Immune response to viral infections

Immune responses to viral infections are highly coordinated and include rapid innate immune responses followed by adaptive immune responses that are specific to antigens (Varchetta and Marcenaro Reference Varchetta and Marcenaro2025). Rapid recognition of viral pathogens is critical in controlling the replication of viruses. The effectiveness of these immune responses is critical in determining the severity of the disease (Carty et al. Reference Carty, Guy and Bowie2021).

Adaptive immunity

Adaptive immunity offers antigen-specific immunity that is crucial for successful viral clearance, long-term immunity, and immune memory. Following antigen presentation by dendritic cells, CD4+ T helper cells coordinate the immune response by facilitating the activation of cytotoxic T lymphocytes and the differentiation of B cells (Figure 1), whereas CD8+ cytotoxic T lymphocytes directly kill virus-infected cells via the action of perforin and granzymes (Zhang and Sun Reference Zhang and Sun2025). B cells also mediate antiviral immunity by secreting high-affinity neutralizing antibodies that neutralize viruses, mediate opsonization, and facilitate viral clearance (Upasani et al. Reference Upasani, Rodenhuis-Zybert and Cantaert2021). High-affinity antibody responses and isotype switching are major determinants of successful immunity and vaccine responses. After the clearance of infection, some antigen-specific T and B cells differentiate into long-lived memory cells that mediate rapid and potent immune responses upon secondary infection with the same virus (Zinaida et al. Reference Zinaida, Paul and Finn2019). The induction and maintenance of adaptive immune responses are extremely sensitive to nutritional factors. Nutrient deficiencies inhibit lymphocyte proliferation, reduce interferon signaling, decrease antibody production, and disrupt immune memory (Tourkochristou et al. Reference Tourkochristou, Triantos and Mouzaki2021). Furthermore, poor nutritional support can also contribute to exaggerated inflammation, resulting in unsuccessful viral control and tissue damage. These findings emphasize the importance of adaptive immune competence and the role of nutritional factors in modulating antiviral immunity and immune protection.

Figure 1.

Host immune response to viral infections and points of nutritional regulation. Host immune responses to viral infections and critical regulatory checkpoints modulated by nutritional immunomodulators. Viral infection triggers innate immunity, such as interferon production and cytokine signaling pathways, followed by activation of adaptive immunity through T and B lymphocytes. Uncontrolled immune activation results in hyperinflammation and tissue injury, whereas controlled immune responses result in viral clearance and the establishment of immune memory. Nutritional immunomodulators modulate various aspects of the immune response by promoting antiviral defense mechanisms and preventing immune pathology.

Figure 1 Long description

Immune response to viral infection, highlighting innate and adaptive immunity, nutritional regulation and outcomes. On the left, a virus infects epithelial cells, triggering innate immunity involving macrophages, dendritic cells, natural killer cells and cytokines. Nutritional regulation in the center includes FN signaling, nutritional effects on cytokines, antioxidants, vitamins and minerals. On the right, adaptive immune response involves CD4+ T helper cells, CD8+ cells and B cells with antibody binding. Protective outcomes include immune balance, viral clearance and homeostasis, while pathological outcomes involve excessive inflammation and tissue damage.

Concept of nutritional immunomodulators

Nutritional immunomodulators are described as nutritional elements that affect the immune system by either promoting beneficial host defenses or inhibiting excessive and harmful immune responses (Figure 2) (Polak et al. Reference Polak, Stępień and Gol2021). These biological compounds modulate the growth, activation, and signaling of the immune cells through various mechanisms, such as the modulation of cytokine production, regulation of the inflammatory response, preservation of redox balance, and regulation of immune cell metabolism (Wu et al. Reference Wu, Lewis and Pae2019). In the context of viral infections, nutritional immunomodulators function mainly as host-targeting agents, which enhance antiviral immunity while maintaining immune homeostasis (Azam et al. Reference Azam, Islam and Wahiduzzaman2023). In contrast to traditional antiviral drugs, which act on viral components or replication mechanisms, nutritional immunomodulators work by carefully modulating the immune system (Medoro et al. Reference Medoro, Davinelli and Colletti2023). They help in the early stages of antiviral immunity, such as interferon responses and NK cell functions, while also facilitating efficient T-cell responses, antibody production, and immune memory (Thirumdas et al. Reference Thirumdas, Kothakota and Pandiselvam2021). Most importantly, these nutrients can also help in the regulation of excessive inflammatory responses, thus preventing the possibility of immunopathological events, such as cytokine storms, which are often seen in severe viral infections (Peter et al. Reference Peter, Sandeep and Rao2021). Nutritional immunomodulators can be generally categorized into several groups depending on their biochemical properties and immunological mechanisms. Vitamins are important for the differentiation of immune cells, mucosal barrier function, and antioxidant mechanisms (Hooda et al. Reference Hooda, Malik and Bhatia2024). Minerals like zinc and selenium are important for immune cell signaling, redox mechanisms, and antiviral enzyme functions. Fatty acids, especially polyunsaturated fatty acids, regulate inflammatory and immune resolution mechanisms (Stefanache et al. Reference Stefanache, Lungu and Butnariu2023). Amino acids are metabolic substrates and signaling molecules that promote immune cell proliferation and effector responses. Phytochemicals, such as flavonoids and polyphenols, have antiviral and anti-inflammatory properties due to multitargeted mechanisms (Castellano and Molinier-Frenkel Reference Castellano and Molinier-Frenkel2020). Finally, probiotics and prebiotics have indirect effects on immune mechanisms through the regulation of gut microbiota and systemic immunity through the gut–immune axis. Collectively, these nutritional immunomodulators represent an integrated system that connects nutritional intake with immune competence, thus underscoring their potential role in viral disease prevention and management as complementary approaches (Table 1).

