Plant Compounds Target Host Immune Signaling to Fight Influenza A Virus

Influenza A virus (IAV) remains one of the most persistent threats to global health, infecting up to one billion people each year and causing an estimated 290,000 to 650,000 deaths worldwide. Seasonal subtypes such as H1N1 and H3N2 circulate continuously, driven by the virus’s remarkable genetic plasticity through antigenic drift and shift, which allows new variants to evade pre-existing immunity. Despite decades of antiviral development, only four drugs are approved by the U.S. Food and Drug Administration for influenza treatment: the neuraminidase inhibitors oseltamivir, zanamivir, and peramivir, and the cap-dependent endonuclease inhibitor baloxavir marboxil. The adamantanes, once widely used as M2 ion channel blockers, are no longer recommended because of widespread resistance among circulating strains, and resistance to neuraminidase inhibitors continues to emerge, leaving a narrow therapeutic arsenal.

A new review published in MicrobiologyOpen examines whether plant-derived compounds could help fill this gap, not by mimicking existing antivirals but by targeting the host signaling pathways that influenza exploits. The work is timely because severe influenza is often driven less by direct viral damage than by immune dysregulation, particularly the excessive cytokine production known as a cytokine storm, which contributes substantially to pulmonary pathology and mortality. Central to this process are key signaling cascades, including the Toll-like receptors (TLRs), the retinoic acid-inducible gene I (RIG-I) pathway, the mitogen-activated protein kinase (MAPK) cascades, and nuclear factor kappa B (NF-κB), which orchestrate antiviral responses through interferon and cytokine induction but can also drive immunopathology when aberrantly activated. The review, which surveyed literature from 2000 to 2025 and focused specifically on human IAV subtypes H1N1 and H3N2, argues that phytochemicals capable of both inhibiting viral replication and fine-tuning these pathways could serve as adjunctive therapies.

The evidence base begins at the level of innate immune recognition. TLR3, TLR7, and TLR8 detect viral RNA species generated during IAV replication, while TLR4 is activated indirectly by host-derived damage-associated molecular patterns released during infection-induced oxidative stress. TLR3 signaling through the adaptor TRIF activates TBK1 and IRF3 to induce IFN-β, yet overexpression of this interferon can itself contribute to cytokine storm and lung damage. Autopsy studies of fatal influenza cases have revealed prolonged TLR4 and MyD88 expression in lung tissue, illustrating that the TLR4/MyD88/NF-κB axis is a double-edged sword, essential for initiating antiviral immunity but potentially detrimental when dysregulated. Against this backdrop, several flavonoids have shown the ability to dampen TLR signaling. Quercetin reduced H1N1-induced cell death and activation of the TLR7/NF-κB p65 axis in a human bronchial epithelial co-culture model, while dihydromyricetin inhibited TLR3 and TRIF expression in infected lung epithelial cells, lowering pro-inflammatory cytokines such as CCL5, IP-10, and MIG.

Notably, dihydromyricetin also demonstrated genuine dual activity, reducing H1N1 and H3N2 plaque formation in a concentration-dependent manner with IC50 values between 11.67 and 23.33 micromolar, and binding the PB2 subunit of the viral polymerase in mini-replicon and surface plasmon resonance assays. Epigallocatechin gallate (EGCG), the major green tea catechin, targets an early stage of the replication cycle of both H1N1 and H3N2 with EC50 values of 5.7 to 17.3 micromolar, and oral administration reduced TLR4 and NF-κB protein levels in a mouse model of H9N2-induced lung injury. Curcumin, the polyphenol from turmeric, engaged TLR, MAPK, and NF-κB signaling concurrently while directly inactivating virions and blocking viral adsorption, and in mice it reduced lung viral titers, inflammatory cytokines, and mortality. Carvacrol, a phenolic compound from Mosla chinensis, downregulated TLR7, RIG-I, MyD88, and NF-κB in infected mice while reducing lung viral RNA load and pulmonary injury.

The RIG-I pathway presents a more nuanced picture. This cytosolic receptor detects viral RNA and, through the mitochondrial adaptor MAVS, activates IRF3 and NF-κB to drive interferon production and chemokine release, yet some studies suggest RIG-I-mediated recruitment of monocyte-derived dendritic cells can paradoxically enhance viral replication in infected lungs. The flavonoid apigenin suppresses this pathway by promoting RIG-I degradation: it disrupts the stabilizing interaction between RIG-I and the chaperone Hsp90α, enhancing ubiquitination by the E3 ligase RNF125 and proteasomal destruction of the receptor. This reduces the cell’s capacity to sense viral RNA and mount type I interferon responses, potentially limiting virus-induced inflammation, and apigenin also dose-dependently decreased expression of viral proteins NS1, NP, M1, and M2 in A549 cells. Similarly, the triterpenoid pterodontic acid reduced viral propagation by inhibiting viral ribonucleoprotein export while lowering RIG-I expression and downstream inflammatory mediators, and the phytosterol β-sitosterol disrupted RIG-I-mediated STAT1 activation, reducing IL-6, IL-8, TNF-α, and IP-10 production.

