial physiological processes. Notably, AHR has critical functions in barrier organs such as the lungs, including regulation of immune responses to infection. AHR activation is a common strategy for many viruses to evade antiviral immunity, but in a recently published study we found that during RSV infection the AHR pathway is downregulated and plays a protective role, and the administration of the dietary AHR pro-ligand indole-3-carbinol (I3C) to RSV-infected mice led to beneficial effects. Here we review and discuss studies indicating nutritional AHR ligands, particularly compounds derived from cruciferous vegetables or generated during the metabolism of tryptophan, may offer therapeutic benefit for RSV disease, by positively modulating inflammation and reducing excessive immune responses, oxidative stress, and viral replication.
1 Introduction
Worldwide, respiratory syncytial virus (RSV) remains the leading cause of young children hospitalization due to lower respiratory tract infections (LRTI) (Asseri, 2025; Lopez et al., 2026). Annually, RSV causes thousands of infant deaths, with highest prevalence in low- and middle-income countries (Parums, 2025; Shaaban et al., 2025). Severe RSV infection can predispose young children to recurrent LRTI, development of asthma, and lung function impairment later in life (Zar et al., 2024). RSV is also a significant cause of severe disease, hospitalization, and mortality in older adults (Popham et al., 2025; Chaumont et al., 2026). The recent approvals of vaccines and monoclonal antibodies represent the most significant advance since the virus discovery (Ontiveros-Zuniga et al., 2026). Maternal immunization and monoclonal antibodies are now available to protect infants, and vaccines for older adults, though low uptake limits their impact on preventing severe disease (Principi et al., 2025; Murray and Chu, 2026). While critical gaps still exist in prevention strategies, there is currently no specific treatment available for RSV infection (Alvarez de Toledo et al., 2026; Lopez et al., 2026).
The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor involved in various physiological and pathophysiological processes, including host response to infections (Torti et al., 2021; Xu et al., 2024). AHR activation can have beneficial or detrimental consequences depending on the ligand (Haarmann-Stemmann et al., 2025). AHR was originally identified as mediator of environmental toxins effects, so its activation was perceived as detrimental. However, further investigations have determined that AHR is also activated by ligands/agonists/activators derived from food, gut microbiota, and host metabolism, and is associated with important biological processes. The discovery that AHR has critical functions at barrier organs (lung, gut, skin), including regulation of innate and adaptive immunity to prevent excessive inflammation, outlined a pathway for AHR-targeting therapeutics (Polonio et al., 2025; Coumoul et al., 2026). Tapinarof, the first AHR agonist for the topical treatment of plaque psoriasis and atopic dermatitis was recently approved, and its mechanisms of action include reduction of T helper (Th)2 and Th17 pro-inflammatory cytokines, increased antioxidant responses via the nuclear factor erythroid 2-related factor 2 (NRF2) pathway, and likely antimicrobial activity (Haarmann-Stemmann et al., 2021; Silverberg et al., 2024), highlighting the therapeutic relevance of activating the AHR pathway in certain conditions.
AHR was also found to have important roles during viral infections, but the mechanisms by which it specifically regulates immune cells and influences disease progression remain incompletely understood. Most viruses, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have been shown to induce AHR activation as a strategy to evade antiviral immunity and promote virus replication (Hu et al., 2023; Barreira-Silva et al., 2025; Grycova et al., 2025). In contrast, we recently found that during RSV infection the AHR pathway is downregulated and plays a protective role, as loss of AHR led to exacerbated inflammatory response, and the administration of the dietary AHR pro-ligand indole-3-carbinol (I3C) to mice led to beneficial effects, including anti-inflammatory and antiviral activity (Haas de Mello et al., 2025).
The beneficial effects of AHR activation have been predominantly associated with naturally occurring nutritional ligands, dietary compounds derived from cruciferous vegetables (broccoli, cabbage, cauliflower) or generated during the metabolism of tryptophan by gut microbiota and host cells (Hubbard et al., 2015; Ghiboub et al., 2020; De Juan and Segura, 2021; Huang, 2024). Considering the global burden of RSV and the lack of treatment options, we reviewed evidence indicating nutritional AHR ligands may help treat RSV infection by reducing excessive immune responses, oxidative stress, and viral replication. Our goals include raising awareness of this exciting area of investigation from our laboratory and its recent developments focused on improving outcomes for individuals affected by severe RSV disease.
2 RSV pathogenesis and disease severity
While RSV in most cases results in upper respiratory tract infection and mild disease, it is also associated with LRTI and severe disease including bronchiolitis and viral pneumonia. Age is a major determinant of disease severity with infants in their first RSV season and older adults being at the greatest risk for severe lower airway disease (Asseri, 2025). RSV employs mechanisms that lead to poor immune memory and susceptibility to reinfection. A short-lived immune response means within weeks or months protection is no longer achieved. However, the individual mechanisms that contribute to impaired protection are poorly characterized, in part because of the difficulty of studying local mucosal immunity in human subjects (Openshaw et al., 2017; Shi et al., 2026).
Severe RSV disease is driven not solely by viral replication but also by dysregulated host immune responses. RSV infection triggers a complex immune response involving innate and adaptive immunity and while these inflammatory mechanisms are essential for viral clearance and resolution of infection, excessive or dysregulated immune activation contributes to lung damage, airway obstruction, and severe respiratory distress, significantly influencing disease outcomes (Tripp et al., 2025; Shi et al., 2026). Dysregulated host immune responses to RSV include excessive cytokine production, Th2 and Th17 cell polarization, and impaired interferon signaling (Openshaw et al., 2017; Barnes et al., 2026). Altered regulatory T cells (Tregs), critical for limiting immune-mediated lung injury, and consequent inability to properly control the host inflammatory response have been also shown to contribute to severe RSV infection (Christiaansen et al., 2016). This dual role of inflammation, as defense against RSV invasion but contributor to disease, is important for the development of therapeutic strategies (Kombe Kombe et al., 2024; Georgakopoulou and Pitiriga, 2025).
