In a recent study published in Pathogens, researchers examined how the innate immune system detects filoviruses.
Study: Filovirus: innate immunity, inflammatory cell death and cytokines. Image credit: ffikretow/Shutterstock
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Filoviruses are single-stranded, negative-sense ribonucleic acid (RNA) viruses. The best-known human-infecting filoviruses are marburgviruses and ebolaviruses. The infection can cause life-threatening symptoms such as inflammation, tissue destruction and hemorrhagic fever, with fatality rates of up to 90%. The innate immune system is an important first line of defense against pathogens such as filoviruses. However, filoviruses can influence the host’s inflammatory response and the death of innate immune cells, resulting in an abnormal immunological response.
Sensory components of the innate immune system
The innate immune system has developed the ability to recognize and react to danger or damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) to protect against infection and cellular disruption. Germline-encoded pattern recognition receptors (PRRs) such as transmembrane-like receptors (TLRs), C-type lectin receptors (CLRs), NOD-type receptors (NLRs), and gene I-inducible cytoplasmic retinoic acid (RIG-). Type I receptors (RLRs) detect DAMPs and PAMPs. When activated, PRRs trigger innate immune reactions, including the generation of proinflammatory cytokines and interferons (IFNs) and the activation of innate immune cell death to eliminate the infected or injured cell. These steps are essential for the initiation of a comprehensive immune response.
Toll-like receptors (TLRs)
TLRs comprise a well-defined category of PRRs that are expressed primarily among innate immune cells such as macrophages, dendritic cells, and mast cells. However, TLRs are also expressed by non-immune cell types such as fibroblasts and epithelial cells. TLRs can also use the Toll/interleukin (IL)-1 receptor (TIR) containing adapter interferon-β (TRIF), the Toll/IL-1 receptor domain-containing adapter protein ( TIR) cytosolic (TIRAP) and TRIF-related adapter molecule (TRAM). MyD88, which is a TIRAP, activates transcription factors along with IL-1 receptor-associated kinase 1 (IRAK1), IRAK2, and IRAK4, along with transforming growth factor-activated kinase 1 (TAK1), receptor-associated of tumor necrosis factor (TNFR). factor 6 (TRAF6) and the IKK complex. In addition, the TRAF family member-associated activator of NF-kappa-B (TANK) binding kinase 1 (TBK1) can activate other transcription factors.
IFN signaling and RIG-I-like receptors
Some RLRs are observed in the nucleus, although most RLRs are found in the cytoplasm. RIG-I, laboratory of genetics and physiology 2 (LPG2) and melanoma differentiation-associated factor 5 (MDA5) are the three RLRs discovered in humans. MDA5 and RIG-I possess two N-terminal caspase activation and recruitment domains (CARDs), one C-terminal domain (CTD), and two DExD/H box RNA helicase domains, whereas LGP2 lacks a CARD. In response to infection, MDA5 and RIG-I recognize viral RNA and release IFN. RIG-I mainly identifies short single-stranded (ss) RNA and double-stranded (ds) RNA, but MDA5 selectively detects long dsRNA. In addition, RIG-I responds effectively to negative-strand viruses, whereas MDA5 effectively responds to positive-strand viruses.
Death of innate immune cells
pyroptosis
Pyroptosis is a lytic form of innate immune cell death mediated by caspase-1. Caspase-1 is triggered in response to activation by DAMPs or PAMPs and cleaves the pro-inflammatory cytokines IL-18 and IL-1-beta together with the pore-forming protein GSDMD. Caspase-1, and consequently pyroptosis, can be induced by creating inflammasomes, which are multiprotein complexes created against a range of stimuli and homeostatic disturbances. Inflammasomes consist of a PRR sensor, caspase-1, and a spring-like protein that includes an apoptosis-associated adapter protein (ASC) CARD.
Apoptosis
Apoptosis is a crucial cell death process to regulate cellular homeostasis. It does not destroy cells or release intracellular substances, but instead causes generalized membrane ruffling and contraction. Both intrinsic and extrinsic mechanisms can initiate apoptosis. In response to mitochondrial alterations, intrinsic apoptosis is characterized by the development of an apoptosome, which includes apoptotic peptidase-activating factor 1 (APAF1), cytochrome c, and caspase-9.
necroptosis
Necroptosis is a type of lytic innate immune cell death mediated by mixed lineage kinase domain-like pseudokinase (MLKL) and receptor-interacting protein kinase 3 (RIPK3) due to stimulation of TLRs, IFN signaling pathways and death receptors. The response of necroptosis to TNF-α is well characterized. During TNF-α-induced necroptosis, a necrosome composed of phosphorylated RIPK3, phosphorylated RIPK1, Fas-associated death domain protein (FADD), and TNFR1-associated death domain protein (TRADD) is formed; more particularly, the physical interaction between RIPK3 and RIPK1 induces the oligomerization and phosphorylation of MLKL, which creates pores in the membrane and initiates cell death. However, necroptosis is hindered in the vicinity of caspase-8; therefore, necroptosis is often considered a backup to other cell death processes. Caspase-8 cleaves RIPK1, preventing its interaction with RIPK3, inhibiting necroptosis and promoting apoptosis.
Overall, the study results showed that filoviruses have different effects on the innate immune system depending on the stage of infection. Understanding the molecular background of how filovirus proteins interact with the host’s innate immune components will improve the medical community’s ability to develop effective therapeutics, determine when to administer them, and reduce the high mortality rate attributed to this group of RNA viruses.