Retinoic acid–inducible gene I–like receptors (RLRs) are cytosolic RNA sensors critical for initiation of antiviral immunity. Activation of RLRs following RNA recognition leads to production of antiviral genes and IFNs for induction of broad antiviral immunity. Although the RLRs are ubiquitously expressed, much of our understanding of these molecules comes from their study in epithelial cells and fibroblasts. However, RLR activation is critical for induction of immune function and long-term protective immunity. Recent work has focused on the roles of RLRs in immune cells and their contribution to programming of effective immune responses. This new understanding of RLR function in immune cells and immune programming has led to the development of vaccines and therapeutics targeting the RLRs. This review covers recent advances in our understanding of the contribution of RLRs to immune cell function during infection and the emerging RLR-targeting strategies for induction of immunity against cancer and viral infection.

The recognition of pathogen-associated molecular patterns (PAMPs) by membrane-bound and cytosolic pattern recognition receptors (PRRs) results in the induction of type I and III IFN responses. IFNs play a critical role in providing antiviral protection through paracrine and autocrine induction of hundreds of effector antiviral genes and are critical to the initiation of adaptive immune responses (13). IFN induction is critical not only for antiviral immunity, but also induction of antitumor immunity and protection against bacteria, fungal, and parasitic infection (46). Further, aberrant expression of IFN promotes autoimmune diseases, such as systemic lupus erythematosus (SLE), inflammatory myositis, Aicardi-Goutières syndrome, rheumatoid arthritis, and other rheumatic diseases (79). Multiple therapeutics targeted at limiting IFN responses have been clinically developed and are in clinical trials or approved for treatment of specific autoimmune disorders (7, 8). As such, rIFN has been developed as an antiviral therapeutic. However, IFN therapies are frequently accompanied by severe side effects, limiting clinical application (10). Given the dual role of IFN in promoting antiviral immunity while exacerbating autoimmunity, understanding the functions of retinoic acid–inducible gene I (RIG-I)-like receptors (RLRs) beyond production of IFN is important for harnessing this pathway for therapeutic benefit. Particularly, unraveling the cell types and mechanisms required for RLR promotion of adaptive immune responses has important implications for human health and disease (11, 12).

IFNs are induced by multiple pathogen-sensing pathways, including the RLRs (the focus of this review), TLRs, nucleotide-binding and oligomerization domain (NOD)-like receptors, and the cyclic GMP–AMP synthase/stimulator of IFN genes DNA-sensing pathways. These are localized in distinct cellular compartments and recognize unique ligands to allow for effective immunity against a variety of pathogens. These pathways have been described in detail in other recent reviews (1316). TLRs are type I transmembrane proteins expressed at the plasma membrane or in endosomes/lysosomes that broadly recognize membrane components and nucleic acids derived from pathogens, leading to activation of transcription factors, such as NF-κB and AP-1, to induce proinflammatory and IFN responses (13, 1719). NOD-like receptors generally detect components of peptidoglycan and nucleic acid PAMPs in the cytosol, leading to type I IFN as well as IL-1 release (2024). The cyclic GMP–AMP synthase/stimulator of IFN genes pathway recognizes host and foreign DNA for activation of TANK-binding kinase 1 (TBK1) and IFN regulatory factor 3 (IRF3), inducing a robust type I IFN response (16, 25, 26).

The RLRs are cytoplasmic RNA sensors that can initiate IFN, antiviral, and proinflammatory responses (27, 28). The family of RLRs consist of RIG-I, melanoma differentiation–associated protein 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2), encoded by DExD-box helicase 58 (DDX58), IFN induced with helicase C domain 1 (IFIH1), and DExH-box helicase 58 (DHX58), respectively (29). All of the RLRs contain a structurally conserved DExD/H-box RNA helicase and C-terminal domain (30). In addition, both RIG-I and MDA5 (but not LGP2) contain two N-terminal caspase activation and recruitment domains (CARDs) (27) (Fig. 1A). Interaction of cognate RNA ligands with the DExD/H helicase causes a confirmational change to displace the CARDs, allowing for their oligomerization and interaction with mitochondrial antiviral signaling protein (MAVS) CARDs (27, 2931). MAVS is embedded in the mitochondrial-associated membranes (MAMs) and in oxidative organelles (peroxisomes) (27). Canonically, MAVS forms a scaffold at the MAM with TNFR-associated factor 2 (TRAF2), TRAF5, and TRAF6 to activate the inhibitor of IκB kinase (IKK) family and TBK1 (32). The inhibitor of IKK family kinases and TBK1 phosphorylate NF-κB, IRF3, and IRF7, which allows for their translocation to the nucleus and transcription of IFN, antiviral genes, proapoptotic genes, and immune cell programming genes (27). LGP2 plays a dual role in propagating MDA5 signaling during the acute stage of infection, but limits signaling downstream of MAVS during resolution of infection (3335) (Fig. 1B).

FIGURE 1.

RLR domains, polymorphisms, and signaling. (A) The RLRs RIG-I, MDA5, and LGP2 all contain a C-terminal repressor domain (CTD) and a helicase domain. RIG-I and MDA5 contain two CARDs. The numbered dashes represent relative locations of SNPs present in coding regions of the RLRs with numbers corresponding to the first column of Table I. (B) Upon virus infection, RIG-I and MDA5 sense cognate RNAs and undergo confirmational change to allow for interaction with and activation of MAVS at MAMs for downstream activation of NF-κB and IRF3, leading to antiviral gene programming, IFN production, immune cell programming genes, and proapoptotic genes. The role of LGP2 is still under investigation, but during acute infection, it stabilizes and propagates MDA5 signaling. However, during resolution of infection, LGP2 dampens RLR signaling.

FIGURE 1.

RLR domains, polymorphisms, and signaling. (A) The RLRs RIG-I, MDA5, and LGP2 all contain a C-terminal repressor domain (CTD) and a helicase domain. RIG-I and MDA5 contain two CARDs. The numbered dashes represent relative locations of SNPs present in coding regions of the RLRs with numbers corresponding to the first column of Table I. (B) Upon virus infection, RIG-I and MDA5 sense cognate RNAs and undergo confirmational change to allow for interaction with and activation of MAVS at MAMs for downstream activation of NF-κB and IRF3, leading to antiviral gene programming, IFN production, immune cell programming genes, and proapoptotic genes. The role of LGP2 is still under investigation, but during acute infection, it stabilizes and propagates MDA5 signaling. However, during resolution of infection, LGP2 dampens RLR signaling.