To prevent effective host immune responses, RSV viral proteins are responsible for suppression of antiviral interferons in the host’s innate immune response which allows for immune evasion and increased infectivity (Thornhill and Verhoeven, 2020; Gutman et al., 2026). These immune-evading mechanisms from RSV can increase susceptibility to reinfection and disrupt the self-limited inflammatory response necessary for controlling virus replication and result in overactivation of inflammatory pathways leading to tissue damage and pulmonary dysfunction (Openshaw et al., 2017; Tavares et al., 2023).
Despite recent advances in prevention options, there is currently no specific treatment for RSV, and therefore an urgent need for developing therapies to treat this disease. Accumulating evidence from studies in other diseases and recent investigations from our laboratory suggest that the modulation of the AHR pathway with nutritional ligands could be explored as a novel therapeutic approach for RSV infection (Haas de Mello et al., 2025).
3 AHR signaling pathway
The AHR is not a cell surface receptor, but a ligand-dependent cytosolic transcription factor activated by a diverse range of exogenous and endogenous compounds. AHR-activating ligands originate from natural/nutritional sources (food/diet, gut microbiota, and host metabolism) as well as environmental pollutants including persistent organic pollutants (e.g., dioxins) and polycyclic aromatic hydrocarbons (e.g., benzo[a]pyrene) (Figure 1A). These ligands can have very different and context-dependent effects on AHR activation, leading to diverse beneficial and harmful, physiological and pathophysiological effects (Sladekova et al., 2023; Haarmann-Stemmann et al., 2025). It is noteworthy that some AHR activators have low affinity (e.g., I3C) or may not have been shown directly bind to AHR but rather function as pro-ligands or precursors that are further converted to ultimate ligands with higher binding potencies (Diao et al., 2025; Polonio et al., 2025; Coumoul et al., 2026).
Figure 1
AHR signaling pathways can be categorized as canonical and non-canonical (Figure 1B). When inactive, AHR is trapped in a cytosolic multiprotein complex containing two heat shock protein 90 (HSP90) molecules, AHR-interacting protein (AIP), cochaperone p23, and c-Src protein kinase. In canonical AHR signaling, upon ligand binding, AHR translocates to the nucleus and heterodimerizes with the AHR nuclear translocator (ARNT), also known as hypoxia-inducible factor 1 beta (HIF-1β), forming an AHR/ARNT complex. This AHR/ARNT heterodimer binds to xenobiotic-responsive elements (XREs) located in the target genes regulatory sequences. Among the multiple classes of AHR target genes are xenobiotic-metabolizing enzymes, including the members of the cytochrome P450 family 1 (CYP1) such as CYP1A1 and CYP1B1 (Bahman et al., 2024; Polonio et al., 2025). Non-canonical AHR signaling involves nuclear and cytosolic pathways, and AHR interacts with important transcription factors, including nuclear factor kappa B (NF-κB), the central inflammation regulator, hypoxia-inducible factor 1 alpha (HIF-1α) which regulates cellular metabolism and adaptation to hypoxic conditions, and NRF2, involved in antioxidant responses. Notably, depending on the ligand, cell type, and context, both canonical and non-canonical events may be involved after AHR activation (Sondermann et al., 2023).
We recently found that during RSV infection the canonical AHR signaling is downregulated (Haas de Mello et al., 2025). The presence of AHR in immune cells controls cytokine production, and the absence or downregulation of AHR can lead to excessive inflammation, ultimately causing tissue damage (Bock, 2020a, 2020b). In agreement, we found that human lung epithelial cells lacking AHR had significantly higher expression of pro-inflammatory genes and increased production of pro-inflammatory mediators following RSV infection when compared with wild-type cells (Haas de Mello et al., 2025).
RSV also affects transcription factors involved in non-canonical AHR signaling, with reported upregulation of NF-κB and HIF-1α, and downregulation of NRF2 (Figure 1C). NF-κB activation during RSV infection and subsequent upregulation of inflammatory genes play a central role in RSV-induced disease as it is initially induced to be antiviral and protective/reparative but overactivation contributes to lung immunopathology, tissue damage, and worse disease prognosis (Lotz and Peebles, 2012; Tian et al., 2018). We have shown that HIF-1α activation impacts airway function and contributes to viral replication (Morris et al., 2020; Morris et al., 2025). RSV infection is also associated with increased reactive oxygen species production and downregulation of NRF2, leading to decreased antioxidant defenses and oxidative damage of the airways, which contribute to bronchiolitis severity (Hosakote et al., 2011; Komaravelli et al., 2015; Ivanciuc et al., 2018). The canonical and non-canonical signaling showcase the functional diversity of AHR in response to certain stimuli and cellular environments.
4 Nutritional AHR ligands: therapeutic potential against RSV-induced disease
As RSV infection often leads to an excessive inflammatory response, which can contribute to lung injury and enhance disease severity, a therapeutic approach to limit immune-mediated tissue damage is of interest (Tavares et al., 2023; Georgakopoulou and Pitiriga, 2025). Although environmental pollutants can induce prolonged AHR activation and immunosuppression, in addition to other deleterious effects, AHR activation by nutritional or physiological ligands, i.e., natural compounds derived from food, gut microbiota, or host metabolism, predominantly have been associated with anti-inflammatory and immunomodulatory effects, supporting the concept that “you AHR what you eat” and the therapeutic applications of nutritional AHR ligands (Hooper, 2011; Lawrence and Sherr, 2012; Huang, 2024; Stockinger et al., 2024; Ran et al., 2026).
