Filoviruses: Innate Immunity, Inflammatory Cell Death, and Cytokines

Abstract

Filoviruses are a group of single-stranded negative sense RNA viruses. The most well-known filoviruses that affect humans are ebolaviruses and marburgviruses. During infection, they can cause life-threatening symptoms such as inflammation, tissue damage, and hemorrhagic fever, with case fatality rates as high as 90%. The innate immune system is the first line of defense against pathogenic insults such as filoviruses. Pattern recognition receptors (PRRs), including toll-like receptors, retinoic acid-inducible gene-I-like receptors, C-type lectin receptors, AIM2-like receptors, and NOD-like receptors, detect pathogens and activate downstream signaling to induce the production of proinflammatory cytokines and interferons, alert the surrounding cells to the threat, and clear infected and damaged cells through innate immune cell death. However, filoviruses can modulate the host inflammatory response and innate immune cell death, causing an aberrant immune reaction. Here, we discuss how the innate immune system senses invading filoviruses and how these deadly pathogens interfere with the immune response. Furthermore, we highlight the experimental difficulties of studying filoviruses as well as the current state of filovirus-targeting therapeutics.

Keywords: ALRs; CLRs; NLRs; PANoptosis; PANoptosome; RIG-I; RLRs; RNA virus; TLRs; apoptosis; caspase; cell death; ebolavirus; filovirus; host–pathogen interactions; inflammasome; inflammation; innate immunity; interferon; marburgvirus; necroptosis; pattern recognition receptors; pyroptosis.

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.