Close modal

As RLRs recognize RNA, many studies have focused on delineating features that allow for RIG-I, MDA5, and LGP2 discrimination of self versus nonself RNA. RIG-I preferentially recognizes short RNAs containing 5′-triphosphate or -diphosphate groups (3641). MDA5 recognizes long RNA duplexes in high m.w. RNAs (41, 42). LGP2 binds RNA with high affinity regardless of the length or modifications in the 5′ end, but its direct role in independent signal activation versus regulation of other RLRs remains unclear (43). In addition, these helicases are under the control of regulatory enzymes and interacting proteins that can further enhance RLR activation (4446). Despite these conserved features, which limit self RNA recognition, RIG-I and MDA5 have been described to recognize self RNA and contribute to antiviral immunity as well as autoimmunity (4751). Several recent reviews have comprehensively covered known RNA ligands of the RLRs (27, 52, 53). Overall, these studies have led to an understanding that each RLR plays unique and distinct roles in antiviral control and, potentially, immune programming (27, 53, 54).

Virus recognition and induction of immunity in infected target cells (epithelial, fibroblasts, and others) leads to antiviral programming and cytokine/chemokine production that promotes APC maturation and migration for adaptive immune programming (55). However, RLRs are expressed within nearly all cell types, suggesting both extrinsic (e.g., other immune cell–, epithelial cell–, or fibroblast-mediated) and intrinsic roles for RLRs in immune cell function (27). Although relatively few studies have focused on RLR functions in specific immune cell subsets, there has been a renewed interest in delineating immune cell roles of these pathways with a focus on developing therapeutics and vaccine adjuvants that target host immune pathways normally activated following virus infection.

Single nucleotide polymorphisms (SNPs) in RIG-I (DDX58), MDA5 (IFIH1), and LGP2 (DHX58) have been identified with linkage to disease susceptibility (Fig. 1A, Table I). For example, minor alleles of DDX58 (rs10813831 and rs3824456) and DHX58 (rs2074160) are associated with spontaneous clearance of hepatitis C virus (HCV) and hepatitis B virus (HBV) (56, 57). Conversely, minor alleles of DDX58 (rs3739674) and IFIH1 (rs1990760) are associated with severe enterovirus 71 (EV71) infection or more severe HCV following solid organ transplant (58, 59). Despite their canonical role in antiviral immunity, SNPs in DDX58, IFIH1, and DHX58 are linked to enhanced risk of developing autoimmune diseases such as atypical Singleton-Merten syndrome, systemic lupus erythematosus (SLE), and type 1 diabetes (T1D) (6065). However, several of these SNPs are protective against psoriasis/psoriatic arthritis and T1D, highlighting the critical role for appropriate RLR function in regulating inflammation and immunity (59, 6668).

Table I.

RLR polymorphisms and disease implications

NumberSNPGenotypeMutationDisease ImplicationsReference
RIG-I (DDX58     
 1 rs3739674 G > C Upstream mutation; reduced expression Increased EV71 severity Li et al. (58
 2 rs10813831 G > A Coding mutation; missense variant Spontaneous HCV clearance; conversely, severe recurrent HCV following liver transplant Wu et al. (56), Erazo Luna et al. (59
 3 rs3824456 C > G Intron mutation Spontaneous HBV clearance Yao et al. (57
 4 rs55789327 G > A Coding mutation; missense variant Rotavirus vaccine IgA seroconversion Miya et al. (69
 5 rs786204848 G > T Coding mutation; missense variant Atypical Singleton-Merten syndrome; congenital glaucoma Jang et al. (60
 6 rs786204847 A > C Coding mutation; missense variant Atypical Singleton-Merten syndrome Jang et al. (60
MDA5 (IFIH1     
 7 rs10930046 T > C Coding mutation; missense variant Decreased psoriasis risk; increased SLE risk Luna et al. (59), Molineros et al. (63), Li et al. (66
 8 rs35744605 C > A Coding mutation; loss of function Reduced T1D risk Chistiakov et al. (67
 9 rs3747517 T > C Coding mutation; missense variant Increased SLE risk Zhang et al. (61), Gorman et al. (62
 10 rs35667974 T > C Coding mutation; loss of function Decreased psoriasis and psoriatic arthritis risk; reduced T1D risk Li et al. (66), Chistiakov et al. (67), Budu-Aggrey et al. (68
 11 rs1990760 C > T Coding mutation; decreased expression, increased methylation Increased T1D and SLE risk; increased EV71 severity Li et al. (58), Zhang et al. (61), Gorman et al. (62), Molineros et al. (63), Liu et al. (64
 12 rs2111485 A > G Intergenic mutation; unknown, no expression change Increased T1D risk; spontaneous HBV clearance Yao et al. (57), Liu et al. (64
LGP2 (DHX58     
 13 rs12600570 C > T Intronic; unknown Elevated fasting plasma glucose Hebbar et al. (65
 14 rs2074160 G > A Coding mutation; unknown Spontaneous HBV clearance Yao et al. (57
NumberSNPGenotypeMutationDisease ImplicationsReference
RIG-I (DDX58     
 1 rs3739674 G > C Upstream mutation; reduced expression Increased EV71 severity Li et al. (58
 2 rs10813831 G > A Coding mutation; missense variant Spontaneous HCV clearance; conversely, severe recurrent HCV following liver transplant Wu et al. (56), Erazo Luna et al. (59
 3 rs3824456 C > G Intron mutation Spontaneous HBV clearance Yao et al. (57
 4 rs55789327 G > A Coding mutation; missense variant Rotavirus vaccine IgA seroconversion Miya et al. (69
 5 rs786204848 G > T Coding mutation; missense variant Atypical Singleton-Merten syndrome; congenital glaucoma Jang et al. (60
 6 rs786204847 A > C Coding mutation; missense variant Atypical Singleton-Merten syndrome Jang et al. (60
MDA5 (IFIH1     
 7 rs10930046 T > C Coding mutation; missense variant Decreased psoriasis risk; increased SLE risk Luna et al. (59), Molineros et al. (63), Li et al. (66
 8 rs35744605 C > A Coding mutation; loss of function Reduced T1D risk Chistiakov et al. (67
 9 rs3747517 T > C Coding mutation; missense variant Increased SLE risk Zhang et al. (61), Gorman et al. (62
 10 rs35667974 T > C Coding mutation; loss of function Decreased psoriasis and psoriatic arthritis risk; reduced T1D risk Li et al. (66), Chistiakov et al. (67), Budu-Aggrey et al. (68
 11 rs1990760 C > T Coding mutation; decreased expression, increased methylation Increased T1D and SLE risk; increased EV71 severity Li et al. (58), Zhang et al. (61), Gorman et al. (62), Molineros et al. (63), Liu et al. (64
 12 rs2111485 A > G Intergenic mutation; unknown, no expression change Increased T1D risk; spontaneous HBV clearance Yao et al. (57), Liu et al. (64
LGP2 (DHX58     
 13 rs12600570 C > T Intronic; unknown Elevated fasting plasma glucose Hebbar et al. (65
 14 rs2074160 G > A Coding mutation; unknown Spontaneous HBV clearance Yao et al. (57

