Figure 1. Filovirus genetic organization and the innate immune sensors and their downstream cell death signaling pathways. (A) Schematic illustration of Ebola virus and Marburg virus genomes. NP, nucleoprotein; VP, viral protein; GP, glycoprotein; sGP, secreted glycoprotein; L, RNA-dependent RNA polymerase. (B) Pathogenic insults such as filovirus infection can activate PRRs such as TLRs, RLRs, CLRs, NLRs, and ALRs. Activation of PRRs, as well as intracellular stressors, induces inflammation and innate immune cell death pathways such as pyroptosis, apoptosis, necroptosis, and PANoptosis. ALR, absent in melanoma 2 (AIM2)-like receptor; APAF-1, apoptotic protease activating factor 1; ASC, apoptosis-associated speck-like protein containing a CARD; CARD, caspase activation and recruitment domain; CASP, caspase; cIAP, cellular inhibitor of apoptosis protein; CLR, C-type lectin receptor; DAMPs, damage-associated molecular patterns; DISC, death-inducing signaling complex; FADD, fas-associated death domain; GSDMD, gasdermin D; IKK, inhibition of nuclear factor-κB kinase; IRAK, interleukin-1 receptor-associated kinase; IRF, interferon regulatory factor; MAVS, mitochondrial antiviral signaling protein; MDA5, melanoma differentiation-associated protein 5; MLKL, mixed lineage kinase domain-like pseudokinase; NLR, NOD-like receptor; PAMPs, pathogen-associated molecular patterns; PRR, pattern recognition receptor; RIG-I, retinoic acid-inducible gene-I, RLR, RIG-I-like receptor; RIPK, receptor-interacting serine/threonine-protein kinase; TAK1, transforming growth factor-beta-activated kinase 1; TLR, toll-like receptor; TNFR, tumor necrosis factor receptor; TRAF, tumor necrosis factor receptor-associated factor; TRADD, tumor necrosis factor receptor 1-associated death domain protein; TRIF, TIR-domain-containing adapter-inducing interferon-β; ZBP1, Z-DNA-binding protein 1. Figure created with Biorender.

Figure 1. Filovirus genetic organization and the innate immune sensors and their downstream cell death signaling pathways. (A) Schematic illustration of Ebola virus and Marburg virus genomes. NP, nucleoprotein; VP, viral protein; GP, glycoprotein; sGP, secreted glycoprotein; L, RNA-dependent RNA polymerase. (B) Pathogenic insults such as filovirus infection can activate PRRs such as TLRs, RLRs, CLRs, NLRs, and ALRs. Activation of PRRs, as well as intracellular stressors, induces inflammation and innate immune cell death pathways such as pyroptosis, apoptosis, necroptosis, and PANoptosis. ALR, absent in melanoma 2 (AIM2)-like receptor; APAF-1, apoptotic protease activating factor 1; ASC, apoptosis-associated speck-like protein containing a CARD; CARD, caspase activation and recruitment domain; CASP, caspase; cIAP, cellular inhibitor of apoptosis protein; CLR, C-type lectin receptor; DAMPs, damage-associated molecular patterns; DISC, death-inducing signaling complex; FADD, fas-associated death domain; GSDMD, gasdermin D; IKK, inhibition of nuclear factor-κB kinase; IRAK, interleukin-1 receptor-associated kinase; IRF, interferon regulatory factor; MAVS, mitochondrial antiviral signaling protein; MDA5, melanoma differentiation-associated protein 5; MLKL, mixed lineage kinase domain-like pseudokinase; NLR, NOD-like receptor; PAMPs, pathogen-associated molecular patterns; PRR, pattern recognition receptor; RIG-I, retinoic acid-inducible gene-I, RLR, RIG-I-like receptor; RIPK, receptor-interacting serine/threonine-protein kinase; TAK1, transforming growth factor-beta-activated kinase 1; TLR, toll-like receptor; TNFR, tumor necrosis factor receptor; TRAF, tumor necrosis factor receptor-associated factor; TRADD, tumor necrosis factor receptor 1-associated death domain protein; TRIF, TIR-domain-containing adapter-inducing interferon-β; ZBP1, Z-DNA-binding protein 1. Figure created with Biorender.