Figure 2.

Classification of nutritional immunomodulators and their immune targets. Main categories of nutritional immunomodulators and their main immune targets. Vitamins, minerals, fatty acids, amino acids, phytochemicals, and probiotics affect antiviral immunity through the regulation of immune signaling pathways, inflammation, redox regulation, immune metabolism, and microbiota–immune system interactions.

Table 1.

Major nutritional immunomodulators and their immunological functions in viral diseases

Vitamins as immunomodulators in viral diseases

Vitamins have crucial roles in the regulation of immune responses and the maintenance of host resistance against viral infections. Vitamins act as cofactors, antioxidants, and signaling molecules, which modulate the development of immune cells, antiviral signaling pathways, and inflammation (Table 2) (Gombart et al. Reference Gombart, Pierre and Maggini2020). The deficiency of essential vitamins has been consistently linked with susceptibility to viral infections, duration of disease, and severity of disease. Among the different micronutrients, vitamins D, C, A, and E have been widely investigated for their immunomodulatory properties in viral infections (Penkert et al. Reference Penkert, Smith and Hrincius2021).

Table 2.

Vitamins as immunomodulators in viral diseases

Vitamin D

Vitamin D is an important regulator of innate and adaptive immunity and has been identified as one of the most widely researched immunomodulatory agents in viral infections (Khashim Alswailmi et al. Reference Khashim Alswailmi, Shah and Nawaz2021). It stimulates innate immunity by inducing antimicrobial peptides, such as cathelicidins and defensins, which have direct antiviral activity. Vitamin D also stimulates antiviral immunity by regulating pattern recognition receptor signaling and augmenting IFN-I responses, thus inhibiting early viral replication. In addition to its role in augmenting antiviral immunity, vitamin D is an important regulator of immune-mediated inflammation (White Reference White2022). It inhibits excessive pro-inflammatory cytokine production, such as interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-α), thus preventing tissue damage due to cytokine storm. By affecting both innate and adaptive immune responses, vitamin D helps achieve immunological balance while fighting viruses. Clinical and epidemiological studies have demonstrated associations between vitamin D deficiency and increased susceptibility to respiratory viral infections, such as influenza and coronavirus disease 2019 (COVID-19) (Ahmed Reference Ahmed2020). Vitamin D supplementation has been associated with decreased disease severity and improved outcomes, including better regulation of immunity and minimizing inflammatory responses, thus establishing its dual role in stimulating antiviral immunity and maintaining immune homeostasis (Figure 3) (Shah et al. Reference Shah, Varna and Sharma2022).

Figure 3.

Effects of vitamin D on the immune system. Vitamin D and 1,25(OH)₂D₃ regulate the innate immune response. The regulatory effect of this molecule has been demonstrated to influence the innate immune system, including macrophages, dendritic cells, NK cells, and ILCs, so, as a crucial molecule, it has a role in the pathophysiology of many diseases. This vitamin also has a role in the generation of an acquired immune response. (Please see text for further information.) Th, T helper cell; IL, interleukin; IFN-γ, interferon-γ.

Figure 3 Long description

Vitamin D regulates the immune system, highlighting its effects on both innate and acquired immunity. At the top, a combination of fruits, vegetables and sunlight is shown contributing to Vitamin D synthesis, which is indicated by an arrow pointing to a human figure with highlighted kidneys. This leads to the production of 1,25-dihydroxyvitamin D3, which influences both the acquired and innate immune systems. The acquired immune system is depicted with B cells, plasma cells and memory B cells, with arrows indicating the production of antibodies. A box lists effects such as inhibiting dendritic cell maturation, reducing interleukin production and decreasing CD40, CD80, CD86 and MHC-II expression. The innate immune system is represented by dendritic cells, macrophages and natural killer cells, with arrows showing their connection to Vitamin D. Another box details effects like reducing tumor necrosis factor-alpha, enhancing antimicrobial peptide production and improving cytotoxic function. On the left, a legend indicates the suppression or induction effects of Vitamin D on various T helper cells, including Th1, Th2, Th9, Th17, Th22 and T-regulatory cells.

Minerals and antiviral immunity

Minerals are vital micronutrients that have important functions in the regulation of the immune system, antiviral mechanisms, and cellular homeostasis. They act as a structural part of immune proteins, a cofactor for enzymes that regulate the immune response, and a redox regulator. Disruptions in the homeostasis of minerals, either through deficiency or toxicity, can greatly affect the susceptibility of the host to viral infections (Figure 4) (Alagawany et al. Reference Alagawany, Attia and Farag2021).

Figure 4.

Vitamins and minerals regulating antiviral immune pathways. Immunomodulatory effects of vitamins and minerals in antiviral protection. Vitamins and minerals modulate the innate and adaptive immune systems through the regulation of interferon, cytokines, antioxidant mechanisms, proliferation of immune cells, and viral replication.