Table shows SNPs in RIG-I, MDA5, and LGP2 as identified by National Center for Biotechnology Information Single Nucleotide Polymorphism database (dbSNP) designation, genotype (major allele > minor allele), associated mutation, disease implication, and applicable references. SNPs with mutations in coding regions are depicted in (Fig. 1A using the number designation from the first column of Table I.

Although many associations with autoimmunity and chronic viral infection have been described, how RLR SNPs regulate susceptibility to these illnesses is not well understood. However, the emergence of novel mouse models containing SNPs equivalent to those found in humans will shed further light on the importance of these RLR SNPs in autoimmune and infectious disease and allow for greater understanding of their mechanism. For example, the IFIH1 rs1990760 minor allele is associated with multiple autoimmune diseases, but the mechanisms underlying this enhanced risk due to this polymorphism had not been elucidated. A murine model expressing risk (rs1990760 minor allele) and nonrisk (rs1990760 major allele) alleles of IFIH1 was developed to determine the role of these haplotypes in IFN regulation, antiviral immunity, and susceptibility to autoimmune disease (62). Mice expressing the risk allele had higher basal IFN-β expression, enhanced protection against encephalomyocarditis virus (EMCV) infection, as well as increased autoantibody production and incidence of diabetes. Similar models and mechanistic studies will broaden our understanding of the implications of RLR SNPs in pathogen resistance and autoimmunity and allow for delineation of how these variants impact immune cell function.

For example, epistatic interaction between the rs55789327 minor allele of DDX58 and a polymorphism in TLR3 is associated with enhanced IgA seroconversion following rotavirus vaccination (69). However, the specific contribution of RIG-I to this process and in which cell types it is important remain unknown. Based on the relative number of peer-reviewed publications, much of our understanding of RLR regulation derives from in vitro studies on epithelial cells and fibroblasts. Thus, it is less well understood how cell identity further contributes to the functions and regulation of RLRs. As immune cells are critical effectors of viral protection and drivers of autoimmunity, understanding the specific roles of RLRs in immune cells is critical for understanding the mechanisms of protective versus deleterious RLR responses and allow for design of targeted therapeutics promoting health while minimizing deleterious tissue damage. Recently, multiple studies have begun to unravel the roles of the RLRs and their functions in programming immune cell–specific responses, described below (Fig. 2).

FIGURE 2.

RLR functions in immune cell subsets. The roles of RIG-I, MDA5, and LGP2 in DCs, macrophages, NK cells, B lymphocytes, T lymphocytes, and granulocytes during infection are summarized. References for each function are color-coded: RIG-I (orange), MDA5 (teal), and LGP2 (magenta).

FIGURE 2.

RLR functions in immune cell subsets. The roles of RIG-I, MDA5, and LGP2 in DCs, macrophages, NK cells, B lymphocytes, T lymphocytes, and granulocytes during infection are summarized. References for each function are color-coded: RIG-I (orange), MDA5 (teal), and LGP2 (magenta).

Close modal

Macrophages

Macrophages play a vital role in controlling viral infection through the induction of downstream IFN-stimulated genes (ISGs) and proinflammatory cytokines. However, infected macrophages have reduced cytopathic function and require RLR sensing to control viral load (70). Murine bone marrow macrophages (BMMs) require MAVS downstream of RIG-I and MDA5 to induce type I IFN and proinflammatory cytokine expression in response to vesicular stomatitis virus (VSV) (71). There is also evidence that both RIG-I and MDA5 contribute to production of MIP1α, RANTES, CXCL10, and IFN-γ in human monocyte-derived macrophages during Middle East respiratory syndrome coronavirus infection (72). Porcine alveolar macrophages depend upon both RIG-I and MDA5 in a redundant fashion to induce IFN-β and ISG15 in response to African swine fever virus, VSV, Sendai virus (SeV), EMCV, and influenza A virus (IAV), which suggest overlapping function between RIG-I and MDA5 in the context of these infections (73, 74). Further, studies using an in vivo murine model of Ebola virus infection found the RLR signaling adapter MAVS is required for secretion of IFN-β and protection against lethality (75). Although the specific role of LGP2 in regulating RLR signaling is unclear, studies suggest LGP2 synergizes with RIG-I and MDA5 to promote proinflammatory cytokine and IFN induction in murine and porcine macrophages (76, 77) (Fig. 1B).

Despite the canonical role for the RLRs in regulating antiviral immunity in macrophages, there is evidence that the RLRs play unique roles in regulating virus infection and macrophage function. RIG-I, but not MDA5, is required in human monocyte-derived macrophages for type I and type III IFN induction following H5N1 IAV infection (78). Murine BMMs lacking MDA5 have diminished IFN-β production compared with wild-type and RIG-I–deficient BMMs during murine hepatitis virus infection (79). These differential requirements are due to the specific RNAs produced by these viruses during infection. Importantly, utilization of whole-body murine genetic double knockouts of MDA5 and RIG-I demonstrate that both RLRs have nonredundant roles in mediating protection against West Nile virus (WNV) as measured by replicating virus and reduced IFN-β production (80, 81). During WNV infection, the RLRs reinforce proinflammatory M1 macrophage programming while suppressing wound-healing M2 macrophages in both murine and human cells (81). Overall, these studies show that the RLRs not only regulate IFN and antiviral gene programming, but also play a direct role in regulating macrophage polarization.