Several nutritional AHR ligands are derived from cruciferous vegetables with key examples being I3C and its derivative, 3,3-diindolylmethane (DIM). I3C and DIM are available as over-the-counter dietary supplements, with reported anti-inflammatory, antimicrobial, and antioxidant properties in various diseases (Srikanth et al., 2025). In terms of specific evidence in RSV, a recent study by our group found RSV-infected mice that were given I3C had decreased levels of pro-inflammatory cytokines, along with reduced viral replication, highlighting the anti-inflammatory and antiviral properties of I3C and its therapeutic potential against RSV (Haas de Mello et al., 2025). Evidence from other contexts that may be relevant but requires confirmation in RSV includes reports that I3C and DIM can downregulate NF-κB and HIF-1α, and reduce oxidative stress through activation of the NRF2 pathway (Srikanth et al., 2025). In addition, I3C showed antiviral activity against in vitro SARS-CoV-2 infection (Novelli et al., 2021; Centofanti et al., 2022) and protection against tissue damage and vascular leakage in influenza-infected mice (Major et al., 2023). DIM (combined with fish oil) improved viral pneumonia outcomes after influenza and SARS-CoV-2 infection in animal models (Kiselev et al., 2025). Importantly, I3C and DIM have been reported to regulate the balance between Tregs and Th17 cells in experimental models of colitis, type 1 diabetes, and acute respiratory distress syndrome (ARDS) (Busbee et al., 2020; Kahalehili et al., 2021; Holloman et al., 2023; Liu et al., 2023), which play a significant role in the pathogenesis of the RSV infection (Mangodt et al., 2015; Zhu and Liu, 2025).
Another main source of nutritional AHR ligands is tryptophan metabolism. Tryptophan is an essential amino acid, meaning it cannot be synthesized endogenously, and must be obtained from the diet. Higher content is found in protein-rich foods such as meat, eggs, dairy, and beans with tryptophan also being sold as dietary supplement (Hubbard et al., 2015; Ghiboub et al., 2020). Tryptophan is metabolized by the gut microbiota and host cells, and this process produces several AHR ligands, with microbiota-derived tryptophan metabolites, such as indole-3-propionic acid (IPA), indole-3-aldehyde (IAld) (also known as indole-3-carboxaldehyde), and indole-3-acetic acid (IAA) being of interest for potential therapeutic applications (Ghiboub et al., 2020; De Juan and Segura, 2021). In terms of specific evidence in RSV, IPA supplementation was investigated in a mouse model and showed to be protective, as it attenuated weight loss and reduced lung viral loads and inflammation (Antunes Fernandes et al., 2026). Similar effects were reported in IPA-treated mice infected with influenza A virus, in addition to improvements in body temperature and survival (Heumel et al., 2024; Antunes Fernandes et al., 2026). Regarding evidence from other contexts that may be relevant to RSV but requires confirmation, IAld and IAA were shown to promote IL-22 production in experimental models of candidiasis and emphysema (Zelante et al., 2013; Yan et al., 2022). Notably, IL-22 was reported to inhibit RSV replication (Das et al., 2020). IAld was also shown to alleviate inflammation by inhibiting the NF-κB signaling pathway and expression of pro-inflammatory cytokines in experimental models of osteoarthritis and colitis (Zhuang et al., 2022; Wang et al., 2023) while also demonstrating antioxidant activity in a model of intestinal inflammation (Cao et al., 2024). IAA showed anti-inflammatory and antioxidant activity in a murine macrophage cell line (Ji et al., 2020), as well as ameliorated colitis in mice, improving gut barrier function (Li et al., 2024).
Although RSV-specific evidence remains limited (Haas de Mello et al., 2025; Antunes Fernandes et al., 2026), the reported effects in other infectious diseases, including viral respiratory infections, as well as in non-infectious diseases support further investigations to explore the therapeutic potential of nutritional AHR ligands in RSV infection. In Table 1 we have provided a summary of in vivo preclinical studies using nutritional AHR ligands in RSV infection, in infections caused by other pathogens, and in non-infectious inflammatory diseases, highlighting the effects that could be relevant in the context of RSV infection.
Table 1
| Compound | Disease | Effects | References |
|---|---|---|---|
| Infectious disease: Respiratory syncytial virus (RSV) | |||
| Food derived (cruciferous vegetables, dietary supplements) | |||
| Indole-3-carbinol (I3C) | RSV infection | Attenuated weight loss, reduced pro-inflammatory mediators (BALF) and viral replication (lungs) | Haas de Mello et al. (2025) |
| Gut microbiota-derived tryptophan metabolites | |||
| Indole-3-propionic acid (IPA) | RSV infection | Attenuated weight loss, reduced lung viral loads and inflammation | Antunes Fernandes et al. (2026) |
| Influenza virus infection | Attenuated weight loss, reduced lung viral loads and inflammation, improved body temperature and survival | ||
| Infectious disease: Other pathogens | |||
| Food derived (cruciferous vegetables, dietary supplements) | |||
| I3C | Influenza virus infection | Protection against tissue damage and vascular leakage | Major et al. (2023) |
| Clostridium difficile infection | Ameliorated disease, increased Tregs, ILC3s, gamma delta T cells, and neutrophilic response without increasing inflammation | Julliard et al. (2017) | |
| Cryptosporidium infection | Antimicrobial activity (reduced parasite burden) | Maradana et al. (2023) | |
| Diindolylmethane (DIM)* | Influenza virus infection | Prevented body weight loss and improved survival | Kiselev et al. (2025) |
| SARS-CoV-2 infection | Improved disease, reduced weight loss, temperature elevation, and lung pathology | ||
| Gut microbiota-derived tryptophan metabolites | |||
| IPA | Influenza virus infection | Improved disease outcomes, reduced viral load and lowered local (lung) and systemic inflammation | Heumel et al. (2024) |
| Indole-3-aldehyde (IAld) | Mucosal candidiasis | Promote IL-22 production | Zelante et al. (2013) |
| Non-infectious disease models | |||
| Food derived (cruciferous vegetables, I3C/DIM dietary supplements) | |||
| I3C | LPS-induced ARDS | Amelioration of ARDS through regulation of Th17 and Th22 cells | Holloman et al. (2023) |
| Disease attenuation and regulation of immune cell trafficking | Holloman et al. (2024) | ||
| DIM | Oxazolone-induced ulcerative colitis | Alleviated disease through Th2/Th17 suppression and Treg induction | Huang et al. (2013) |
| Food derived (protein-rich foods, tryptophan dietary supplements) | |||
| Tryptophan | DSS-induced ulcerative colitis | Ameliorated disease, increased Il22 mRNA and decreased pro-inflammatory cytokines | Islam et al. (2017) |
| Gut microbiota-derived tryptophan metabolites | |||
| IAld | DSS-induced ulcerative colitis | Suppressed NF-κB inflammatory pathway | Wang et al. (2023) |
| LPS-induced intestinal inflammation | Reduced pro-inflammatory cytokines and NLRP3 inflammasome activation | Cao et al. (2024) | |
| Cigarette smoke-induced COPD | Reduced inflammation by inhibiting the NF-κB pathway | Wang et al. (2025) | |
| Indole-3-acetic acid (IAA) | DSS-induced ulcerative colitis | Improved intestinal barrier function and reduced inflammation | Li et al. (2024) |
Summary of in vivo preclinical studies using nutritional aryl hydrocarbon receptor (AHR) ligands in infectious and non-infectious diseases.