Figure 4 Long description

Micronutrient regulation of antiviral immunity is depicted with vitamins and minerals. The vitamins section includes: Vitamin D, which enhances interferon signaling and antimicrobial peptide production; Vitamin C, which neutralizes reactive oxygen species (ROS) and supports immune cell function; Vitamin A, which maintains epithelial barrier integrity and supports immune cell differentiation; Vitamin E, which reduces oxidative stress and supports immune cell membrane integrity. The minerals section includes: Zinc, which inhibits viral replication and supports immune cell function; Selenium, which maintains redox balance and supports immune enzyme activity. The central circle reads: Micronutrient Regulation of Antiviral Immunity. Arrows connect vitamins and minerals to the mediation of immune cells and responses, including dendritic macrophage and killer T and B lymphocytes. Below, benefits are listed: reduced oxidative stress, enhanced antiviral immunity, controlled inflammation and immune homeostasis. The final statement reads: Improved host defense and protection against viral infections.

Fatty acids and lipid mediators

Fatty acids are known to be important components of the immune cell membrane and precursors of bioactive lipid mediators that control inflammation and immune responses. In viral infections, the ratio of pro-inflammatory to pro-resolving lipid mediators has been shown to play a crucial role in determining the severity of the disease and tissue injury (S. Zhang et al. Reference Zhang, Kebing and Liu2024). Polyunsaturated fatty acids, specifically omega-3 fatty acids, have been identified as important immunomodulatory agents that can modulate inflammatory responses without impairing antiviral immunity (Fenton et al. Reference Fenton, Hord and Ghosh2013).

Omega-3 fatty acids: Omega-3 fatty acids, such as eicosapentaenoic acid and docosahexaenoic acid, have strong anti-inflammatory and immunomodulatory properties in viral infections. Omega-3 fatty acids act by modulating the immune cell membrane and influencing the activation of pro-inflammatory pathways like nuclear factor (NF)-κB (Arnardottir et al. Reference Arnardottir, Pawelzik and Öhlund Wistbacka2021). Consequently, omega-3 fatty acids lower the production of inflammatory cytokines like IL-6 and TNF-α, which are commonly associated with the pathogenesis of severe viral infections and cytokine storm syndrome. Moreover, omega-3 fatty acids not only inhibit the production of inflammatory cytokines but also actively resolve inflammation by producing specialized pro-resolving lipid mediators like resolvins, protectins, and maresins (Lampova et al. Reference Lampova, Doskocil and Kourimska2022). These lipid molecules enhance the clearance of inflammatory cells, restore tissue homeostasis, and prevent chronic inflammation without suppressing antiviral immunity (Z. Li et al. Reference Li, Deng and Yang2026). Via modulating the immune signaling of cytokines and immune resolution of inflammation, omega-3 fatty acids help regulate immune homeostasis and antiviral immunity (Bodur et al. Reference Bodur, Yilmaz and Ağagündüz2025). By modulating cytokine production and immune resolution, omega-3 fatty acids play a pivotal role in maintaining immune homeostasis and preventing adverse outcomes in viral infections associated with hyperinflammation (Hathaway et al. Reference Hathaway, Pandav and Patel2020). There is also evidence from clinical studies as well as experiments indicating the benefits of omega-3 fatty acids in limiting inflammation-induced damage to tissues and improving immune regulation in cases of severe viral infections (Bodur et al. Reference Bodur, Yilmaz and Ağagündüz2025).

Omega-6 fatty acids: Omega-6 fatty acids are critical parts of the immune response and have been shown to play vital roles in cell membrane function, energy production, and the immune response. They are precursors to bioactive lipid mediators, such as prostaglandins and leukotrienes, which play roles in the initiation of the inflammatory response that is required for a successful host defense against invading pathogens (Innes and Calder Reference Innes and Calder2018). However, high levels of omega-6 fatty acids can lead to an imbalance in the immune response, resulting in a pro-inflammatory environment. High levels of lipid mediators derived from omega-6 fatty acids can lead to the production of high levels of inflammatory cytokines and can prolong the inflammatory signal, which can lead to increased immune-mediated tissue damage in viral infections. While omega-6 fatty acids play a key role in the early response of the immune system to infections and are necessary for protection, excess omega-6-driven immune signaling might cause immune imbalance during severe viral infections (R. Xu et al. Reference Xu, Molenaar and Chen2025). A high ratio of omega-6 to omega-3 fatty acids has been linked to increased inflammatory responses and adverse outcomes in diseases that are characterized by an imbalance of the immune response (H. K. Kim et al. Reference Kim, Kang and Go2022a). The optimal balance of omega-6 and omega-3 fatty acids is essential for inflammation regulation and preservation of antiviral immune homeostasis.

Amino acids and immune regulation

Amino acids have pivotal roles in the metabolism, signaling, and effector functions of immune cells, especially during viral infections, where the activation of immunity significantly elevates metabolic demands. In addition to their role as protein precursors, some amino acids have been identified as crucial immunoregulatory molecules that regulate antiviral immunity, inflammation, and immune tolerance (Kanno et al. Reference Kanno, Miyako and Endo2025). Changes in amino acid availability during infection can thus significantly impact immune function and outcomes.

