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Microbiology and Biotechnology Letters

Review(총설)

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Molecular and Cellular Microbiology (MCM)  |  Host-Microbe Interaction and Pathogenesis

Microbiol. Biotechnol. Lett. 2024; 52(2): 105-113

https://doi.org/10.48022/mbl.2405.05008

Received: June 2, 2024; Accepted: June 5, 2024

The Innate Immune Viral Sensors and Their Functional Crosstalk

Ji-Seung Yoo1,2*

1KNU Institute for Microorganisms, 2School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Republic of Korea

Correspondence to :
Ji-Seung Yoo,        jisyoo@knu.ac.kr

Abstract

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The precise and elaborate regulation of signaling cascades by diverse cytoplasmic and endosomal antiviral sensors is crucial for maintaining immune homeostasis and defending against viral pathogens. Receptors and enzymes that recognize foreign nucleic acids play a pivotal role in inducing antiviral interferon programs, serving as the first line of defense against various DNA and RNA viruses. Recent research has increasingly highlighted the crosstalk between nucleic acid sensors in detecting multiple virus invasions, resulting in amplified antiviral signals and compensating for any missing roles. This review provides an update on recent findings regarding the interplay of RNA sensors for DNA virus recognition.

Keywords: Antiviral innate immunity, RNA virus sensors, DNA virus sensors, interferon, inflammation, host-microbe interaction

Graphical Abstract


Introduction

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The distinction and protection of ‘self’ from ‘non-self’ are essential for maintaining life. In multicellular organisms, protection against harmful agents is accomplished through two primary mechanisms: biological barriers, such as the integumentary system comprising skin and mucosal linings, and the intricate immune response orchestrated by the host. In various organisms, including humans, the latter can be categorized into innate and adaptive immunity. Innate immunity, playing alongside biological barriers, serves as the primary defense against pathogen invasion [1].

The activation of the innate immune system is triggered by the recognition of detrimental substances, termed pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), by germline-encoded pattern recognition receptors (PRRs). Among PRRs, cellular receptors that recognize foreign nucleic acids plays a crucial role in antiviral innate immune responses [2].

Upon recognition, cellular defense mechanisms promptly initiate the elimination of invading viruses by initiating the interferon (IFN) and proinflammatory cytokine production. Conversely, viral pathogens have developed numerous strategies to circumvent the host's sensing mechanisms in response to these stringent conditions. Therefore, viruses and their hosts are continually adapting novel strategies to outcompete each other in this life-or-death evolutionary battle [3, 4].

For strategic advantage in this battle, host cells employ various innate immune sensors to cooperatively counteract a broad spectrum of pathogens. One key strategy involves the crosstalk between viral DNA and RNA sensors, which allows these sensors to complement each other and synergistically enhance the overall antiviral response.

In this minireview, current understanding regarding host strategies for detecting DNA virus invasion via PAMP RNA sensors will be updated. The interplay between multiple viral sensors and enzymes including RNase and RNA polymerase will be discussed.

Cytosolic PAMP RNA Sensors

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RIG-I-Like Receptors

Two decades ago, Fujita and colleagues identified the RIG-I-like receptors (RLRs) as the ‘long-sought’ cytoplasmic sensors for RNA viruses [5, 6]. RLRs comprise three proteins: Retinoic acid-inducible gene I (RIG-I), Melanoma differentiation-associated protein 5 (MDA5), and Laboratory of Genetics and Physiology 2 (LGP2). They share a conserved structural framework, characterized by an N-terminal caspase activation and recruitment domain (CARD), a central DExD/H-box RNA helicase domain, and a C-terminal regulatory domain (CTD). RLRs employ their RNA helicase domain to interact with RNA ligands [7].

At their N-terminus, both RIG-I and MDA5 are characterized by tandem caspase recruitment domains (CARDs), which serve to transmit antiviral signals to downstream adapter molecules. These adapter molecules include mitochondrial antiviral signaling protein (MAVS), also known as IFN-β promoter stimulator 1 (IPS-1), virus-induced signaling adaptor (VISA), or caspase activation recruitment domain adaptor inducing IFN-β (CARDIF) [8]. In contrast, LGP2 lacks a CARD domain, thus assuming a regulatory role in antiviral responses [7]. While oligomerization of RLRs is essential for initiating the antiviral signal, the underlying molecular mechanisms governing the activation and regulation of antiviral responses exhibit distinct features. Specifically, while the CTD plays a pivotal role in facilitating RIG-I activation, the helicase domain of MDA5 appears indispensable for eliciting the antiviral response [9, 10]. Given these discrepant activation patterns, the authentic RNA ligands recognized by these receptors also vary.