ARDS, acute respiratory distress syndrome; BALF, bronchoalveolar lavage fluid; COPD, chronic obstructive pulmonary disease; DSS, dextran sodium sulfate; ILC3s, group 3 innate lymphoid cells; LPS, lipopolysaccharide; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; Th, T helper; Treg, regulatory T cell; ROS, reactive oxygen species; NLRP3, NOD-like receptor family pyrin domain containing 3. *DIM formulation with fish oil.
5 Discussion
The RSV global burden and the lack of specific treatments underscore the need to investigate new ways to treat RSV-induced disease. Nutritional AHR ligands derived from cruciferous vegetables and produced during the metabolism of tryptophan were investigated in the context of several diseases, and have demonstrated anti-inflammatory, antioxidant, and antiviral properties, which highlight their therapeutic potential for RSV infection. Some of these compounds could restore AHR activity that is dampened during RSV infection and positively modulate RSV-induced inflammatory response and reduce oxidative stress, while ensuring viral replication is controlled.
To our knowledge, RSV-specific relevant in vivo evidence is currently limited to two studies, which include our own where we tested I3C (Haas de Mello et al., 2025) and a recent study that evaluated supplementation of IPA (Antunes Fernandes et al., 2026). Although the evidence for therapeutic benefit of nutritional AHR ligands in other respiratory viruses and inflammatory diseases provides reason for further investigation in RSV models, most data come from preclinical studies (cells and animal models) and is not yet validated in humans. In addition, there are still many open questions to be answered in the field, including molecular mechanisms underlying differential outcomes of AHR activation by xenobiotics vs. natural ligands, what levels and duration of AHR activation are beneficial vs. detrimental, as well as uncertain or absent data on absorption, distribution, metabolism, and excretion (ADME) for many AHR ligands (Stockinger et al., 2024; Coumoul et al., 2026).
As AHR plays diverse roles and its activation effects depend on the ligand and context, further research is essential. Ligand-based targeting of AHR is complicated and besides canonical signaling, AHR exerts diverse effects through non-canonical pathways as it interacts with important transcription factors that regulate immune responses, adaptation to hypoxia, and oxidative stress (Sondermann et al., 2023), which are important in the context of RSV and affect infection outcomes (Komaravelli et al., 2015; Morris et al., 2025). Inflammation is a necessary part of the immune system’s response to infection, and although reducing excessive immune responses might confer benefit to severe disease patients, immunosuppression must be considered, as reduction in lymphocyte recruitment and activation can delay viral clearance (Tavares et al., 2023). Although AHR activation by natural or nutritional compounds have been shown to modulate beneficial immunological responses and to have immunoregulatory effects instead of the profound immunosuppression or immunotoxicity associated with environmental pollutants (Esser et al., 2018; De Juan and Segura, 2021), the effects on RSV clearance should always be evaluated. An ideal therapy for RSV would promote balance between effective viral clearance and minimizing immune-mediated lung damage (Georgakopoulou and Pitiriga, 2025).
Moving forward, additional preclinical studies in RSV models are needed before clinical studies become a realistic option. Repurposing dietary supplements seem to have major advantages since pharmacological and safety profiles may have already been demonstrated for other indications (Coumoul et al., 2026). I3C and DIM have been tested in clinical trials for cancer, making them promising candidates for repurposing (Reyes-Hernandez et al., 2023; Srikanth et al., 2025). Prophylactic dietary interventions, such as increased consumption of cruciferous vegetables, could potentially also be explored. To allow future translation from model systems to humans, it is imperative to use experimental models that take into consideration the critical physiological functions of AHR and the distribution of the agonist in different tissues, as agonists of similar potency have different ADME properties (Stockinger et al., 2024).
In conclusion, future investigations into the mechanisms and physiological implications of agonistic nutritional AHR ligands could pave the way for discovery of an urgently needed therapeutic option against RSV and improve outcomes for the affected vulnerable populations. However, as AHR activation cannot be generalized as beneficial or harmful and is highly ligand-dependent, using nutritional AHR ligands as treatment for RSV will require more research.
Statements
Author contributions
SG: Investigation, Writing – original draft. AC: Writing – review & editing. AH: Conceptualization, Supervision, Writing – review & editing.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This work was supported in part by The University of Texas Medical Branch (UTMB) Early Faculty Research Award (2025) and Institute for Human Infections and Immunity FY2026 Pilot Grant (to AH). The funders had no role in the writing of the manuscript or decision to submit for publication.