Figure 2. Illustration of filovirus modulation of the RLR signaling pathway. A typical RLR-mediated immune response to viral RNA activates RIG-I and MDA5. Downstream of RLR activation, IRF3 and IRF7 are phosphorylated through a TBK1/IKK-dependent pathway. The phosphorylation of these transcription factors leads to the production of IFNs, which stimulate the JAK/STAT pathway and allow for the transcription of ISGs. Filoviruses can disrupt this innate immune pathway largely through Ebola virus VP35 (eVP35) and Marburg virus VP35 (mVP35). Both forms of VP35 can directly bind viral RNA, which prevents its recognition by RLR sensors, disrupts RIG-I activation by targeting PACT, acts as an alternate substrate for IKKɛ and TBK1, and prevents the phosphorylation of IRF3. In addition, VP35 can cause sumoylation of IRF7 to inhibit its transcription of type I IFNs. eVP24 inhibits type III IFN secretion through an importin-α-dependent nuclear mechanism and inhibits the translocation of phosphorylated STAT1. mVP40 inhibits JAK1-mediated signaling. IFN, interferon; ISG, IFN-stimulated gene; IKKɛ, inhibitor of nuclear factor kappa-B kinase subunit epsilon; IRF, interferon regulatory factor; ISGF3, ISG, interferon stimulated gene factor 3; ISRE, interferon-sensitive response element; JAK, tyrosine-protein kinase; MAVS, mitochondrial antiviral-signaling protein; MDA5, melanoma differentiation-associated protein 5; PACT, protein kinase R (PKR) activator; RIG-I, retinoic acid-inducible gene-I; STAT, signal transducer and activator of transcription; TBK1, TANK-binding kinase 1; VP24, viral protein 24; VP35, viral protein 35; VP40, viral protein 40. Figure created with Biorender.

Figure 2. Illustration of filovirus modulation of the RLR signaling pathway. A typical RLR-mediated immune response to viral RNA activates RIG-I and MDA5. Downstream of RLR activation, IRF3 and IRF7 are phosphorylated through a TBK1/IKK-dependent pathway. The phosphorylation of these transcription factors leads to the production of IFNs, which stimulate the JAK/STAT pathway and allow for the transcription of ISGs. Filoviruses can disrupt this innate immune pathway largely through Ebola virus VP35 (eVP35) and Marburg virus VP35 (mVP35). Both forms of VP35 can directly bind viral RNA, which prevents its recognition by RLR sensors, disrupts RIG-I activation by targeting PACT, acts as an alternate substrate for IKKɛ and TBK1, and prevents the phosphorylation of IRF3. In addition, VP35 can cause sumoylation of IRF7 to inhibit its transcription of type I IFNs. eVP24 inhibits type III IFN secretion through an importin-α-dependent nuclear mechanism and inhibits the translocation of phosphorylated STAT1. mVP40 inhibits JAK1-mediated signaling. IFN, interferon; ISG, IFN-stimulated gene; IKKɛ, inhibitor of nuclear factor kappa-B kinase subunit epsilon; IRF, interferon regulatory factor; ISGF3, ISG, interferon stimulated gene factor 3; ISRE, interferon-sensitive response element; JAK, tyrosine-protein kinase; MAVS, mitochondrial antiviral-signaling protein; MDA5, melanoma differentiation-associated protein 5; PACT, protein kinase R (PKR) activator; RIG-I, retinoic acid-inducible gene-I; STAT, signal transducer and activator of transcription; TBK1, TANK-binding kinase 1; VP24, viral protein 24; VP35, viral protein 35; VP40, viral protein 40. Figure created with Biorender.

Table 1. Filovirus proteins and their cellular targets.

Table 1. Filovirus proteins and their cellular targets.

Viral ProteinCellular TargetOutcomeReferenceseVP24Karyopherin α1Blocks nuclear translocation of phosphorylated STAT1[89,90,91,94]Importin α, othersInhibits IFN-λ1 production[79,93]eVP35
mVP35Viral dsRNAPrevents RLR-mediated recognition of virus[84,85]PACTPrevents RIG-I activation[86,87]IKKε, TBK1Decreases IRF3 phosphorylation[88]IRF7Drives sumoylation of IRF7[88]mVP40JAK1, STAT1/2, TYK2Inhibits JAK/STAT phosphorylation and nuclear translocation of STAT1/2[92]