Glutamine is a major metabolic substrate for the rapidly proliferating immune cells, such as lymphocytes and macrophages. It is involved in the synthesis of nucleotides, energy production, and cytokine production, and hence the activation of immune cells during viral infections (J. Li et al. Reference Li, Wang and Deng2023). Depletion of glutamine, which is a common feature of severe infections and inflammation, inhibits the proliferation of lymphocytes, reduces the phagocytic activity of macrophages, and affects the antiviral immune response. Glutamine plays a significant part in the regulation of immune cell metabolism and cytokines, making an important contribution to maintaining adequate antiviral immunity during virus infections.

Arginine has an important role in antiviral immunity because of its role in the production of nitric oxide (Garren et al. Reference Garren, Ashcraft and Qian2021). Nitric oxide produced by activated macrophages has direct antiviral effects because it can inhibit the replication of viruses and the survival of infected cells. Arginine also affects the function of T cells. Low levels of arginine can inhibit the production of nitric oxide (Burrack and Morrison Reference Burrack and Morrison2014). Regulation of the synthesis of nitric oxide and T cells through arginine plays an important role in innate and adaptive immunity for antiviral immune responses. Moreover, studies have revealed that poor arginine metabolism affects the immune system regulation during serious virus infection.

Tryptophan modulates immune responses mainly by its metabolism via the kynurenine pathway. Stimulation of the kynurenine pathway has been shown to modulate immune tolerance and inflammation by regulating T-cell proliferation and cytokine secretion (Ou et al. Reference Ou, Xu and Su2025). In viral infections, imbalanced tryptophan metabolism has been implicated in immune suppression or hyperinflammation. Balanced regulation of tryptophan availability and metabolism is, therefore, crucial for the regulation of immune responses and the prevention of immune dysfunction (A.-Y. Chen et al. Reference Chen, Zhao and Wang2025a). Through regulation of tolerance, inflammation, and T-cell function, tryptophan metabolism is crucial for antiviral immune homeostasis. Collectively, these amino acids emphasize the intimate relationship between immune metabolism and antiviral protection and the significance of sufficient amino acid availability for the support of properly regulated immune responses during viral infections.

Convergent mechanisms of nutritional immunomodulation in antiviral immunity

Although vitamins, minerals, fatty acids, amino acids, phytochemicals, and probiotics are often discussed as distinct categories, growing evidence indicates that their immunological effects converge on a limited set of regulatory checkpoints that shape antiviral defense and immune-mediated pathology. When examined comparatively rather than individually, recurring mechanistic themes become evident, suggesting that nutritional immunomodulation operates through shared biological pathways rather than isolated nutrient-specific actions (Govers et al. Reference Govers, Calder and Savelkoul2022).

One of the most consistent points of convergence is modulation of IFN-I responses, a central component of early antiviral immunity. Vitamin D enhances antimicrobial peptide production and influences pattern recognition receptor signaling, thereby modulating interferon responsiveness. Zinc contributes to the stability of intracellular signaling pathways and supports interferon-mediated antiviral gene expression (Velija et al. Reference Velija, Almira and Tawil Djinan2021). Similarly, phytochemicals, including polyphenols such as resveratrol and flavonoids, have been shown to enhance interferon-stimulated gene activation while simultaneously restraining excessive inflammatory transcriptional programs. Despite differences in their primary biochemical roles, these nutrients appear to converge on a shared outcome: strengthening early antiviral priming while limiting dysregulated downstream inflammation. Notably, clinical benefit is most consistently observed in individuals with baseline deficiencies, suggesting that nutritional interventions may primarily restore impaired interferon competence rather than amplify already optimal antiviral responses (Senrina et al. Reference Senrina, Van Blydenstein and Venter2022).

Another major regulatory node is redox homeostasis. Viral infections are characterized by increased oxidative stress resulting from both viral replication and immune activation. Several nutritional classes – including vitamin C, vitamin E, selenium, polyphenols, and catechins – exert immunomodulatory effects through preservation of redox balance. Redox status influences key immune pathways such as NF-κB activation, cytokine transcription, and immune cell viability. Selenium-dependent selenoproteins limit oxidative damage and may even influence viral mutation rates. Vitamin C protects immune cells from oxidative dysfunction, while phytochemicals modulate intracellular antioxidant signaling pathways (Jayawardena et al. Reference Jayawardena, Sooriyaarachchi and Chourdakis2020). Importantly, these nutrients do not merely function as passive antioxidants; rather, they regulate redox-sensitive immune signaling networks. This convergence highlights redox control as a central checkpoint in antiviral immunity rather than a secondary supportive mechanism. Metabolic adaptation represents another shared axis of regulation. Immune cell activation during viral infection requires rapid metabolic reprogramming. Amino acids such as glutamine and arginine serve as critical substrates for lymphocyte proliferation and macrophage effector functions. Zinc and iron influence enzymatic processes essential for cellular metabolism, whereas fatty acids shape membrane composition and lipid mediator synthesis. Omega-3 fatty acids provide a particularly illustrative example of metabolic–immune integration (SeyedAlinaghi et al. Reference SeyedAlinaghi, Shahidi and Mojdeganlou2024). In addition to reducing pro-inflammatory cytokine production, they generate specialized pro-resolving mediators that actively coordinate the resolution of inflammation without impairing viral clearance. These observations support the emerging field of immunometabolism, which emphasizes that nutrient availability can shape immune cell fate decisions and influence the balance between effector and regulatory responses.