Dendritic cells

Among APCs, dendritic cells (DCs) play a critical role in presenting foreign Ag for the activation of adaptive immune responses important for pathogen clearance and long-term memory protection. Although extrinsic inflammation induced by RLR signaling in epithelial and other cells impacts DC activation, there is evidence that DC activation, maturation, and Ag presentation capability are dependent upon intrinsic RLR signaling. Human monocyte-derived DCs (moDCs) infected with IAV or measles virus rely on MDA5 and RIG-I for type I IFN induction, similar to murine bone marrow–derived DCs (BMDCs) during rabies virus and WNV infection (80, 8284). MDA5 signaling in BMDCs is required for cytokine production during norovirus and EMCV infection (85, 86). LGP2-deficient DCs infected with reovirus, EMCV, SeV, and VSV have diminished production of type I IFN, thereby suggesting LGP2 regulates MDA5 and/or RIG-I signaling (77) (Fig. 1B).

Although human moDCs and murine BMDCs serve as tractable models, there is evidence that different DC subsets present in vivo rely differentially upon PRR pathways. Infection of murine embryonic fibroblasts and conventional DCs (cDCs) with Newcastle disease virus led to a RIG-I–dependent induction of type I IFN. By contrast, the absence of RIG-I did not affect the production of IFN in plasmacytoid DCs (pDCs) during infection. In pDCs, Newcastle disease virus–induced IFN expression required the expression of the RNA sensors TLR7 and TLR9 (87). However, treatment of human pDCs with a RIG-I–activating HCV-derived PAMP led to production of type III IFN (88). Mass spectrometry analysis of splenic DC subsets revealed that RIG-I and MDA5 was readily detected in CD4+ and double-negative (CD4CD8α) cDC subsets, but low or undetectable in CD8α+ cDCs, suggesting that RLR expression unique to specific DC subsets may regulate their functions during acute viral infection (89). In addition, differences in the expression and utilization of signal transduction molecules downstream of PRRs across DC subsets could further dictate the cell type–specific regulation of dsRNA detection (90).

Temporal changes in RLR expression may also allow for varying roles of RIG-I, MDA5, and/or LGP2 in specific cell subsets over the course of infection. During in vivo lymphocytic choriomeningitis virus infection, induction of type I IFN (day 1 postinfection) is RIG-I–dependent, whereas the later IFN response (day 2 postinfection) is MAVS-MDA5–dependent (91). Human DCs upregulate RIG-I, MDA5, and LGP2 following Zika virus, suggesting these RLRs may contribute differentially to DC function and immune responses as infection progresses (92). Together, this supports that abundance of nucleic acid sensors, coregulatory molecules, and downstream effectors all play critical roles in the spatial and temporal antiviral functions of RLRs. As we continue to uncover additional functions for RLRs in coordinating innate and adaptive responses beyond antiviral control, focusing on understanding their unique roles in immune cells will allow for the development of targeted therapeutics and adjuvants to fine-tune DC function for optimal activation of adaptive immunity.

In support of this, the RLRs regulate DC function for downstream activation of adaptive immunity. RIG-I and MAVS signaling in DCs are required for generation of cytolytic CD8+ T cell function following IAV infection in vitro and in vivo (84, 93). Particularly, RIG-I signaling in murine BMDCs is necessary for presenting Ag to both CD4+ and CD8+ T cells during IAV infection (93). RLR signaling in DCs also regulates CD4+ T cell immunity. Upon infection with dengue virus, human DCs become activated to secrete IL-27, leading to polarization of T follicular helper (TFH) cells and production of IgM and IgG in a RIG-I– and MDA5-dependent manner, as shown by small interfering RNA knockdown of MAVS (94, 95). Full MAVS knockout or deletion of MAVS in CD11c+ cells, but not B cells, led to increased virus titers and enhanced WNV-specific IgG and neutralizing Ab responses (96). Overall, RLR signaling in DCs is required not only for antiviral activity, but also to support DC activation and generation of robust adaptive immune responses.

T cells

APCs, primarily DCs, are required for T cell activation. As such, both cell-intrinsic and -extrinsic dependencies on RLR expression have been described for T cell activation and function across various infectious models. RLRs can play nonredundant roles in CD4+ T cell activation. RIG-I is required for priming of CD4+ T cells during IAV infection in mice (93). During H5N1 IAV infection, RIG-I is required for priming of CD4+ T cells and Th1 polarization (97). However, in the context of dengue virus infection, both RIG-I and MDA5 are required for Th1 polarization (94). Interestingly, the absence of RLR expression in DCs appeared to be required for Th1 polarization during dengue virus. Further, both RIG-I and MDA5 in DCs are required for CD4+ TFH cell responses during dengue virus infection (95). TFH cells play an important role in germinal centers to support B cell– and Ab-mediated responses. Therefore, it is likely this role for RIG-I and MDA5 in regulating TFH cells also impacts the development of B cell and Ab responses during infection.

Although the RLRs clearly contribute to CD4+ T cell function, much more is known about RLR regulation of CD8+ T cell responses. During IAV infection, RIG-I is important for CD8+ T cell priming, and mice lacking MAVS and RIG-I have reduced CD8+ T cell production of IFN-γ, TNF, and granzyme B (93). Mixed bone marrow chimeras (lethal irradiation of wild-type mice and reconstitution with RIG-I–deficient bone marrow) and in vitro studies showed that RIG-I in both DCs and CD8+ T cells is required for CD8+ T cell priming and function during IAV infection (93). Mice lacking MDA5 have dysfunctional effector CD8+ T cell responses during WNV and murine hepatitis virus infection (98). During WNV infection, T cell–extrinsic MDA5 signaling is required for CD8+ T cell priming to control CNS infection (99). Additionally, virus-specific CD8+ T cell responses were significantly reduced in MDA5-deficient mice following chronic lymphocytic choriomeningitis virus infection (100). This study showed MDA5-dependent induction of type I IFN extrinsic of T cells was required to prevent CD8+ T cell exhaustion (100). MDA5 also contributes to memory generation, as MDA5 expression in nonhematopoietic cells enhanced survival and memory of CD8+ T cells during herpes virus infection (101). LGP2 also contributes to regulation of T cell immunity. During WNV infection, WNV-specific CD8+ T cell populations and cell survival are reduced in mice lacking LGP2, but whether LGP2 functions intrinsically in CD8+ T cells or extrinsically in another cell type, such as an APC, to regulated WNV-specific CD8+ T cell immunity is currently unknown (102).