For instance, RIG-I recognizes multiple molecular patterns, including the 5'-di- or tri-phosphate moiety of RNA ligands [11, 12]. Additionally, RIG-I specifically identifies the panhandle structure, characterized by partial double-stranded (ds) RNA, as a ligand [13]. Notably, RIG-I demonstrates a preference for relatively short dsRNA molecules (approximately less than 300 nucleotides), while MDA5 displays an affinity for longer (> 1 kilobase) and highly complex structured RNA species [14]. This diverse sensing capabilities of RLRs enable them to serve both individual and collaborative roles in detecting various RNA virus invasions (Fig. 1).

Figure 1.Cytosolic and endosomal RNA sensing pathway. Cytosolic RNA sensors, RLRs, OAS, and PKR, and the endosomal RNA receptors, TLR3 and TLR7, are described. Upon activation by various dsRNA species, RLRs trigger antiviral IFN signaling pathways. OAS synthesizes 2'-5' oligoadenylates, which serve as secondary messengers that activate RNase L, thereby initiating innate immune responses. PKR, when activated by dsRNA sensing, induces a global translation shutoff in infected cells. TLR3 and TLR7 recognize RNA species within the endosome. TLR3 is specifically activated by dsRNA, while TLR7 senses ssRNA. Upon activation, TLR3 and TLR7 initiate cellular signaling pathways that lead to the production of IFNs and proinflammatory cytokines.

Upon activation, RIG-I undergoes multimerization facilitated by its CARD domain, while MDA5 forms a fiber-like polymer on dsRNA, with intermittent incorporation of LGP2 accelerating MDA5 fiber formation [9, 10]. In the activated state, both RIG-I and MDA5 transmit antiviral signals to downstream adapter molecules and kinases. MAVS, activated by CARD-CARD interaction via RIG-I and MDA5, serves as a critical platform for the activation of various kinases, including IKKε and TBK1. Subsequently, these kinases phosphorylate transcription factors such as IRF3, IRF7, and NF-κB, thereby initiating the transcription of type I and type III IFN genes. Ultimately, the generated IFNs initiate a cellular antiviral program by engaging specific IFN receptors, including IFN-alpha/beta receptor 1 (IFNAR1), IFNAR2, and interleukin (IL)-10 receptor 2 (IL-10R2), which operate through both autocrine and paracrine signaling pathways [15].

Protein Kinase R

Protein Kinase R (PKR) is a serine/threonine protein kinase recognized for its pivotal role in the innate immune response by detecting cytosolic dsRNA, a representative PAMP RNA generated during viral replication. Extensive research has further elucidated the multifaceted functions of PKR, highlighting its involvement in diverse cellular signaling pathways, including the regulation of mRNA transcription, cell proliferation, and programmed cell death [16].

Structurally, PKR consists of two distinct functional domains: an N-terminal tandem dsRNA-binding domain (dsRBD1 and dsRBD2) and a C-terminal kinase domain [17]. Binding of dsRNA triggers a conformational alteration in PKR, facilitating dimerization and autophosphorylation at multiple residues, notably threonine 446 and 451 within the activation loop of the kinase domain. This phosphorylation event enables PKR to subsequently phosphorylate downstream substrates involved in various cellular pathways.

In viral infections, PKR functions as a pivotal sentinel of the host's innate antiviral defense mechanism, exerting inhibitory effects on viral replication and facilitating viral clearance. Upon activation, PKR phosphorylates downstream targets, notably translation initiation factor eIF2α, leading to the attenuation of protein synthesis and the initiation of cellular stress responses, including apoptosis and autophagy (Fig. 1). Furthermore, recent investigations have unveiled PKR's involvement in the IFN signaling pathway by inducing the formation of antiviral stress granules (avSGs) [4, 18−20]. Within these structures, a multitude of antiviral proteins, such as RLRs, PKR itself, oligoadenylate synthetases (OASs), ribonuclease L (RNase L), tripartite motif-containing protein 25 (TRIM25), and PAMP viral RNA ligands, engage in intricate interactions. Additionally, PKR regulates transcription factors, kinases, and other signaling molecules implicated in inflammation and metabolism, thus underscoring its profound impact on cellular physiology [21].

