In the unrelenting battle between host cells and invading pathogens, the nuanced interplay of metabolism and immune defense is gaining unprecedented attention. A groundbreaking study led by Jin et al., recently published in Nature Microbiology, sheds light on a vital metabolic intermediary—oxaloacetate (OAA)—revealing its central role as a molecular sentinel that orchestrates the innate immune response against influenza virus infection. This pioneering research not only deciphers the intracellular signaling cascade initiated by OAA but also positions this metabolite as a potential therapeutic agent bolstering antiviral immunity across a spectrum of viral threats.
Metabolic processes within cells have long been recognized for their foundational role in providing energy and biosynthetic precursors; however, their direct involvement in modulating immune functions has remained elusive. Jin and colleagues addressed this knowledge gap by deploying a sophisticated approach combining pharmacological inhibition with comprehensive metabolomic profiling. Their analysis pinpointed the pivotal metabolic pathway involving oxaloacetate, a key tricarboxylic acid (TCA) cycle intermediate, as integrally linked to the host’s defense strategy against influenza virus. The study propounds that variations in intracellular OAA concentrations dynamically influence innate immune signaling, thereby dictating cellular fate during viral invasion.
At the molecular forefront of this defense is cytosolic malate dehydrogenase 1 (MDH1), an enzyme traditionally recognized for catalyzing the reversible oxidation of malate to oxaloacetate in the cytoplasm. Intriguingly, Jin et al. report that MDH1 transcends its metabolic enzyme role to act as a metabolic sensor. Elevated cytosolic OAA fosters the dimerization of MDH1, which then serves as a scaffold platform critical for recruiting the transcription factor ETS2. This scaffolding function is essential for subsequent post-translational modification events that ultimately potentiate antiviral transcriptional programs.
The recruited ETS2 transcription factor undergoes phosphorylation at serine residue 313 by the serine/threonine kinase TAOK1, an event indispensable for activating ETS2’s nuclear translocation. Once inside the nucleus, phosphorylated ETS2 facilitates the transcriptional upregulation of the gene encoding TBK1, a pivotal kinase orchestrating the induction of type I interferons—key cytokines that prime the antiviral state. This molecular relay, initiated by OAA sensing, highlights a direct biochemical linkage between a metabolic intermediate and the antiviral innate immune axis.
The importance of this signaling axis becomes starkly evident when considering the functional consequences of perturbing the pathway. The authors demonstrate that exogenous supplementation with OAA substantially enhances antiviral defenses, conferring robust protection not only against influenza virus strains but also suggesting broad-spectrum antiviral potential. Conversely, genetic disruption of ATP citrate lyase (Acly)—an enzyme upstream in the metabolic pathway supplying cytosolic acetyl-CoA—results in diminished OAA availability, significantly undermining the host’s antiviral capacity and increasing vulnerability to lethal H1N1 influenza challenge in murine models.
This coupling between cellular metabolism and immune signaling exemplifies an emerging paradigm in immunometabolism, where metabolites transcend their canonical metabolic roles to serve as dynamic signaling entities capable of modulating transcriptional landscapes. The elucidation of OAA as a metabolic signal integrator reveals an elegant mechanism through which host cells calibrate their antiviral responses contingent on intracellular nutrient status and metabolic fluxes.
From a mechanistic standpoint, the discovery that MDH1 functions dually as an enzyme and a signaling scaffold protein underscores an evolutionary adaptation to streamline cellular responses. The dual functionality enables rapid sensing of metabolite levels and conversion of metabolic signals into nuclear gene expression programs, thereby facilitating timely antiviral defenses without necessitating de novo protein synthesis or extensive signaling intermediates.
Furthermore, the phosphorylation of ETS2 by TAOK1 at a precise serine residue highlights the intricate layers of regulation governing transcription factor activity. This post-translational modification not only activates ETS2 but also showcases how kinase signaling pathways intersect with metabolic cues to fine-tune immune effector gene expression. The consequence is a robust amplification of TBK1 expression, setting the stage for an enhanced type I interferon response critical for antiviral immunity.
In vivo experiments with Acly-deficient mice amplify the physiological relevance of these findings. Deficiency in Acly-mediated acetyl-CoA production and downstream OAA levels precipitates a failure to mount effective antiviral responses, culminating in heightened morbidity and mortality following influenza virus infection. These results potentiate the therapeutic promise of metabolic modulation strategies aimed at restoring or enhancing OAA availability to augment host immunity.
Intriguingly, OAA supplementation in vitro and in animal models bolsters antiviral defenses, suggesting a paradigm shift where metabolic intermediates could be repurposed as immune adjuvants or antiviral therapeutics. This approach could complement existing antiviral treatments and vaccines, potentially overcoming issues of viral resistance by leveraging host metabolic pathways to tip the balance in favor of immune clearance.
The implications of this study extend well beyond influenza virus. Given the conserved nature of metabolic enzymes and the centrality of type I interferons in antiviral immunity, the OAA sensing pathway may represent a universal mechanism harnessed by host cells to detect and respond to diverse viral infections. Future research may elucidate whether similar mechanisms operate in other viral contexts, possibly redefining the metabolic-immune interface as a fertile ground for antiviral drug discovery.
The integration of metabolomics with molecular biology and immunology techniques in this research underscores the power of interdisciplinary approaches to unravel complex biological networks. Jin and colleagues’ work champions a systems biology perspective, revealing how metabolite signaling informs and modulates the immune landscape. The discovery of OAA as a nexus of metabolism and immunity lays a foundational framework for subsequent investigations into metabolic regulation of host-pathogen interactions.
In summary, the study by Jin et al. heralds a new era in understanding innate immunity, where metabolites are not passive players but active determinants of cellular fate during viral infection. By delineating the OAA-MDH1-ETS2-TAOK1-TBK1 axis, this research elucidates a previously uncharted signaling pathway that bridges metabolism and immune defense, offering novel targets for antiviral therapeutics and deepening our grasp of host-pathogen dynamics.
As respiratory viruses such as influenza continue to pose significant global health challenges, innovative strategies grounded in molecular understanding of host defense will be paramount. The identification of oxaloacetate as a critical metabolite signal presents an exciting avenue for enhancing antiviral immunity through targeted metabolic interventions, potentially revolutionizing prophylactic and therapeutic modalities against influenza and other viral pathogens.
This study not only enriches the fundamental biological narrative of immunometabolism but also conveys a hopeful message: harnessing endogenous metabolic signals can empower the immune system’s fight against viral invaders, expanding the arsenal of tools available to combat infectious diseases.
Subject of Research: Innate immune antiviral defense mechanisms linked to metabolic pathways in influenza virus infection.
Article Title: Oxaloacetate sensing promotes innate immune antiviral defence against influenza virus infection.
Article References:
Jin, S., He, X., Wang, Z. et al. Oxaloacetate sensing promotes innate immune antiviral defence against influenza virus infection. Nat Microbiol (2025). https://doi.org/10.1038/s41564-025-02107-3
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