It is important to note that the individual contributions of RIG-I, MDA5, and LGP2 cannot be directly compared in vivo, as commonly used mice deficient in RIG-I are embryonic lethal in a full C57BL/6 background and have to be maintained on a mixed Sv129 × C57BL/6 background or on an Sv129 background (87, 103, 104). As MDA5- and LGP2-deficient mice are on the C57BL/6 background, currently, any comparison of these mice compared with those lacking RIG-I include the caveat that differences in experimental models may be due to background strain differences. Additionally, a lack of floxed RLR mice has prevented the investigation of the RLRs in individual cell subsets to date. However, regardless of whether the contribution is intrinsic to T cells or extrinsically regulated by RLR signaling in cells known to regulate T cell immunity, RLRs clearly contribute to T cell immunity. Given this, the RLRs have been targeted, particularly in the context of cancer, to prime cytotoxic antitumor T cell immunity (11, 12, 105, 106).

B cells

Our understanding of the mechanisms by which RLRs support B cell responses is starting to emerge, and multiple studies have demonstrated that adjuvant use of RLR agonists can promote B cell and Ab responses. Administration of RIG-I agonist RNA as an adjuvant administered with H5N1 virus-like particles to mice led to a decrease in viral titers and an increase in IgG2a responses (97). Inclusion of a RIG-I agonist in an influenza virus DNA vaccine vector increased IFN-β in cell culture and serum Ab levels (107). The use of in vitro transcribed defective interfering RNA from SeV as an adjuvant for H1N1 IAV vaccination increased IgG subtypes, IgA in the airways, and enhancement of survival following lethal challenge (108). In addition to enhancement of Ab titers, one study using administration of a RIG-I–targeting adjuvant in combination with H1N1 IAV vaccination to mice led to increased IgG Ab titer, enhanced germinal center formation, and earlier accumulation of virus-specific plasma cells in the bone marrow compared with vaccination alone (109). These results suggest targeting of RIG-I as an adjuvant may not only increase Ab titers, but also enhance the durability of these responses. In humans, one polymorphism of RIG-I is correlated with enhanced IgA seroconversion following vaccination against rotavirus infection (69). Together, these studies indicate an important role for the RLRs in regulating B cell immunity that can be harnessed to boost protective immunity, but to date, these studies have not delineated whether RIG-I signaling in DCs and/or B cells is required for this adjuvant effect. Although it is likely RLR regulation of DC function contributes to this effect, B cells isolated from PBMCs of HCV-positive patients displayed upregulation of both protein and mRNA transcripts for RIG-I and IRF2, suggesting there may be an intrinsic role for RIG-I in regulating B cell responses during HCV infection (110).

NK cells

There are few studies addressing the role of RLRs in NK cells during virus infection. However, the effects of synthetic agonists on viral sensors, such as RLRs, in NK cells has been investigated. Human and murine NK cells cocultured with DCs and treated with polyinosinic-polycytidylic acid [poly(I:C)], a synthetic dsRNA analog known to activate MDA5, promotes IFN-γ production by NK cells (111). This IFN-γ production by NK cells is significantly reduced with the loss of MAVS and is dependent upon DCs (111). As poly(I:C) also activates the membrane-bound dsRNA sensor TLR3, defining the target of this ligand that modulates NK function is necessary. Injection of mice with poly(I:C) led to IFN-γ production in NK cells that was dependent upon both MDA5 and TLR3 (112). Mixed bone marrow chimera mice identified a requirement for MDA5 in the stromal compartment for NK cell type I IFN production in response to poly(I:C) (112). As observed in murine models, RLR agonists can also activate human NK cells (111). Human NK cells infected with HBV and treated with poly(I:C) have diminished levels of perforin, granzyme B, and IFN-γ, compared with control (113). HBV infection reduced RIG-I expression and dampened NF-κB and MAPK signaling (113). Targeting RIG-I activation by 5′-triphosphate ssRNA treatment of NK cells led to increased surface expression of TRAIL, suggesting there is also an NK cell–intrinsic RLR role (114). Together, these studies demonstrate a requirement for both RIG-I and MDA5 in regulating NK cell function.

Granulocytes

Mast cells primarily reside in the skin and mucosal tissues and act as immune sentinels for various types of viruses. The expression of RLRs in mast cells is vital for initiating a state of inflammation to combat virus infection. Silencing of MDA5 and RIG-I using small interfering RNA in human mast cells led to an increase in VSV titer during in vitro infection (115). Further, both RIG-I and MDA5 are required for murine mast cell production of IFN-α, IFN-β, CXCL10, and IL-6 during VSV infection (116). Additionally, knockdown of MDA5 and RIG-I sensors in the KU812 mast cell line diminished CXCL10, CCL4, and CCL5 in response to Ab-enhanced dengue virus (117). Primary human cord blood–derived mast cells infected with dengue virus in the presence of dengue immune sera led to an increase in mRNA expression of MDA5, RIG-I, as well as type I IFNs (117). Together, these studies support an important and potentially inducible role for RIG-I and MDA5 in regulating antiviral responses and chemokine/cytokine production in mast cells.

Eosinophils contribute to fungal and allergic disease, where they secrete chemokines/cytokines, degranulate, and form extracellular traps (118). However, whether eosinophils can respond to challenge for control of viral infection is an emerging area of research (119). Murine models have shown that RLR mRNA expression is lower than that observed in DCs (119). Expression of both DDX58 and IFIH1 was induced by in vitro infection with IAV H1N1. Similarly, human eosinophils have low expression of DDX58 and IFIH1 compared with expression of other PRRs known to promote eosinophil activation, such as NOD1 and NOD2 (120, 121). However, upon IAV challenge, RIG-I mRNA expression can be rapidly induced, suggesting there may be a temporal role for RIG-I in eosinophils following upregulation of the receptor (122).