2'-5'-Oligoadenylate Synthetase (OAS)

The OAS family genes, known to be IFN-inducible, comprise four proteins, OAS1, OAS2, OAS3, and OASL, the OAS protein family displays structural heterogeneity. While OAS1 possesses a single catalytically functional OAS domain, OAS2 and OAS3 contain intrinsic OAS domains in addition to duplicated ones (OAS2 harboring an extra OAS domain and OAS3 possessing two additional OAS domains), all lacking catalytic activity. Similarly, OASL (OAS-like) carries a single but enzymatically inactive OAS domain, complemented by a distinct ubiquitinlike (UBL) domain at its C-terminus. This unique feature confers a specialized antiviral function to OASL [22].

OAS proteins initiate their antiviral functions by recognizing cytoplasmic viral dsRNA. Similar to PKR, OAS1 initially exists as an inactive monomer. However, upon activation induced by viral dsRNA, OAS1 undergoes oligomerization, resulting in the formation of a functional tetrameric structure. This tetramer catalyzes the synthesis of unique 2'-5'-linked oligoadenylate (2-5A) molecules, which serve as secondary messengers that activate RNase L [23]. Activated RNase L subsequently degrades both cellular and viral RNA, thereby hindering viral replication [24]. Furthermore, the cleaved RNA fragments generated by RNase L serve as ligands for RIG-I, thereby enhancing antiviral IFN signaling [25]. In contrast, due to its lack of catalytic activity, OASL regulates antiviral innate immune pathways by augmenting the function of RIG-I [26] (Fig. 1).

Endosomal PAMP RNA Sensors

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Toll-like receptors (TLRs) represent a diverse family of proteins classified as pattern recognition receptors. These receptors play critical roles as sentinels within the innate immune system, facilitating the transition from innate to adaptive immune responses. The diverse expression patterns and functional capabilities of individual TLRs in specific cellular environments determine their intrinsic functions in immune surveillance and response regulation. While human TLRs consist of ten isoforms (TLR1-TLR10), mice possess twelve TLR variants (TLR1-TLR9 and TLR10-TLR13). Among these, TLR3, TLR7, TLR8, TLR9, and TLR13 are predominantly localized within endosomes, enabling them to recognize foreign nucleic acids [27].

TLR3 can detect endosomal dsRNA species from virus-infected cells or cell debris. In contrast, TLR7 and TLR8 recognize single-stranded (ss) RNA from various sources, including viruses and endogenous ligands, highlighting their importance in combating RNA-based pathogens and modulating autoimmune responses [3] (Fig. 1). Notably, TLR13, which is absent in humans but predominantly expressed in murine macrophages and dendritic cells, detects ssRNAs derived from a conserved region within the peptidyl transferase loop of bacterial 23S ribosomal RNA (rRNA) [28]. This unique feature of TLR13 enables the murine innate immune system to effectively detect a wide range of bacterial infections.

Cytosolic DNA Sensing Pathway

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DAI/ZBP1

The DNA-dependent activator of IFN (DAI), also known as Z-DNA binding protein 1 (ZBP1), has been proposed as a sensor for cytosolic DNA [29]. DAI/ZBP1 comprises three domains: an N-terminal Z-DNA binding domain, an internal receptor-interacting protein homotypic interaction motif (RHIM) domain involved in programmed cell death, and a C-terminal domain facilitating interactions with downstream signaling molecules. Upon DNA binding, DAI/ZBP1 undergoes conformational changes that promote its oligomerization and activation, initiating signaling cascades that lead to the production of type I IFNs and proinflammatory cytokines [29] (Fig. 2).

Figure 2.Intracellular and endosomal DNA sensing pathway. Intracellular DNA sensors, cGAS, DAI/ZBP1, IFI16, and AIM2, and the endosomal DNA sensor, TLR9, are shown. Upon DNA exposure to the cytoplasm, cGAS and DAI/ZBP1 trigger IFN signaling pathways by activating the central adapter molecule, STING. PYHIN-containing proteins IFI16 and AIM2 induce cellular inflammation by recruiting the signaling adapter molecule ASC and the protease caspase-1, leading to the production of proinflammatory cytokines such as IL-1β and IL-18. Within the endosome, TLR9 recognizes CpG-DNA and subsequently initiates the antiviral IFN response.

Initially, DAI/ZBP1 was regarded as a cytosolic DNA virus sensor capable of triggering the IFN signaling pathway. However, subsequent studies have revealed that DAI/ZBP1 plays a redundant role in cytoplasmic DNA sensing, rather than serving as a universal DNA sensor inducing IFN production. Notably, even the deletion of the DAI/ZBP1 gene in mice does not significantly impact IFN production. Nevertheless, recent research has suggested its distinct role in regulating cell death and inflammatory responses upon viral infection.