Acknowledgments
We thank Roberto P. Garofalo and Casey W. Wright for helpful discussion.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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References
1
Alvarez de ToledoM.TaverasJ. I.RamiloO.MejiasA. (2026). Antiviral therapies for respiratory syncytial virus infection: current expectations. Curr. Opin. Infect. Dis.39, 153–159. doi: 10.1097/QCO.0000000000001184,
2
Antunes FernandesK.SandersF.CafieroT. R.HuangC.ReyesJ.BiswasA.et al. (2026). Maternal helminths rewire the microbiota to promote offspring antiviral immunity. Cell Host Microbe34, 1050–1066.e9. doi: 10.1016/j.chom.2026.04.009,
3
AsseriA. A. (2025). Respiratory syncytial virus: a narrative review of updates and recent advances in epidemiology, pathogenesis, diagnosis, management and prevention. J. Clin. Med.14:3880. doi: 10.3390/jcm14113880,
4
BahmanF.ChoudhryK.Al-RashedF.Al-MullaF.SindhuS.AhmadR. (2024). Aryl hydrocarbon receptor: current perspectives on key signaling partners and immunoregulatory role in inflammatory diseases. Front. Immunol.15:1421346. doi: 10.3389/fimmu.2024.1421346,
5
BarnesM. V. C.StretchS. W. H.SwiebodaD.EfstathiouC.CulleyF. J.HanselT. T.et al. (2026). Mucosal IL-36 is a defining feature of severe paediatric bronchiolitis. Mucosal Immunol.19, 1907–1921. doi: 10.1016/j.mucimm.2026.01.012,
6
Barreira-SilvaP.LianY.KaufmannS. H. E.Moura-AlvesP. (2025). The role of the AHR in host-pathogen interactions. Nat. Rev. Immunol.25, 178–194. doi: 10.1038/s41577-024-01088-4,
7
BockK. W. (2020a). Aryl hydrocarbon receptor (AHR)-mediated inflammation and resolution: non-genomic and genomic signaling. Biochem. Pharmacol.182:114220. doi: 10.1016/j.bcp.2020.114220,
8
BockK. W. (2020b). Aryl hydrocarbon receptor (AHR) functions: balancing opposing processes including inflammatory reactions. Biochem. Pharmacol.178:114093. doi: 10.1016/j.bcp.2020.114093,
9
BusbeeP. B.MenzelL.AlrafasH. R.DopkinsN.BeckerW.MirandaK.et al. (2020). Indole-3-carbinol prevents colitis and associated microbial dysbiosis in an IL-22-dependent manner. JCI Insight5:e127551. doi: 10.1172/jci.insight.127551,
10
CaoJ.BaoQ.HaoH. (2024). Indole-3-Carboxaldehyde alleviates LPS-induced intestinal inflammation by inhibiting ROS production and NLRP3 Inflammasome activation. Antioxidants (Basel)13:1107. doi: 10.3390/antiox13091107,
11
CentofantiF.AlonziT.LatiniA.SpitalieriP.MurdoccaM.ChenX.et al. (2022). Indole-3-carbinol in vitro antiviral activity against SARS-Cov-2 virus and in vivo toxicity. Cell Death Discov.8:491. doi: 10.1038/s41420-022-01280-2,
12
ChaumontA.GouldH.FlamaingJ.WisemanD. J.VandermeulenC.JongertE.et al. (2026). The role of immunosenescence and chronic medical conditions on the immune response to respiratory syncytial virus in older individuals. Expert Rev. Clin. Immunol.1–16. doi: 10.1080/1744666X.2026.2672499,
13
ChristiaansenA. F.SyedM. A.Ten EyckP. P.HartwigS. M.DurairajL.KamathS. S.et al. (2016). Altered Treg and cytokine responses in RSV-infected infants. Pediatr. Res.80, 702–709. doi: 10.1038/pr.2016.130,
14
CoumoulX.BaroukiR.EsserC.Haarmann-StemmannT.LawrenceB. P.LehmannJ.et al. (2026). The aryl hydrocarbon receptor: structure, signaling, physiology and pathology. Signal Transduct. Target. Ther.11:20. doi: 10.1038/s41392-025-02500-8,
15
DasS.St CroixC.GoodM.ChenJ.ZhaoJ.HuS.et al. (2020). Interleukin-22 inhibits respiratory syncytial virus production by blocking virus-mediated subversion of cellular autophagy. iScience23:101256. doi: 10.1016/j.isci.2020.101256,
16
De JuanA.SeguraE. (2021). Modulation of immune responses by nutritional ligands of aryl hydrocarbon receptor. Front. Immunol.12:645168. doi: 10.3389/fimmu.2021.645168,
17
DiaoX.ShangQ.GuoM.HuangY.ZhangM.ChenX.et al. (2025). Structural basis for the ligand-dependent activation of heterodimeric AHR-ARNT complex. Nat. Commun.16:1282. doi: 10.1038/s41467-025-56574-7,
18
EsserC.Haarmann-StemmannT.HochrathK.SchikowskiT.KrutmannJ. (2018). AHR and the issue of immunotoxicity. Curr. Opin. Toxicol.10, 91–97. doi: 10.1016/j.cotox.2018.03.001
19
GeorgakopoulouV. E.PitirigaV. C. (2025). Immunomodulation in respiratory syncytial virus infection: mechanisms, therapeutic targets, and clinical implications. Microorganisms13:1876. doi: 10.3390/microorganisms13081876,
20
GhiboubM.VerburgtC. M.SovranB.BenningaM. A.de JongeW. J.Van LimbergenJ. E. (2020). Nutritional therapy to modulate tryptophan metabolism and aryl hydrocarbon-receptor signaling activation in human diseases. Nutrients12:2846. doi: 10.3390/nu12092846,
21
GrycovaA.VyhlidalovaB.DvorakZ. (2025). The role of aryl hydrocarbon receptor in antiviral immunity: a focus on RNA viruses. Crit. Rev. Microbiol.51, 1255–1269. doi: 10.1080/1040841X.2025.2497789,
22
GutmanJ.PalettaA. L.Birnberg-WeissF.PratoC. A.BoudgousteA.GoldinC. J.et al. (2026). Unraveling the dual immunomodulatory and immunogenic roles of the central conserved cysteine-rich region in respiratory syncytial virus G protein. Front. Microbiol.17:1794062. doi: 10.3389/fmicb.2026.1794062,