Neutrophils rapidly infiltrate infected tissue to phagocytose pathogens, debris, and cells and form extracellular traps to aid in clearance of viral infection. Transfection of human neutrophils with poly(I:C) to activate MDA5 results in upregulation of type I IFN, TNF, IL-12, multiple chemokines/cytokines, and ISGs, demonstrating neutrophils sense and respond to virus infection in a canonical fashion (123). IFN-β and TNF production by murine neutrophils during EMCV infection is dependent upon MDA5 (123). Human neutrophils treated with ssRNA40 derived from HIV-1 led to upregulation of RIG-I and MDA5, similar to elevated levels in neutrophils isolated from HIV-1–positive patients (124, 125). Intriguingly, RIG-I and MDA5 have been observed in secretory vesicles of neutrophils and presence of RIG-I bound to 5′-triphosphate ssRNA at the plasma membrane of neutrophils (126). Although the relevance of this noncanonical distribution of the RLRs in neutrophils is unknown, they suggest RLRs may function in a unique fashion in neutrophils that can be exploited to modulate their function during infection or inflammation.

Targeting RLRs as therapeutics

Given the role of RLRs in priming immune responses, there has been much interest in the development of RLR agonists as therapeutics and vaccine adjuvants. A number of studies in the area of cancer immunity have shown that activation of RIG-I or MDA5 leads to apoptosis of tumor cells, releasing damage-associated molecular patterns and activating DCs to present tumor Ag for activation of antitumor cytotoxic CD8+ T cell responses (11, 12, 105, 106) As such, multiple groups have developed and investigated synthetic RNAs and small-molecule compounds to harness RIG-I activation as a therapeutic. The treatment of tumor cell lines with 5′-triphosphate RNA or poly(I:C) leads to cell death, upregulation of proinflammatory cytokines and IFN, and Ag presentation by DCs for activation of tumor-specific T cells (127). A double-stranded, triphosphorylated, 14-bp stem-loop RNA (SL14) that specifically activates RIG-I in a MAVS-dependent manner rapidly upregulated ISGs and IFN following i.v. injection (128). A double-stranded, triphosphorylated stem-loop RNA of 20 bp (SLR20) induced RIG-I signaling and slowed tumor progression in an in vivo murine model via induction of apoptosis and pyroptosis for enhanced activation and tumor infiltration of CD4+ and CD8+ T cells (129). Intratumoral administration of SL14 in s.c. melanoma, colon cancer, and breast cancer tumor lines significantly slowed tumor progression and metastasis in mice (130). This stem-loop RNA was taken up by CD11b+ cells that migrated to draining lymph nodes and led to an increase in cytotoxic T cells in the tumor (130). Depletion studies showed that both CD4+ and CD8+ T cells were partially required to mediate RIG-I–induced antitumor immunity (130).

There is also growing evidence that specific targeting of the RLRs can function as effective antivirals and/or vaccine adjuvants independent of the induction of apoptosis. The same stem-loop RNA RIG-I agonist investigated in preclinical models as a cancer therapeutic provided mice with protection against severe acute respiratory syndrome coronavirus 2 infection with multiple variants when administered prophylactically or as a therapeutic (131). RIG-I agonist derived from the 3′ untranslated region of HCV blocked Zika virus infection of human moDCs more efficiently than type I IFN (92). A 5′-triphosphate–containing RNA agonist, known as M8, activates and differentiates human monocyte-derived DCs (97). Administration of M8 as an adjuvant with an H5N1 virus-like particle-based vaccine to mice significantly increased survival and reduced virus titer and pulmonary pathology upon challenge (97). Additionally, M8 enhanced IgG2a, IFN-γ production by CD8+ T cells, and IL-2, TNF, and IFN-γ production by CD4+ T cells compared with vaccination alone (97). A small-molecule compound that activates IRF3 downstream of RIG-I adjuvants 2009 pandemic H1N1 split subunit vaccine (pH1N1 SV) to enhance survival and reduced pulmonary viral burden upon subsequent lethal challenge in mice compared with vaccination alone (132). Administration of this compound with pH1N1 SV led to enhanced neutralizing Ab responses and production of IL-4 and IL-10 by CD4+ T cells compared with vaccination alone (132). Together, these studies show targeting of the RLR pathways, primarily RIG-I, as a promising therapeutic avenue for enhancement of immunity in multiple vaccination, infection, and cancer. In sum, RLR activation induces gene programs beyond IFN for promotion of adaptive immune responses, but work is still needed to understand the cell type and context-specific programs regulated by RIG-I, MDA5, and LGP2 in modulating innate and adaptive immune responses.

Although unique roles for RIG-I, MDA5, and LGP2 in regulating immune cell–specific responses have been identified, the cell-intrinsic and -extrinsic nature of these requirements and their mechanisms of immune cell programming downstream of the RLRs largely remains to be elucidated. The studies described above reveal differences in RLR substrates, receptor abundance, basal expression levels, and varying temporal usage during infection across cell types all contribute to differences in RLR regulation of immune cell function. However, our ability to understand these intricacies of RLR function has been hampered by the current unavailability of conditional floxed animal models. The emergence of new tools, such as genome editing technologies and advances in generation of transgenic murine models, will aid in these efforts. Studies investigating the roles of these RLR agonists using RIG-I, MDA5 and LGP2 knockout mice, potentially in specific cell subtypes, will aid in unraveling the complex functions of RLR signaling in regulating antitumor and antiviral adaptive immune responses. Further understanding of the requirement for each RLR in specific subtypes will aid in development and refinement of specific RLR agonists for optimal context-specific immune activation.

Figures were created using BioRender.

This work was supported by National Institutes of Health Award K22AI146480 (to E.A.H.).

Abbreviations used in this article:

     
  • BMDC

    bone marrow–derived dendritic cell

  •  
  • BMM

    bone marrow macrophage

  •  
  • CARD

    caspase activation and recruitment domain

  •  
  • cDC

    conventional dendritic cell

  •  
  • DC

    dendritic cell

  •  
  • DDX58

    DExD-box helicase 58

  •  
  • DHX58

    DExH-box helicase 58

  •  
  • EMCV

    encephalomyocarditis virus

  •  
  • EV71

    severe enterovirus 71

  •  
  • HBV

    hepatitis B virus

  •  
  • HCV

    hepatitis C virus

  •  
  • IAV

    influenza A virus

  •  
  • IFIH1

    IFN induced with helicase C domain 1

  •  
  • IRF

    IFN regulatory factor

  •  
  • ISG

    IFN-stimulated gene

  •  
  • LGP2

    laboratory of genetics and physiology 2

  •  
  • MAM

    mitochondrial-associated membrane

  •  
  • MAVS

    mitochondrial antiviral signaling protein

  •  
  • MDA5

    melanoma differentiation–associated protein 5

  •  
  • moDC

    monocyte-derived dendritic cell

  •  
  • NOD

    nucleotide-binding and oligomerization domain

  •  
  • PAMP

    pathogen-associated molecular pattern

  •  
  • pDC

    plasmacytoid dendritic cell

  •  
  • poly(I:C)