The MAPK pathway illustrates perhaps the most mechanistically interesting dimension of phytochemical action, because different compounds manipulate the same kinases in opposite directions with antiviral benefit in both cases. ERK1 signaling facilitates the nuclear export of viral ribonucleoprotein complexes, a critical step in the IAV replication cycle, so blocking ERK phosphorylation directly restricts propagation. The isoquinoline alkaloid berberine blocked H1N1 growth in macrophages and epithelial cells by interfering with ERK1-mediated vRNP nuclear export, while patchouli alcohol, a sesquiterpene from Pogostemonis herba, suppressed ERK1/2 activation with clear anti-influenza activity across multiple H1N1 strains. Conversely, EGCG and the compound DMO-CAP activate rather than inhibit MAPK cascades to enhance antiviral host programs: EGCG induces human β-defensin 3 and IFN-λ2 expression through p38, ERK, and JNK activation, while DMO-CAP triggers the Nrf2/HO-1 axis, which amplifies interferon-stimulated genes. This apparent paradox is resolved by recognizing that ERK inhibition disrupts pro-viral vRNP export whereas ERK activation promotes antiviral interferon induction, both mediated through the same kinase.

NF-κB adds a further layer of complexity because it serves the virus directly as well as the host. Beyond driving inflammatory gene expression, NF-κB signaling is required for viral genomic RNA synthesis and induces pro-apoptotic factors such as TRAIL and Fas ligand, which facilitate caspase-mediated nuclear export of vRNPs. Pterodontic acid exploits this dependency by inhibiting TRAIL and FasL expression, downregulating caspase-3/7 activity and impairing vRNP export. The flavonoid cirsimaritin reduced NF-κB p65 nuclear phosphorylation in infected THP-1 cells while suppressing multiple IAV subtypes with IC50 values of 5.8 to 11.1 micrograms per milliliter, and andrographolide, a diterpenoid from Andrographis paniculata, increased survival and reduced viral loads in a lethal H1N1 mouse model, with a combination study showing that pairing it with a viral entry inhibitor produced greater survival benefit than either compound alone. Among extracts, total flavonoids from Mosla scabra reduced lung viral load and inflammatory infiltration in mice more effectively than amantadine at the highest dose tested, and total flavones from Abelmoschus manihot suppressed viral RNA by day three post-infection in vivo.

The review is candid about the field’s weaknesses, and these are substantial. Many studies assess cytokine markers without measuring infectious viral titers, making it impossible to distinguish direct antiviral effects from indirect immunomodulation that merely creates a less permissive environment. Molecular binding targets are rarely identified, and the concentrations used in cell culture consistently exceed what is pharmacokinetically achievable in human lung tissue. Quercetin’s oral absorption in humans ranges from only 3 to 17 percent, with peak plasma levels rarely exceeding 1 to 2 micromolar, far below the 10 to 50 micromolar concentrations used in vitro. Berberine’s oral bioavailability falls below 5 percent due to P-glycoprotein efflux and hepatobiliary re-excretion, β-sitosterol’s is approximately 0.41 percent, and EGCG undergoes extensive gastrointestinal degradation. No pharmacokinetic data exist for any compound reviewed in bronchoalveolar lavage fluid or lung tissue, the primary site of replication, and safety concerns such as EGCG-associated hepatotoxicity at high supplemental doses and CYP enzyme inhibition that could affect co-prescribed drugs add further complications.

Despite these barriers, the review identifies a clear path forward. Because TLR and RIG-I signaling converge on shared components such as TRAF6, TAK1, and IRF3, compounds like miquelianin and carvacrol can engage multiple pathways through a single molecular target, functioning as modulators of an integrated innate immune network rather than selective inhibitors of discrete cascades. The authors recommend that molecular target identification through thermal shift assays and docking validation become standard practice, that pharmacokinetic evaluation be extended to respiratory tissue rather than plasma alone, that human airway organoid models serve as physiologically relevant intermediates, and that crude extracts undergo bioassay-guided fractionation to define active constituents. Clinical translation to date has involved complex extracts such as standardized black elderberry and Cistus incanus preparations, with limited or inconsistent results, and none of the defined phytochemicals discussed has yet entered a dedicated anti-influenza trial. If the recommended mechanistic rigor is adopted, the structural diversity and broad immunomodulatory activity of these plant compounds represent a genuine and underexploited opportunity for host-directed adjunctive therapy against a virus that continues to outpace the limited drugs available against it.

Subject of Research: Immunomodulatory and antiviral effects of phytochemicals on host signaling pathways during influenza A virus infection

Article Title: Dual Antiviral and Immunomodulatory Effects of Phytochemicals in Influenza A Virus Infection: Targeting Key Host Signaling Pathways

Article References: Chowdhury, D., Vanderven, H. A., Wangchuk, P., & Sarker, S. (2026). Dual Antiviral and Immunomodulatory Effects of Phytochemicals in Influenza A Virus Infection: Targeting Key Host Signaling Pathways. MicrobiologyOpen, 15(5), Article e70424. https://doi.org/10.1002/mbo3.70424

Image Credits: AI Generated

DOI: 10.1002/mbo3.70424

Keywords: influenza A virus, phytochemicals, TLR signaling, RIG-I, MAPK, NF-κB, cytokine storm, flavonoids, antiviral therapy, immunomodulation, host-directed therapy, natural products