PYHIN-Containing Proteins, IFI16 and AIM2

Members of the Pyrin and hematopoietic interferoninducible nuclear (HIN) domain (PYHIN) family play pivotal roles in detecting non-self nucleic acids, triggering responses from both the inflammasome and the IFN pathways. The absent in melanoma 2 (AIM2)-like receptor (ALR) family comprises four genes in the human genome and fourteen genes in the murine system. Among them, IFN-γ-inducible protein 16 (IFI16) and AIM2 are two extensively studied proteins [30].

IFI16 has been suggested as a player in functioning as a cytosolic DNA sensor and regulator of immune responses. IFI16 consists of an N-terminal pyrin domain (PYD), two DNA-binding HIN domains (HIN-A and HIN-B), and a C-terminal protein interaction domain. Upon DNA binding, IFI16 undergoes conformational changes facilitating its oligomerization and activation. Activated IFI16 recruits and interacts with signaling molecules such as stimulator of IFN genes (STING) and TBK1 (TRAF family member-associated NF-κB activator (TANK)-binding kinase 1), leading to the phosphorylation of transcription factors nuclear factor kappa-lightchain-enhancer of activated B cells (NF-κB) and IFN regulatory factor (IRF) 3/7, subsequently inducing antiviral and inflammatory responses. Genetic variants in IFI16 have been linked to susceptibility to viral infections, including herpes simplex virus (HSV) and human papillomavirus (HPV) [31].

The AIM2 protein, another member of the HIN-200 domain-containing family, serves as a detector of cytosolic DNA originating from intracellular pathogens such as bacteria and viruses, as well as from cellular damage. AIM2 comprises an N-terminal pyrin domain (PYD) and a C-terminal single HIN-200 domain, which specifically binds to double-stranded DNA. Upon DNA recognition, AIM2 undergoes oligomerization, forming an inflammasome complex by recruiting the adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD). Subsequently, pro-caspase-1 is recruited to the inflammasome, leading to the cleavage of pro-IL-1β and pro-IL-18 into their mature, bioactive forms [32−35] (Fig. 2).

cGAS

Despite the identification of several cytosolic DNA sensors, many aspects of DNA sensing mechanisms remain elusive. In particular, the cell type-specific phenotypic expression of certain DNA sensors raises questions regarding the existence of a universal sensor for foreign DNA. However, the discovery of cyclic GMPAMP synthase (cGAS), a cellular protein expressed ubiquitously across tissues, has provided clear explanations for these previously ambiguous questions.

cGAS recognizes cytosolic DNA and initiates an antiviral IFN response. Human cGAS comprises a positively charged N-terminus and a C-terminal fragment that contains a nucleotidyltransferase (NTase) domain and a male abnormal 21 (Mab21) domain. The NTase domain is critical for the enzymatic activity involved in cyclic GMP-AMP (cGAMP) synthesis, while the Mab21 domain functions in dsDNA recognition [36].

Upon binding to DNA, cGAS undergoes a conformational change that activates its catalytic function, resulting in the synthesis of cGAMP from ATP and GTP. cGAMP subsequently binds to and activates the adaptor protein stimulator of IFN genes (STING). This activation prompts STING to translocate from the endoplasmic reticulum to perinuclear puncta, where it recruits and activates downstream signaling molecules such as TBK1 and IRF3, leading to the production of type I IFN and proinflammatory cytokines [37] (Fig. 2).

Endosomal DNA Sensor

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Toll-like receptor 9 (TLR9), originally identified in mouse macrophages, functions as an innate immune sensor localized within endosomes. TLR9 consists of a leucine-rich repeat (LRR) domain and a Toll/IL-1 receptor (TIR) domain. Similar to other members of the TLR family, the TIR domain of TLR9 is essential for recruiting the signaling adaptor protein MyD88. TLR9, like TLR3 and TLR7, is an endosomal receptor that detects nucleic acids, but it is unique in recognizing DNA specifically [38].

TLR9 specifically identifies unmethylated cytosinephosphate-guanosine (CpG) motifs, which are prevalent in various pathogens including bacteria, viruses, fungi, and parasites. Upon recognition of CpG DNA, the formation of the TLR9-MyD88 complex activates the NF-κB pathway and facilitates the nuclear translocation of IRF7, culminating in the expression of inflammatory cytokines and type I IFNs [38] (Fig. 2).