    polyinosinic-polycytidylic acid

  •  
  • PRR

    pattern recognition receptor

  •  
  • RIG-I

    retinoic acid–inducible gene I

  •  
  • RLR

    retinoic acid–inducible gene I-like receptor

  •  
  • SeV

    Sendai virus

  •  
  • SLE

    systemic lupus erythematosus

  •  
  • SNP

    single nucleotide polymorphism

  •  
  • TBK1

    TANK-binding kinase 1

  •  
  • T1D

    type 1 diabetes

  •  
  • TFH

    T follicular helper

  •  
  • TRAF

    TNFR-associated factor

  •  
  • VSV

    vesicular stomatitis virus

  •  
  • WNV

    West Nile virus

1.
Hemann
E. A.
,
M.
Gale
Jr.
,
R.
Savan
.
2017
.
Interferon lambda genetics and biology in regulation of viral control.
Front. Immunol.
8
:
1707
.
2.
Dowling
J. W.
,
A.
Forero
.
2022
.
Beyond good and evil: molecular mechanisms of type I and III IFN functions.
J. Immunol.
208
:
247
256
.
3.
Iwasaki
A.
,
R.
Medzhitov
.
2010
.
Regulation of adaptive immunity by the innate immune system.
Science
327
:
291
295
.
4.
McNab
F.
,
K.
Mayer-Barber
,
A.
Sher
,
A.
Wack
,
A.
O’Garra
.
2015
.
Type I interferons in infectious disease.
Nat. Rev. Immunol.
15
:
87
103
.
5.
Zitvogel
L.
,
L.
Galluzzi
,
O.
Kepp
,
M. J.
Smyth
,
G.
Kroemer
.
2015
.
Type I interferons in anticancer immunity.
Nat. Rev. Immunol.
15
:
405
414
.
6.
Lazear
H. M.
,
J. W.
Schoggins
,
M. S.
Diamond
.
2019
.
Shared and distinct functions of type I and type III interferons.
Immunity
50
:
907
923
.
7.
Psarras
A.
,
P.
Emery
,
E. M.
Vital
.
2017
.
Type I interferon-mediated autoimmune diseases: pathogenesis, diagnosis and targeted therapy.
Rheumatology (Oxford)
56
:
1662
1675
.
8.
Crow
M. K.
,
M.
Olferiev
,
K. A.
Kirou
.
2019
.
Type I interferons in autoimmune disease.
Annu. Rev. Pathol.
14
:
369
393
.
9.
Hall
J. C.
,
A.
Rosen
.
2010
.
Type I interferons: crucial participants in disease amplification in autoimmunity.
Nat. Rev. Rheumatol.
6
:
40
49
.
10.
Sleijfer
S.
,
M.
Bannink
,
A. R.
Van Gool
,
W. H.
Kruit
,
G.
Stoter
.
2005
.
Side effects of interferon-alpha therapy.
Pharm. World Sci.
27
:
423
431
.
11.
Bourquin
C.
,
A.
Pommier
,
C.
Hotz
.
2020
.
Harnessing the immune system to fight cancer with Toll-like receptor and RIG-I-like receptor agonists.
Pharmacol. Res.
154
:
104192
.
12.
Wu
Y.
,
X.
Wu
,
L.
Wu
,
X.
Wang
,
Z.
Liu
.
2017
.
The anticancer functions of RIG-I-like receptors, RIG-I and MDA5, and their applications in cancer therapy.
Transl. Res.
190
:
51
60
.
13.
Duan
T.
,
Y.
Du
,
C.
Xing
,
H. Y.
Wang
,
R. F.
Wang
.
2022
.
Toll-like receptor signaling and its role in cell-mediated immunity.
Front. Immunol.
13
:
812774
.
14.
Wicherska-Pawłowska
K.
,
T.
Wróbel
,
J.
Rybka
.
2021
.
Toll-like receptors (TLRs), NOD-like receptors (NLRs), and RIG-I-like receptors (RLRs) in innate immunity. TLRs, NLRs, and RLRs ligands as immunotherapeutic agents for hematopoietic diseases.
Int. J. Mol. Sci.
22
:
13397
.
15.
Huérfano
S.
,
V.
Šroller
,
K.
Bruštíková
,
L.
Horníková
,
J.
Forstová
.
2022
.
The interplay between viruses and host DNA sensors.
Viruses
14
:
666
.
16.
Hopfner
K. P.
,
V.
Hornung
.
2020
.
Molecular mechanisms and cellular functions of cGAS-STING signalling.
Nat. Rev. Mol. Cell Biol.
21
:
501
521
.
17.
Fitzgerald
K. A.
,
J. C.
Kagan
.
2020
.
Toll-like receptors and the control of immunity.
Cell
180
:
1044
1066
.
18.
Cui
J.
,
Y.
Chen
,
H. Y.
Wang
,
R. F.
Wang
.
2014
.
Mechanisms and pathways of innate immune activation and regulation in health and cancer.
Hum. Vaccin. Immunother.
10
:
3270
3285
.
19.
Kawasaki
T.
,
T.
Kawai
.
2014
.
Toll-like receptor signaling pathways.
Front. Immunol.
5
:
461
.
20.
Ouyang
Y.
,
H.
Liao
,
Y.
Hu
,
K.
Luo
,
S.
Hu
,
H.
Zhu
.
2022
.
Innate immune evasion by human respiratory syncytial virus.
Front. Microbiol.
13
:
865592
.
21.
Sabbah
A.
,
T. H.
Chang
,
R.
Harnack
,
V.
Frohlich
,
K.
Tominaga
,
P. H.
Dube
,
Y.
Xiang
,
S.
Bose
.
2009
.
Activation of innate immune antiviral responses by Nod2.
Nat. Immunol.
10
:
1073
1080
.
22.
Keestra-Gounder
A. M.
,
R. M.
Tsolis
.
2017
.
NOD1 and NOD2: beyond peptidoglycan sensing.
Trends Immunol.
38
:
758
767
.
23.
Weber
