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Review
. 2020 Jun 7;26(21):2781-2791.
doi: 10.3748/wjg.v26.i21.2781.

Innate immune recognition and modulation in hepatitis D virus infection

Stephanie Jung  1 , Sebastian Maximilian Altstetter  1 , Ulrike Protzer  1
Affiliations
Review

Innate immune recognition and modulation in hepatitis D virus infection

Stephanie Jung et al. World J Gastroenterol. .

Abstract

Hepatitis D virus (HDV) is a global health threat with more than 15 million humans affected. Current treatment options are largely unsatisfactory leaving chronically infected humans at high risk to develop liver cirrhosis and hepatocellular carcinoma. HDV is the only human satellite virus known. It encodes only two proteins, and requires Hepatitis B virus (HBV) envelope protein expression for productive virion release and spread of the infection. How HDV could evolve and why HBV was selected as a helper virus remains unknown. Since the discovery of Na+-taurocholate co-transporting polypeptide as the essential uptake receptor for HBV and HDV, we are beginning to understand the interactions of HDV and the immune system. While HBV is mostly regarded a stealth virus, that escapes innate immune recognition, HBV-HDV coinfection is characterized by a strong innate immune response. Cytoplasmic RNA sensor melanoma differentiation antigen 5 has been reported to recognize HDV RNA replication and activate innate immunity. Innate immunity, however, seems not to impair HDV replication while it inhibits HBV. In this review, we describe what is known up-to-date about the interplay between HBV as a helper and HDV's immune evasion strategy and identify where additional research is required.

Keywords: Hepatitis B virus; Hepatitis D virus; Immune evasion; Immunosuppression; Innate immunity; Pathogen-associated molecular pattern molecules.

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Conflict of interest statement

Conflict-of-interest statement: The authors declare no conflict of interests concerning the content of this article.

Figures

Figure 1
Figure 1
RNA-sensing by pattern recognition receptors. Intracellular pathogenic RNA is sensed by endosomal Toll-like receptors (TLRs) and retinoic acid inducible gene I (RIG I) like receptors. TLR3 detects double-stranded RNA (dsRNA), whereas TLR7 and TLR8 detect single-stranded RNA in a sequence-specific manner and signal via their Toll/interleukin-1 receptor homology domains. RIG I and melanoma differentiation antigen 5 bind cytoplasmatic dsRNA structures and activate conformational changes leading to the exposure of Caspase activation and recruitment domains (CARDs). Signalling-deficient laboratory of genetics and physiology 2 only consists of a helicase and a C-terminal domain and functions as an accessory receptor. This enables interaction of CARDs with mitochondrial antiviral signalling protein (MAVS), resulting in subsequent signalling cascades that release nuclear factor “kappa-light-chain-enhancer” of activated B-cells inducing a proinflammatory cytokine response. MAVS also activates interferon regulatory factor 3/7 signalling and signal transducers and activators of transcription 1/2-dependent type I interferon production and antiviral state with upregulation of interferon-stimulated genes in the host cell. TLRs: Toll-like receptors; RIG I: Retinoic acid inducible gene I; LGP2: Laboratory of genetics and physiology 2; ssRNA: Single-stranded RNA; CTD: C-terminal domain; RLRs: RIG I like receptors; NF-κB: Nuclear factor “kappa-light-chain-enhancer” of activated B-cells; MAVS: Mitochondrial antiviral signalling protein; TIR: Toll/interleukin-1 receptor; dsRNA: Double-stranded RNA; MDA5: Melanoma differentiation antigen 5; CARDs: Caspase activation and recruitment domains; IRF: Interferon regulatory factor; STAT1/2: Signal transducers and activators of transcription 1/2; Type I IFN: Type I interferon; ISGs: Interferon-stimulated genes.
Figure 2
Figure 2
Immune evasion and immunomodulation in hepatitis D virus infection. Pattern recognition of hepatitis D virus RNA was reported to be both inhibited by hepatitis B virus (HBV) specific proteins like HBV X protein, HBV envelope proteins, HBV polymerase as well as the hepatitis delta antigen and in particular its large variant. Inhibitions of major pathways are indicated with red flat arrows, activation of cytokine response is indicated in green pointed arrows. HBV: Hepatitis B virus; HDV: Hepatitis D virus; HBx: Hepatitis B virus X protein; HBV env: Hepatitis B virus envelope proteins; HBV pol: Hepatitis B virus polymerase; HDAg: Hepatitis delta antigen; L-HDAg: Large hepatitis delta antigen; TLRs: Toll-like receptors; RIG I: Retinoic acid inducible gene I; LGP2: Laboratory of genetics and physiology 2; ssRNA: Single-stranded RNA; CTD: C-terminal domain; RLRs: RIG I like receptors; NF-κB: Nuclear factor “kappa-light-chain-enhancer” of activated B-cells; MAVS: Mitochondrial antiviral signalling protein; TIR: Toll/interleukin-1 receptor; dsRNA: Double-stranded RNA; MDA5: Melanoma differentiation antigen 5; CARDs: Caspase activation and recruitment domains; IRF: Interferon regulatory factor; STAT1/2: Signal transducers and activators of transcription 1/2; Type I IFN: Type I interferon; ISGs: Interferon-stimulated genes.
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