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Metabolic reprogramming tips vaccinia virus infection outcomes by stabilizing interferon-g induced IRF1

ABSTRACT: Interferon (IFN) induced activities are critical, early determinants of immune responses and infection outcomes. A key facet of IFN responses is the upregulation of hundreds of mRNAs termed interferon-stimulated genes (ISGs) that activate intrinsic and cell-mediated defenses. While primary interferon signaling is well-delineated, other layers of regulation are less explored but implied by aberrant ISG expression signatures in many diseases in the absence of infection. Consistently, our examination of tonic ISG levels across uninfected human tissues and individuals revealed three ISG subclasses. As tissue identity and many comorbidities with increased virus susceptibility are characterized by differences in metabolism, we characterized ISG responses in cells grown in media known to favor either aerobic glycolysis (glucose) or oxidative phosphorylation (galactose supplementation). While these conditions over time had a varying impact on the expression of ISG RNAs, the differences were typically greater between treatments than between glucose/galactose. Interestingly, extended interferon-priming led to divergent expression of two ISG proteins: upregulation of IRF1 in IFN-g/glucose and increased IFITM3 in galactose by IFN-a and IFN-g. In agreement with a hardwired response, glucose/galactose regulation of interferon-g induced IRF1 is conserved in unrelated mouse and cat cell types. In galactose conditions, proteasome inhibition restored interferon-g induced IRF1 levels to that of glucose/interferon-g. Glucose/interferon-g decreased replication of the model poxvirus vaccinia at low MOI and high MOIs. Vaccinia replication was restored by IRF1 KO. In contrast, but consistent with differential regulation of IRF1 protein by glucose/galactose, WT and IRF1 KO cells in galactose media supported similar levels of vaccinia replication regardless of IFN- priming. Also associated with glucose/galactose is a seemingly second block at a very late stage in viral replication which results in reductions in herpes- and poxvirus titers but not viral protein expression. Collectively, these data illustrate a novel layer of regulation for the key ISG protein, IRF1, mediated by glucose/galactose and imply unappreciated subprograms embedded in the interferon response. In principle, such cellular circuitry could rapidly adapt immune responses by sensing changing metabolite levels consumed during viral replication and cell proliferation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE226242 | GEO | 2024/10/17

REPOSITORIES: GEO

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Project description:Evolutionarily successful poxviruses presented effective and diverse strategies to circumvent or overcome host defense mechanisms. Poxviruses encode many immunoregulatory proteins to evade host immunity for a productive infection and unique means of inhibiting DNA-sensing dependent type 1 interferon (IFN-I) responses is anticipated due to the biology of its dsDNA genome in nature and an exclusive cytoplasmic life cycle. We found the key DNA sensing inhibition by poxvirus infection was dominant during the early stage of poxvirus infection independent from DNA replication. In an effort of identifying poxvirus novel means to subdue antiviral proinflammatory responses e.g., IFN-I response, we focused on the function of one early gene that is the known host range determinant from the highly conserved poxvirus host range C7L superfamily, myxoma virus (MYXV) M062. Host range factors are unique features of poxviruses that determine the species and cell type tropism. Almost all sequenced mammalian poxviruses retain at least one homologue of the poxvirus host range C7L superfamily. In MYXV, a rabbit specific poxvirus, the dominant and broad-spectrum host range determinant of the C7L superfamily is the M062R gene. M062R gene product is essential for MYXV infection in almost all cells tested from different mammalian species and specifically inhibits the function of host Sterile α Motif Domain-containing 9 (SAMD9), as M062R-null (ΔM062R) MYXV causes abortive infection in a SAMD9-dependend manner. In this study we investigated the immunostimulatory property of the ΔM062R. We found that the replication-defective ΔM062R infection activated host DNA sensing pathway in the cGAS dependent fashion and knocking down SAMD9 expression attenuated proinflammatory responses. Moreover, transcriptomic analyses showed a unique feature of host gene expression landscape that is different from dsDNA stimulated inflammatory state. This study built a link between the anti-neoplastic SAMD9 and the regulation of the innate immune responses.

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Metabolic reprogramming tips vaccinia virus infection outcomes by stabilizing interferon-g induced IRF1

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