Importantly, nutritional immunomodulators do not simply “boost” immunity. Comparative analysis suggests a more nuanced function: recalibration of inflammatory thresholds rather than indiscriminate immune activation (Zhu et al. Reference Zhu, Zhu and Chu2025). Vitamin D suppresses excessive IL-6 and TNF-α production; omega-3 fatty acids shift lipid mediator profiles toward resolution; flavonoids attenuate NF-κB and mitogen-activated protein kinase (MAPK) signaling; and probiotics influence cytokine networks through microbiome-mediated pathways. This pattern of regulation suggests that nutritional strategies may be particularly relevant in viral diseases characterized by hyperinflammation, where immune dysregulation contributes substantially to pathology (Yaseen et al. Reference Yaseen, Jamshaid and Saif2022).

Maintenance of epithelial and mucosal integrity represents an additional shared mechanism. Vitamin A supports epithelial differentiation and Immunoglobulin A (IgA) production, zinc contributes to barrier stabilization, and probiotics enhance mucosal immune priming via the gut–lung axis. These actions underscore that antiviral defense extends beyond intracellular viral inhibition to include preservation of structural and functional immune barriers. Adequate micronutrient status therefore appears to support a multilayered defense strategy encompassing barrier protection, innate priming, adaptive coordination, and controlled inflammatory resolution (Jayawardena et al. Reference Jayawardena, Sooriyaarachchi and Chourdakis2020). The microbiome further integrates these mechanisms. Probiotics and prebiotics influence immune responses indirectly through microbial metabolites such as short-chain fatty acids (SCFAs), which modulate dendritic cell activity, T-cell differentiation, and interferon responses. Additionally, certain polyphenols interact with gut microbial communities, suggesting crosstalk between dietary phytochemicals and microbial metabolism. Nutritional immunomodulation thus operates not only at the level of individual nutrients but within a dynamic host–microbiome network. Despite these convergent mechanisms, clinical outcomes remain heterogeneous. Effects are often context-dependent, with benefits most apparent in deficient or high-risk populations. The timing of supplementation relative to the infection stage may influence outcomes, and preventive and therapeutic applications likely differ mechanistically (Govers et al. Reference Govers, Calder and Savelkoul2022). Collectively, current evidence supports the view that nutritional immunomodulation functions primarily as restoration of immune homeostasis rather than immune amplification. Recognizing this distinction is critical for trial design, population stratification, and translational implementation. Finally, reductionist approaches that focus on single nutrients may underestimate synergistic or antagonistic interactions within broader nutritional networks. Interactions among vitamins, minerals, fatty acids, amino acids, and microbiota-derived metabolites likely shape immune trajectories in complex and context-dependent ways. Future research should therefore move beyond isolated supplementation paradigms toward systems-based nutritional immunology frameworks capable of capturing these interactions.

Phytochemicals as natural immunomodulators

Phytochemicals are bioactive, non-nutritive plant compounds that have strong immunomodulatory and antiviral effects. Due to their multitarget effects, phytochemicals have gained considerable attention as natural host-targeting agents that can modulate the immune system and directly affect the viral life cycle (Ben-Shabat et al. Reference Ben-Shabat, Yarmolinsky and Porat2020). Unlike traditional antiviral agents that target a single step of the viral life cycle, phytochemicals can modulate multiple steps of viral entry, replication, inflammation, and oxidative damage simultaneously, which makes them highly useful in managing complex viral infections involving immune system dysregulation (Roshni et al. Reference Roshni, Vaishali and Ganesh2022).

Flavonoids, like luteolin and quercetin, are one of the most well-studied types of antiviral phytochemicals because of their broad-spectrum antiviral properties and immunomodulatory effects. Flavonoids demonstrate direct antiviral activity by inhibiting important steps of the viral life cycle (Lu et al. Reference Lu, Zhang and Ren2023). On the level of viral entry, flavonoids can interfere with virus–host receptor interactions by binding to viral surface proteins or host receptors, thus inhibiting viral attachment and entry into the host cell. Moreover, flavonoids inhibit viral replication by blocking the activity of essential viral enzymes, such as viral proteases and RNA-dependent RNA polymerases, thus inhibiting viral genome replication and protein processing (Badshah et al. Reference Badshah, Faisal and Muhammad2021).

In addition to their direct antiviral properties, flavonoids have an important role in modulating the host immune response. They can modulate important intracellular signaling pathways, including the NF-κB and MAPK signaling pathways. Inhibition of these pathways leads to reduced transcription of pro-inflammatory cytokines like IL-6, TNF-α, and IL-1β, which are often upregulated in the setting of severe viral infections. By suppressing excessive inflammatory signaling while maintaining antiviral immune responses, flavonoids have been shown to improve immune homeostasis and prevent tissue damage caused by viral infections. The dual role of flavonoids in suppressing viral entry and replication, as well as in modulating the host inflammatory response, makes them promising natural immunomodulators (Y. Liu and Jiao Reference Liu and Jiao2025). The multitargeted mechanisms of action and safety profiles of flavonoids make them suitable candidates for investigation as adjunct therapies in the prevention and treatment of viral infections.