Interplay of RNA Recognition Receptors for DNA Virus Sensing

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The sensing of cytosolic DNA has been primarily attributed to established DNA sensors, which activate innate immune responses upon DNA binding. However, recent findings indicate an expanded role for RNA sensors-initially identified for their viral RNA recognitionin detecting cytosolic DNA and initiating antiviral immune responses through common downstream signaling pathways. This section discusses the emerging paradigm of cytosolic DNA sensing by RNA sensors, including the molecular mechanisms underlying this process, the signaling pathways involved, and the implications for antiviral host defense (Fig. 3).

Figure 3.Sensing of DNA viruses by RNA recognizing proteins. Various mechanisms for sensing DNA virus invasion via RNArecognizing proteins are described. RNA polymerase III detects cytosolic dsDNA and generates 5'-triphosphate-containing dsRNAs, which subsequently activate the antiviral IFN program through RIG-I. Additionally, certain RNA species derived from viral DNA can be directly recognized by RIG-I and/or MDA5 in an RNA polymerase III-independent manner. PKR also plays a role in DNA virus sensing by recognizing RNA species derived from DNA viruses, leading to cell death.

Cooperative Sensing of dsDNA by RIG-I and RNA Polymerase III

RNA polymerase III (RNA Pol III) is traditionally recognized for its essential role in transcribing transfer RNA (tRNA) and other small non-coding RNAs. However, recent studies have unveiled an intriguing additional function of RNA Pol III in DNA sensing, particularly in the recognition of cytosolic DNA. Pol III recognizes specific DNA motifs, such as Alu repeats and AT-rich sequences, within cytosolic DNA. Upon binding to these DNA elements, Pol III generates short dsRNA transcripts that harboring a 5′ triphosphate moiety which are eventually recognized by RIG-I [32, 39].

It has been reported that AT-rich dsDNA from herpes simplex virus 1 (HSV-1) is transcribed into dsRNA with 5' triphosphates by RNA Pol III, which are subsequently recognized by RIG-I [40]. Similarly, RNA Pol III transcribes AT-rich dsDNA from Epstein-Barr virus (EBV), resulting in the production of small RNAs EBER1 and EBER2 that serve as ligands for RIG-I [41]. Additionally, adenovirus encodes virus-associated RNAs (VARNAs), which are transcripts derived from RNA Pol III and form dsRNA structures, can trigger IFN signaling via RIG-I [42]. Interestingly, while RNA Pol III is also responsible for sensing the AT-rich DNA from the varicella-zoster virus (VZV) and inducing antiviral IFN signaling, the specific RNA sensors for these dsRNA products have yet to be identified [43].

Sensing of DNA Virus-Derived RNA Species by RNA Sensors

Recent studies indicate that distinct RNA species generated by Kaposi's sarcoma-associated herpesvirus (KSHV) are directly recognized by both RIG-I and MDA5, independent of RNA polymerase III [44]. Moreover, it has been reported that RNA species generated by vaccinia virus (VV) can trigger the IFN signaling pathway via RIG-I and MDA5. Additionally, these RNA species can also activate PKR, leading to cell death [45]. Furthermore, Myxoma virus (MV), a large cytoplasmic DNA virus, is recognized by RIG-I in primary human macrophages, leading to the initiation of type I IFN production. However, the precise mechanisms of this regulatory process remain incompletely understood [46].

Closing Remarks

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Viruses employ diverse strategies to evade immune detection, leading hosts to develop advanced countermeasures for viral detection and response. This review provides an updated understanding of antiviral sensors and emphasizes their synergistical interplay that enhance the effectiveness in antiviral sensing.

During DNA virus infections, various RNA sensors and enzymes collaborate to detect viral invasion. RLRs can directly sense specific RNA species generated during the DNA virus life cycle, and RNA polymerase III uses cytosolic DNA as a template for RNA transcription, which is then recognized by various RNA sensors. This interplay augments innate antiviral responses against both RNA and DNA viruses.

Despite significant achievement in our understanding of DNA/RNA sensor-mediated innate immune responses, many aspects of the interplay between these mechanisms still remain elusive. Deciphering the detailed mechanisms of these synergistic networks will enable the development of immunostimulatory therapies and small molecule agonists, which can be used as antivirals, vaccine adjuvants, and cancer treatments. A comprehensive understanding of the interplay between DNA and RNA sensing mechanisms is expected to significantly impact antiviral and cancer therapies, highlighting the importance of continued research in this field.

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