23
Haarmann-StemmannT.ReichertD.CoumoulX.LawrenceB. P.PerdewG. H.SherrD. H.et al. (2025). The Janus-facedness of the aryl hydrocarbon receptor pathway report of the 6th international AHR meeting: research, prevention, therapy. Biochem. Pharmacol.234:116808. doi: 10.1016/j.bcp.2025.116808,
24
Haarmann-StemmannT.SutterT. R.KrutmannJ.EsserC. (2021). The mode of action of tapinarof may not only depend on the activation of cutaneous aryl hydrocarbon receptor signaling but also on its antimicrobial activity. J. Am. Acad. Dermatol.85, e33–e34. doi: 10.1016/j.jaad.2021.01.103,
25
Haas de MelloA.QuY.LiuT.GarofaloR. P.CasolaA. (2025). Respiratory syncytial virus downregulates the airway aryl hydrocarbon receptor pathway: implication for the development of a novel therapeutic target. Am. J. Physiol. Lung Cell. Mol. Physiol.329, L716–L731. doi: 10.1152/ajplung.00134.2025,
26
HeumelS.de Rezende RodovalhoV.UrienC.SpecqueF.Brito RodriguesP.RobilC.et al. (2024). Shotgun metagenomics and systemic targeted metabolomics highlight indole-3-propionic acid as a protective gut microbial metabolite against influenza infection. Gut Microbes16:2325067. doi: 10.1080/19490976.2024.2325067,
27
HollomanB. L.CannonA.WilsonK.NagarkattiP.NagarkattiM. (2023). Aryl hydrocarbon receptor activation ameliorates acute respiratory distress syndrome through regulation of Th17 and Th22 cells in the lungs. MBio14:e0313722. doi: 10.1128/mbio.03137-22,
28
HollomanB. L.WilsonK.CannonA.NagarkattiM.NagarkattiP. S. (2024). Indole-3-carbinol attenuates lipopolysaccharide-induced acute respiratory distress syndrome through activation of AhR: role of CCR2+ monocyte activation and recruitment in the regulation of CXCR2+ neutrophils in the lungs. Front. Immunol.15:1330373. doi: 10.3389/fimmu.2024.1330373,
29
HooperL. V. (2011). You AhR what you eat: linking diet and immunity. Cell147, 489–491. doi: 10.1016/j.cell.2011.10.004,
30
HosakoteY. M.JantziP. D.EshamD. L.SprattH.KuroskyA.CasolaA.et al. (2011). Viral-mediated inhibition of antioxidant enzymes contributes to the pathogenesis of severe respiratory syncytial virus bronchiolitis. Am. J. Respir. Crit. Care Med.183, 1550–1560. doi: 10.1164/rccm.201010-1755OC
31
HuJ.DingY.LiuW.LiuS. (2023). When AHR signaling pathways meet viral infections. Cell Commun. Signal21:42. doi: 10.1186/s12964-023-01058-8,
32
HuangF. C. (2024). Therapeutic potential of nutritional aryl hydrocarbon receptor ligands in gut-related inflammation and diseases. Biomedicine12:2912. doi: 10.3390/biomedicines12122912,
33
HuangZ.JiangY.YangY.ShaoJ.SunX.ChenJ.et al. (2013). 3,3'-Diindolylmethane alleviates oxazolone-induced colitis through Th2/Th17 suppression and Treg induction. Mol. Immunol.53, 335–344. doi: 10.1016/j.molimm.2012.09.007,
34
HubbardT. D.MurrayI. A.PerdewG. H. (2015). Indole and tryptophan metabolism: endogenous and dietary routes to ah receptor activation. Drug Metab. Dispos.43, 1522–1535. doi: 10.1124/dmd.115.064246,
35
IslamJ.SatoS.WatanabeK.WatanabeT.ArdiansyahHiraharaK.et al. (2017). Dietary tryptophan alleviates dextran sodium sulfate-induced colitis through aryl hydrocarbon receptor in mice. J. Nutr. Biochem.42, 43–50. doi: 10.1016/j.jnutbio.2016.12.019
36
IvanciucT.SbranaE.CasolaA.GarofaloR. P. (2018). Protective role of nuclear factor erythroid 2-related factor 2 against respiratory syncytial virus and human metapneumovirus infections. Front. Immunol.9:854. doi: 10.3389/fimmu.2018.00854,
37
JiY.YinW.LiangY.SunL.YinY.ZhangW. (2020). Anti-inflammatory and anti-oxidative activity of Indole-3-acetic acid involves induction of HO-1 and neutralization of free radicals in RAW264.7 cells. Int. J. Mol. Sci.21:1579. doi: 10.3390/ijms21051579,
38
JulliardW.De WolfeT. J.FechnerJ. H.SafdarN.AgniR.MezrichJ. D. (2017). Amelioration of Clostridium difficile infection in mice by dietary supplementation with Indole-3-carbinol. Ann. Surg.265, 1183–1191. doi: 10.1097/SLA.0000000000001830,
39
KahalehiliH. M.NewmanN. K.PenningtonJ. M.KolluriS. K.KerkvlietN. I.ShulzhenkoN.et al. (2021). Dietary Indole-3-Carbinol activates AhR in the gut, alters Th17-microbe interactions, and exacerbates insulitis in NOD mice. Front. Immunol.11:606441. doi: 10.3389/fimmu.2020.606441,
40
KiselevV.LenevaI.IvaninaA.PoromovA.FalynskovaI.KartashovaN.et al. (2025). 3,3'-Diindolylmethane improves the viral pneumonia outcomes after influenza and SARS-CoV-2 infection in animal models. Viruses17:964. doi: 10.3390/v17070964,
41
KomaravelliN.TianB.IvanciucT.MautempsN.BrasierA. R.GarofaloR. P.et al. (2015). Respiratory syncytial virus infection down-regulates antioxidant enzyme expression by triggering deacetylation-proteasomal degradation of Nrf2. Free Radic. Biol. Med.88, 391–403. doi: 10.1016/j.freeradbiomed.2015.05.043,
42
Kombe KombeA. J.FotoohabadiL.GerasimovaY.NanduriR.Lama TamangP.KandalaM.et al. (2024). The role of inflammation in the pathogenesis of viral respiratory infections. Microorganisms12:2526. doi: 10.3390/microorganisms12122526,