Polyphenols, such as resveratrol, display antiviral properties due to their ability to target various steps of the viral lifecycle while also modulating the host immune response. Polyphenols have been demonstrated to interact with viral replication by modulating host and viral factors necessary for viral genome replication and protein expression (Burkard et al. Reference Burkard, Piotrowsky and Leischner2025). Resveratrol has been shown to possess the ability to inhibit viral replication in various viral models by suppressing viral transcriptional activity and modulating intracellular signaling pathways necessary for viral replication. Apart from its direct antiviral properties, resveratrol also boosts the host’s antiviral immune response by activating interferon signaling pathways, which play a critical role in the early control of viral replication (Chen et al. Reference Chen, Song and Lixia2022a). The activation of interferon-induced genes also plays a role in the induction of an antiviral state in infected and adjacent cells, thus preventing the spread of the virus. At the same time, resveratrol also has potent anti-inflammatory properties by suppressing the overactivation of immune signaling pathways that are responsible for the production of inflammatory cytokines (Ortega-Prieto and Jimenez-Guardeño Reference Ortega-Prieto and Jimenez-Guardeño2024). This leads to a decrease in the production of pro-inflammatory mediators that are commonly involved in immune-mediated tissue injury during severe viral infections. Another important function of resveratrol is its role in redox balance regulation, where it reduces the oxidative stress caused by viral infection and immune activation (Chen et al. Reference Chen, Song and Zhao2022b). Resveratrol, through its regulation of antioxidant defense pathways and immune signaling, helps to maintain the function of immune cells and protect them from oxidative stress. The antiviral, immunomodulatory, and antioxidant functions of resveratrol and other polyphenols highlight their importance in viral infections and their potential as complementary immunomodulatory therapies in viral diseases.

Curcumin, a bioactive polyphenolic compound extracted from turmeric (Curcuma longa), has strong anti-inflammatory and antioxidant effects, which contribute to its immunomodulatory and antiviral activities. Curcumin acts on the immune system by inhibiting major intracellular signaling pathways, such as the NF-κB and MAPK pathways (Alesci et al. Reference Alesci, Nicosia and Fumia2022, Nicoliche et al. Reference Nicoliche, Bartolomeo and Lemes2024). Inhibition of these pathways results in decreased transcription of pro-inflammatory cytokines like IL-6, TNF-α, and IL-1β, which are often upregulated in the setting of severe viral infections and mediate immune-related tissue damage. Besides modulating inflammatory responses, curcumin also boosts the antioxidant capacity of cells by eliminating reactive oxygen species and inducing the expression of endogenous antioxidant enzymes (M. Liu et al. Reference Liu, Wang and Song2025). This helps to reduce oxidative stress, which preserves the function of immune cells and prevents oxidative damage caused by viral infection and chronic immune activation. By regulating redox balance, curcumin optimizes immune function and prevents excessive inflammation. Curcumin has also been shown to interact with various steps of the viral life cycle (Allegra et al. Reference Allegra, Mirabile and Ettari2022). Experimental studies have indicated that curcumin can prevent viral entry by interfering with the binding of viral surface proteins to host receptors, as well as prevent viral replication by modulating host signaling pathways involved in viral transcription and protein synthesis. By integrating its antiviral, anti-inflammatory, and antioxidant properties, curcumin presents considerable potential as a natural immunomodulator and complementary strategy for managing immune responses during viral infections (Ardebili et al. Reference Ardebili, Pouriayevali and Aleshikh2021).

Catechins, especially those found in high concentrations in green tea, like epigallocatechin gallate (EGCG), have been found to possess strong antiviral and immunomodulatory properties. These compounds have been found to affect the integrity of the viral membrane, thus interfering with the stability of the virus and its ability to bind to and enter the host cells (Dinda et al. Reference Dinda, Dinda and Dinda2023). Moreover, catechins have been found to inhibit the function of viral enzymes, such as proteases and polymerases, which are crucial for viral replication. In this way, catechins have been found to inhibit the replication of the virus at both the early and late stages of the viral life cycle. In addition to their direct antiviral properties, catechins play roles in immune regulation through the promotion of cellular antioxidant mechanisms and the reduction of oxidative stress induced by viral infection and immune activation (Mhatre et al. Reference Mhatre, Gurav and Shah2021). By neutralizing reactive oxygen species and increasing the expression of cellular antioxidant mechanisms, catechins help to maintain the viability and function of immune cells during inflammation. In addition, catechins modulate inflammatory signaling pathways, such as the NF-κB and MAPK pathways, resulting in the suppression of pro-inflammatory cytokine production. By simultaneously regulating viral replication, oxidative stress, and inflammation, catechins help to maintain immune homeostasis and prevent immune-mediated tissue damage during viral infections (J. M. Kim and Heo Reference Kim and Heo2022). The multitarget pharmacological properties of catechins emphasize their potential as natural immunomodulators and complementary therapies in the treatment of viral infections (J. Xu et al. Reference Xu, Zhao and Zheng2017).

Phytochemicals have been shown to work together in modulating antiviral immunity by inhibiting viral entry and replication, regulating inflammatory signaling pathways, and reducing oxidative stress (Table 3). The broad-spectrum mechanisms and good safety profiles of phytochemicals make them promising natural immunomodulators that can be used in the management of viral infections (Table 4) (Chojnacka et al. Reference Chojnacka, Skrzypczak and Izydorczyk2021).

Table 3.