43
LawrenceB. P.SherrD. H. (2012). You AhR what you eat?Nat. Immunol.13, 117–119. doi: 10.1038/ni.2213,
44
LiM.DingY.WeiJ.DongY.WangJ.DaiX.et al. (2024). Gut microbiota metabolite indole-3-acetic acid maintains intestinal epithelial homeostasis through mucin sulfation. Gut Microbes16:2377576. doi: 10.1080/19490976.2024.2377576,
45
LiuS.YanW.LvQ.YangL.MiaoY.HuY.et al. (2023). 3, 3′-diindolylmethane, a natural aryl hydrocarbon receptor agonist, alleviates ulcerative colitis by enhancing “glycolysis-lactate-STAT3” and TIP60 signals-mediated Treg differentiation. Mol. Immunol.163, 147–162. doi: 10.1016/j.molimm.2023.09.009,
46
LopezE. L.FerollaF. M.AcostaP. L. (2026). Respiratory syncytial virus - from discovery to vaccines. J. Med. Microbiol.75:002134. doi: 10.1099/jmm.0.002134,
47
LotzM. T.PeeblesR. S.Jr. (2012). Mechanisms of respiratory syncytial virus modulation of airway immune responses. Curr Allergy Asthma Rep12, 380–387. doi: 10.1007/s11882-012-0278-z,
48
MajorJ.CrottaS.FinsterbuschK.ChakravartyP.ShahK.FredericoB.et al. (2023). Endothelial AHR activity prevents lung barrier disruption in viral infection. Nature621, 813–820. doi: 10.1038/s41586-023-06287-y,
49
MangodtT. C.Van HerckM. A.NullensS.RametJ.De DooyJ. J.JorensP. G.et al. (2015). The role of Th17 and Treg responses in the pathogenesis of RSV infection. Pediatr. Res.78, 483–491. doi: 10.1038/pr.2015.143,
50
MaradanaM. R.MarzookN. B.DiazO. E.MkandawireT.DinyN. L.LiY.et al. (2023). Dietary environmental factors shape the immune defense against Cryptosporidium infection. Cell Host Microbe31, 2038–2050.e4. doi: 10.1016/j.chom.2023.11.008,
51
MorrisD. R.QuY.AgrawalA.GarofaloR. P.CasolaA. (2020). HIF-1α modulates Core metabolism and virus replication in primary airway epithelial cells infected with respiratory syncytial virus. Viruses12:1088. doi: 10.3390/v12101088,
52
MorrisD. R.QuY.Haas de MelloA.Jones-HallY. L.LiuT.WeglarzM.et al. (2025). Role of hypoxia-inducible factors in respiratory syncytial virus infection-associated lung disease. Int. J. Mol. Sci.26:3182. doi: 10.3390/ijms26073182,
53
MurrayA.ChuH. Y. (2026). A promise fulfilled: updates on respiratory syncytial virus vaccines and monoclonal antibodies. J. Allergy Clin. Immunol.157, 38–44. doi: 10.1016/j.jaci.2025.10.023
54
NovelliG.LiuJ.BiancolellaM.AlonziT.NovelliA.PattenJ. J.et al. (2021). Inhibition of HECT E3 ligases as potential therapy for COVID-19. Cell Death Dis.12:310. doi: 10.1038/s41419-021-03513-1,
55
Ontiveros-ZunigaL. F.Sosa-MondragonS. I.Osuna-RamosJ. F.Llanas-VazquezR. S.Canedo-FigueroaD. M.Velazquez-CervantesM. A.et al. (2026). Therapeutic targeting of respiratory syncytial virus: current pharmacological options and future directions in antiviral development. Microbiol. Res.309:128536. doi: 10.1016/j.micres.2026.128536,
56
OpenshawP. J. M.ChiuC.CulleyF. J.JohanssonC. (2017). Protective and harmful immunity to RSV infection. Annu. Rev. Immunol.35, 501–532. doi: 10.1146/annurev-immunol-051116-052206,
57
ParumsD. V. (2025). Editorial: surveillance of seasonal respiratory syncytial virus (RSV) infection in children and vulnerable adults drives vaccine development and new immunization programs. Med. Sci. Monit.31:e949558. doi: 10.12659/MSM.949558,
58
PolonioC. M.McHaleK. A.SherrD. H.RubensteinD.QuintanaF. J. (2025). The aryl hydrocarbon receptor: a rehabilitated target for therapeutic immune modulation. Nat. Rev. Drug Discov.24, 610–630. doi: 10.1038/s41573-025-01172-x,
59
PophamK.St GeorgeK.FelsenC.DumyatiG.TesiniB. L. (2025). Disproportionate impact of respiratory syncytial virus (RSV) among older adults in long-term care settings. J. Am. Med. Dir. Assoc.26:105760. doi: 10.1016/j.jamda.2025.105760,
60
PrincipiN.PerroneS.EspositoS. (2025). Challenges and limitations of current RSV prevention strategies in infants and young children: a narrative review. Vaccines (Basel)13:717. doi: 10.3390/vaccines13070717,
61
RanL.LiC.WangP.TangJ.QuZ.HaoY.et al. (2026). Aryl hydrocarbon receptor: a potential target for natural products in the treatment of inflammatory bowel disease. Front. Immunol.17:1720700. doi: 10.3389/fimmu.2026.1720700,
62
Reyes-HernandezO. D.Figueroa-GonzalezG.Quintas-GranadosL. I.Gutierrez-RuizS. C.Hernandez-ParraH.Romero-MonteroA.et al. (2023). 3,3'-Diindolylmethane and indole-3-carbinol: potential therapeutic molecules for cancer chemoprevention and treatment via regulating cellular signaling pathways. Cancer Cell Int.23:180. doi: 10.1186/s12935-023-03031-4,
63
ShaabanF. L.GroenendijkR. W.BaralR.CaballeroM. T.CroweJ. E.Jr.EnglundJ. A.et al. (2025). The path to equitable respiratory syncytial virus prevention for infants: challenges and opportunities for global implementation. Lancet Glob. Health13, e2165–e2174. doi: 10.1016/S2214-109X(25)00379-1,
64
ShiJ.HuangX.YeC.LuY.LiuY.WeiY.et al. (2026). Respiratory syncytial virus (RSV): a comprehensive overview from basic biology to clinical prevention and control. Med. Res. Rev.46, 672–712. doi: 10.1002/med.70025,
65
SilverbergJ. I.BoguniewiczM.QuintanaF. J.ClarkR. A.GrossL.HiranoI.et al. (2024). Tapinarof validates the aryl hydrocarbon receptor as a therapeutic target: a clinical review. J. Allergy Clin. Immunol.154, 1–10. doi: 10.1016/j.jaci.2023.12.013,
66
SladekovaL.ManiS.DvorakZ. (2023). Ligands and agonists of the aryl hydrocarbon receptor AhR: facts and myths. Biochem. Pharmacol.213:115626. doi: 10.1016/j.bcp.2023.115626,
67
SondermannN. C.FassbenderS.HartungF.HatalaA. M.RolfesK. M.VogelC. F. A.et al. (2023). Functions of the aryl hydrocarbon receptor (AHR) beyond the canonical AHR/ARNT signaling pathway. Biochem. Pharmacol.208:115371. doi: 10.1016/j.bcp.2022.115371,
68
SrikanthY.ReddyD. H.AnushaV. L.DumalaN.ViswanadhM. K.ChakravarthiG.et al. (2025). Unveiling the multifaceted pharmacological actions of Indole-3-Carbinol and Diindolylmethane: a comprehensive review. Plants (Basel)14:827. doi: 10.3390/plants14050827,
69
StockingerB.DiazO. E.WincentE. (2024). The influence of AHR on immune and tissue biology. EMBO Mol. Med.16, 2290–2298. doi: 10.1038/s44321-024-00135-w,
70
TavaresL. P.NijmehJ.LevyB. D. (2023). Respiratory viral infection and resolution of inflammation: roles for specialized pro-resolving mediators. Exp. Biol. Med. (Maywood)248, 1635–1644. doi: 10.1177/15353702231199082,
71
ThornhillE. M.VerhoevenD. (2020). Respiratory syncytial virus's non-structural proteins: masters of interference. Front. Cell. Infect. Microbiol.10:225. doi: 10.3389/fcimb.2020.00225,
72
TianB.YangJ.ZhaoY.IvanciucT.SunH.WakamiyaM.et al. (2018). Central role of the NF-κB pathway in the Scgb1a1-expressing epithelium in mediating respiratory syncytial virus-induced airway inflammation. J. Virol.92, e00441–18. doi: 10.1128/jvi.00441-18,
73
TortiM. F.GiovannoniF.QuintanaF. J.GarciaC. C. (2021). The aryl hydrocarbon receptor as a modulator of anti-viral immunity. Front. Immunol.12:624293. doi: 10.3389/fimmu.2021.624293,
74
TrippR. A.JonesL. P.MartinD. E. (2025). Intersection of inflammation and viral replication: the central role of MAPK signaling in viral respiratory infections. Front. Microbiol.16:1735254. doi: 10.3389/fmicb.2025.1735254,
75
WangM.GuoJ.HartA. L.LiJ. V. (2023). Indole-3-aldehyde reduces inflammatory responses and restores intestinal epithelial barrier function partially via aryl hydrocarbon receptor (AhR) in experimental colitis models. J. Inflamm. Res.16, 5845–5864. doi: 10.2147/JIR.S432747,
76
WangP.TaoW.LiQ.MaW.JiaW.KangY. (2025). Indole-3-aldehyde alleviates lung inflammation in COPD through activating aryl hydrocarbon receptor to inhibit HDACs/NF-kappaB/NLRP3 signaling pathways. J. Mol. Med. (Berl)103, 157–174. doi: 10.1007/s00109-024-02506-9,
77
XuL.LinL.XieN.ChenW.NongW.LiR. (2024). Role of aryl hydrocarbon receptors in infection and inflammation. Front. Immunol.15:1367734. doi: 10.3389/fimmu.2024.1367734,
78
YanZ.ChenB.YangY.YiX.WeiM.Ecklu-MensahG.et al. (2022). Multi-omics analyses of airway host-microbe interactions in chronic obstructive pulmonary disease identify potential therapeutic interventions. Nat. Microbiol.7, 1361–1375. doi: 10.1038/s41564-022-01196-8,
79
ZarH. J.CachoF.KootbodienT.MejiasA.OrtizJ. R.SteinR. T.et al. (2024). Early-life respiratory syncytial virus disease and long-term respiratory health. Lancet Respir. Med.12, 810–821. doi: 10.1016/s2213-2600(24)00246-7,
80
ZelanteT.IannittiR. G.CunhaC.De LucaA.GiovanniniG.PieracciniG.et al. (2013). Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity39, 372–385. doi: 10.1016/j.immuni.2013.08.003,
81
ZhuM.LiuJ. (2025). Predictive value of Th17/Treg immune imbalance for disease severity and poor prognosis in children with respiratory syncytial virus pneumonia. Front. Pediatr.13:1725402. doi: 10.3389/fped.2025.1725402,
82
ZhuangH.LiB.XieT.XuC.RenX.JiangF.et al. (2022). Indole-3-aldehyde alleviates chondrocytes inflammation through the AhR-NF-kappaB signalling pathway. Int. Immunopharmacol.113:109314. doi: 10.1016/j.intimp.2022.109314
Summary
Keywords
aryl hydrocarbon receptor, dietary AHR ligands, gut microbiota, immune response, nutritional AHR ligands, respiratory syncytial virus, therapeutic interventions
Citation
Green SE, Casola A and Haas de Mello A (2026) Therapeutic potential of nutritional aryl hydrocarbon receptor ligands for respiratory syncytial virus infection: a mini review. Front. Microbiol. 17:1887894. doi: 10.3389/fmicb.2026.1887894
Received
21 May 2026
Revised
23 July 2026
Accepted
27 July 2026
Published
10 August 2026
Volume
17 - 2026
Edited by
Swayam Prakash, University of California, Irvine, United States
Reviewed by
Shifu Aggarwal, Massachusetts General Hospital and Harvard Medical School, United States
Shadi Shahriari, University of Canberra, Australia
Updates
Copyright
© 2026 Green, Casola and Haas de Mello.
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) and the copyright owner(s) 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: Aline Haas de Mello, alhaasde@utmb.edu
Disclaimer
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