Synergistic and antagonistic interactions between nutritional immunomodulators in antiviral immunity

Table 4.

Phytochemicals as natural antiviral immunomodulators

Gut microbiota, probiotics, and viral immunity

The gut microbiota is a key factor in the regulation of systemic immune responses and immune homeostasis. There is growing evidence that the intestinal microbial flora affects the susceptibility of the host to viral infections not only in the gastrointestinal tract but also in other mucosal surfaces, such as the respiratory system (Yuhao et al. Reference Yuhao, Wu and Huntington2020). This two-way interaction between the gut and the lungs, known as the gut–lung axis, allows microbial-derived factors to modulate immune responses in the respiratory tract, thus affecting the outcome of viral respiratory infections. By producing microbial metabolites, such as SCFAs, the gut microbiota regulates the development and function of innate and adaptive immune cells, such as macrophages, dendritic cells, and T lymphocytes (Yoo et al. Reference Yoo, Groer and Dutra2020). One of the major mediators of the immune conversation between the gut and lung is microbial metabolites such as SCFAs, tryptophan metabolites, and secondary bile acids. These metabolites play the role of signal molecules by connecting the microbiota of the intestines to the regulation of immunity both systemically and locally in the lungs. SCFAs like acetate, propionate, and butyrate are produced due to microbial fermentation of dietary fibers in the intestine. SCFAs regulate antiviral responses of the respiratory tract using different approaches, such as improving epithelial barrier function, regulating dendritic cells’ maturation, promoting regulatory T-cell differentiation, and regulating macrophages’ inflammatory response. In addition, SCFAs have an effect on IFN-I signaling pathways and antiviral cytokines, leading to improved early recognition of viruses and decreased inflammatory response of the lungs to respiratory viral infection. Research has shown that SCFAs are able to increase antiviral defense against influenza by increasing the proper function of innate immunity without causing an inflammatory response related to lung damage. Microbial metabolites derived from tryptophan have also been shown to have significant immunoregulatory functions within the gut–lung axis. Intestinal microbes break down tryptophan into indoles, which activate aryl hydrocarbon receptors to signal immune and epithelial cell processes. These signaling pathways promote the stability of mucosal barriers, cytokine production, and antiviral immune responses. In addition, tryptophan metabolites also affect the differentiation of regulatory T cells and innate lymphoid cells (ILCs), thus playing a part in immune tolerance and inflammatory responses during viral respiratory infections. Disrupted tryptophan metabolism is linked with immune imbalance and hyper-inflammation in severe viral infections. Furthermore, secondary metabolites resulting from microbial metabolism are also instrumental in systemic immune control, affecting macrophages, inflammatory pathways, and T cells. Bile acid signaling is known to affect nuclear receptors and transcription factors controlling cytokines and antiviral immune responses. By this mechanism, bacterial bile acid metabolic function plays an essential role in maintaining immune homeostasis during viral infection. Overall, microbial metabolites form a cascade that links gut microbial composition with immune programming and antiviral activity of the respiratory system. Any change in gut microbial diversity or their metabolites can lead to dysfunction in the interferon response, mucosal immunity, and increased vulnerability to respiratory virus infections. This is especially true when considering zoonotic respiratory viruses like influenza viruses and coronavirus, which have significant morbidity and mortality associated with excessive inflammation and immune dysfunction. New data indicate that altering microbial metabolites through probiotic treatment, prebiotics, dietary fiber, and nutritional intervention can be used as a potent strategy against zoonotic respiratory viruses. These microbial metabolites increase antiviral immunity by promoting interferon signaling and improving antigen presentation, both of which are essential for the early recognition and control of viral infections. An imbalance of the gut microbial flora, or gut dysbiosis, has been linked to impaired interferon responses, exaggerated inflammation, and increased susceptibility to viral infections. Probiotics, which are live microorganisms that provide a health benefit to the host when administered in adequate amounts, have been identified as significant modulators of antiviral immunity (Alwin and Karst Reference Alwin and Karst2021). Probiotic treatment has been demonstrated to improve IFN-I production and the expression of interferon-stimulated genes, thus improving innate antiviral immunity. Moreover, probiotics modulate inflammatory signaling, thus improving cytokine production and minimizing immune-mediated tissue injury in the course of infection. Apart from their role in innate immunity, probiotics also modulate adaptive immunity by improving B-cell function, antibody production, and T-cell activity (Amrouche and Chikindas Reference Amrouche and Chikindas2022). Various studies have demonstrated that probiotic treatment improves the efficacy of vaccines by improving seroconversion and antibody production after vaccination. This is particularly important in the context of viral vaccines, which require the induction of strong and lasting immune memory for long-term protection. From a clinical perspective, the use of probiotics has been linked to a decreased incidence, duration, and severity of viral respiratory infections such as influenza and other upper respiratory tract infections (Kanauchi et al. Reference Kanauchi, Low and Jounai2023). Through the enhancement of mucosal immunity, interferon production, and the regulation of inflammation by the gut–lung axis, probiotics have been shown to improve host resistance to viral infections. Taken together, the above evidence points to the importance of the gut microbiota and probiotics in nutritional immunomodulation for their potential in antiviral immunity (Gutierrez-Merino et al. Reference Gutierrez-Merino, Isla and Combes2020).

Challenges and limitations

Despite the increasing body of evidence that validates the use of nutritional immunomodulators in viral disease treatment, there are some challenges and limitations that impede their effective clinical application. One of the major challenges is the absence of standardized dosage regimens. Nutritional needs are highly variable depending on age, sex, physiological condition, initial nutritional status, genetic predisposition, and disease severity (Dalimunthe et al. Reference Dalimunthe, Tan and Felice Chrismary2026). Most clinical trials have employed diverse doses and formulations, making it challenging to determine the optimal levels of intake or to compare treatment outcomes across trials. Another major limitation is associated with bioavailability and nutritional composition. The absorption, distribution, metabolism, and utilization of nutrients can be highly variable depending on their chemical composition, carrier matrix, and interactions with other nutritional components (Nicoliche et al. Reference Nicoliche, Bartolomeo and Lemes2024). For instance, fat-soluble vitamins and polyphenols have been shown to have poor bioavailability, which can impede their immunomodulatory potential despite promising in vitro data. Another challenge posed by population heterogeneity is in the interpretation of clinical evidence. Variations in underlying nutritional status, presence of comorbidities, immune status, and risk of exposure make it difficult to obtain consistent results from observational studies and randomized controlled trials (Yaseen et al. Reference Yaseen, Jamshaid and Saif2022). In some instances, the benefits of supplementation may be more apparent in populations with pre-existing deficiencies in nutrients, whereas populations with adequate nutritional status may demonstrate little to no effect. This makes it difficult to generalize results to the larger population. Additionally, the point and duration of nutritional intervention in relation to exposure to the virus and the progression of disease can be unclear in most studies (H.-K. Kim et al. Reference Kim, Park and Han2021). This is particularly true when it comes to the distinction between preventive, early therapeutic, and late-stage treatments during severe infection. The immunological effects of nutritional immunomodulators may vary greatly depending on the point of administration, but this has not been adequately investigated in clinical studies. The potential risks of over-supplementation must also be taken into consideration (SeyedAlinaghi et al. Reference SeyedAlinaghi, Shahidi and Mojdeganlou2024). Over-supplementation of certain vitamins, such as iron, vitamin A, or fat-soluble vitamins, could result in immune dysregulation, oxidative damage, or increased viral replication. However, the outcomes of safety are frequently under-reported in clinical trials, making it difficult to establish a safe upper limit for therapeutic use. Finally, many of the existing clinical trials are conducted on single-nutrient therapies, whereas the immune system is regulated by complex interactions of nutrient networks (Jayawardena et al. Reference Jayawardena, Sooriyaarachchi and Chourdakis2020). This simplification may neglect interactions between nutrients, such as synergistic or antagonistic interactions. Furthermore, the clinical end points of viral load, immune parameters, and clinical severity are not standardized across studies, making it even more difficult to compare studies. Taken together, these factors underscore the need for well-designed, large-scale clinical trials that are mechanistically based and include standardized dosing, bioavailability, immune phenotyping, and safety analysis (J. H. Kim et al. Reference Kim, Kang and Go2022a). Overcoming these issues is crucial for the development of nutritional immunomodulation from a supportive care modality to an evidence-based approach for viral disease management.

Future perspectives

The growing knowledge of immunology, metabolism, and host–pathogen interactions offers new avenues for the advancement of nutritional immunomodulation as a strategic tool in viral disease control. Future studies should focus on the development of precision nutrition strategies that go beyond the current supplementation paradigm and take into consideration individual differences in immune phenotypes, genetic makeup, metabolic conditions, and microbiome composition. The integration of nutrigenomics and immunophenomics with nutritional therapies may provide new avenues for the identification of individuals who would most benefit from personalized nutritional therapies. The development of systems immunology and multi-omics platforms is anticipated to play a crucial role in the dissection of the intricate networks by which nutrients modulate antiviral immunity. Transcriptomic, metabolomic, and microbiome analyses may offer novel mechanistic insights into how nutritional immunomodulators modulate interferon, inflammation, immune metabolism, and redox homeostasis during viral infections. The use of nutritional immunomodulators as complementary therapies for antiviral medications and vaccines is another promising area. Nutritional approaches that can boost innate immune priming, aid adaptive immune memory, and modulate post-vaccination inflammation could potentially improve the safety, efficacy, and durability of vaccines. This is especially important for high-risk groups such as older individuals, those with chronic conditions, and immunocompromised patients, who have been shown to have poor responses to vaccines. Another area that should be investigated in the future is the use of functional foods and bioactive dietary preparations that can provide immunomodulatory nutrients with improved bioavailability and synergistic interactions. Breakthroughs in formulation technology, such as nano-delivery systems and microbiome-directed therapies, could potentially address existing issues of nutrient absorption and stability. From a public health point of view, nutritional immunomodulation has great potential in pandemic preparedness and immune system resilience. The integration of evidence-based nutritional approaches into public health strategies may enhance overall immune system competency in the population, making them less susceptible to viral infections. Notably, nutritional approaches can be implemented as a cost-effective and adaptable strategy to complement conventional medical practices, especially in developing countries. Taken together, these future directions emphasize the importance of interdisciplinarity in immunology, nutrition, and public health. By converging mechanistic research with clinical and public health strategies, nutritional immunomodulation can progress from a complementary strategy to a fundamental part of a comprehensive antiviral disease management strategy.