A.
,
P.
Wasiliew
,
M.
Kracht
.
2010
.
Interleukin-1beta (IL-1beta) processing pathway.
Sci. Signal.
3
:
cm2
.
24.
Li
X.
,
Z.
Dong
,
Y.
Liu
,
W.
Song
,
J.
Pu
,
G.
Jiang
,
Y.
Wu
,
L.
Liu
,
X.
Huang
.
2021
.
A novel role for the regulatory Nod-like receptor NLRP12 in anti-dengue virus response.
Front. Immunol.
12
:
744880
.
25.
Motwani
M.
,
S.
Pesiridis
,
K. A.
Fitzgerald
.
2019
.
DNA sensing by the cGAS-STING pathway in health and disease.
Nat. Rev. Genet.
20
:
657
674
.
26.
Chen
Q.
,
L.
Sun
,
Z. J.
Chen
.
2016
.
Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing.
Nat. Immunol.
17
:
1142
1149
.
27.
Rehwinkel
J.
,
M. U.
Gack
.
2020
.
RIG-I-like receptors: their regulation and roles in RNA sensing.
Nat. Rev. Immunol.
20
:
537
551
.
28.
Thoresen
D.
,
W.
Wang
,
D.
Galls
,
R.
Guo
,
L.
Xu
,
A. M.
Pyle
.
2021
.
The molecular mechanism of RIG-I activation and signaling.
Immunol. Rev.
304
:
154
168
.
29.
Brisse
M.
,
H.
Ly
.
2019
.
Comparative structure and function analysis of the RIG-I-like receptors: RIG-I and MDA5.
Front. Immunol.
10
:
1586
.
30.
Loo
Y. M.
,
M.
Gale
Jr
.
2011
.
Immune signaling by RIG-I-like receptors.
Immunity
34
:
680
692
.
31.
Reikine
S.
,
J. B.
Nguyen
,
Y.
Modis
.
2014
.
Pattern recognition and signaling mechanisms of RIG-I and MDA5.
Front. Immunol.
5
:
342
.
32.
Bruns
A. M.
,
C. M.
Horvath
.
2015
.
LGP2 synergy with MDA5 in RLR-mediated RNA recognition and antiviral signaling.
Cytokine
74
:
198
206
.
33.
Rodriguez
K. R.
,
A. M.
Bruns
,
C. M.
Horvath
.
2014
.
MDA5 and LGP2: accomplices and antagonists of antiviral signal transduction.
J. Virol.
88
:
8194
8200
.
34.
Duic
I.
,
H.
Tadakuma
,
Y.
Harada
,
R.
Yamaue
,
K.
Deguchi
,
Y.
Suzuki
,
S. H.
Yoshimura
,
H.
Kato
,
K.
Takeyasu
,
T.
Fujita
.
2020
.
Viral RNA recognition by LGP2 and MDA5, and activation of signaling through step-by-step conformational changes.
Nucleic Acids Res.
48
:
11664
11674
.
35.
Esser-Nobis
K.
,
L. D.
Hatfield
,
M.
Gale
Jr
.
2020
.
Spatiotemporal dynamics of innate immune signaling via RIG-I-like receptors.
Proc. Natl. Acad. Sci. USA
117
:
15778
15788
.
36.
Goubau
D.
,
M.
Schlee
,
S.
Deddouche
,
A. J.
Pruijssers
,
T.
Zillinger
,
M.
Goldeck
,
C.
Schuberth
,
A. G.
Van der Veen
,
T.
Fujimura
,
J.
Rehwinkel
, et al
2014
.
Antiviral immunity via RIG-I-mediated recognition of RNA bearing 5′-diphosphates.
Nature
514
:
372
375
.
37.
Pichlmair
A.
,
O.
Schulz
,
C. P.
Tan
,
T. I.
Näslund
,
P.
Liljeström
,
F.
Weber
,
C.
Reis e Sousa
.
2006
.
RIG-I-mediated antiviral responses to single-stranded RNA bearing 5′-phosphates.
Science
314
:
997
1001
.
38.
Hornung
V.
,
J.
Ellegast
,
S.
Kim
,
K.
Brzózka
,
A.
Jung
,
H.
Kato
,
H.
Poeck
,
S.
Akira
,
K. K.
Conzelmann
,
M.
Schlee
, et al
2006
.
5′-triphosphate RNA is the ligand for RIG-I.
Science
314
:
994
997
.
39.
Schmidt
A.
,
T.
Schwerd
,
W.
Hamm
,
J. C.
Hellmuth
,
S.
Cui
,
M.
Wenzel
,
F. S.
Hoffmann
,
M. C.
Michallet
,
R.
Besch
,
K. P.
Hopfner
, et al
2009
.
5′-triphosphate RNA requires base-paired structures to activate antiviral signaling via RIG-I.
Proc. Natl. Acad. Sci. USA
106
:
12067
12072
.
40.
Schlee
M.
,
A.
Roth
,
V.
Hornung
,
C. A.
Hagmann
,
V.
Wimmenauer
,
W.
Barchet
,
C.
Coch
,
M.
Janke
,
A.
Mihailovic
,
G.
Wardle
, et al
2009
.
Recognition of 5′ triphosphate by RIG-I helicase requires short blunt double-stranded RNA as contained in panhandle of negative-strand virus.
Immunity
31
:
25
34
.
41.
Kato
H.
,
O.
Takeuchi
,
E.
Mikamo-Satoh
,
R.
Hirai
,
T.
Kawai
,
K.
Matsushita
,
A.
Hiiragi
,
T. S.
Dermody
,
T.
Fujita
,
S.
Akira
.
2008
.
Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5.
J. Exp. Med.
205
:
1601
1610
.
42.
Wu
B.
,
A.
Peisley
,
C.
Richards
,
H.
Yao
,
X.
Zeng
,
C.
Lin
,
F.
Chu
,
T.
Walz
,
S.
Hur
.
2013
.
Structural basis for dsRNA recognition, filament formation, and antiviral signal activation by MDA5.
Cell
152
:
276
289
.
43.
Bamming
D.
,
C. M.
Horvath
.
2009
.
Regulation of signal transduction by enzymatically inactive antiviral RNA helicase proteins MDA5, RIG-I, and LGP2.
J. Biol. Chem.
284
:
9700
9712
.
44.
Zhang
W.
,
G.
Wang
,
Z. G.
Xu
,
H.
Tu
,
F.
Hu
,
J.
Dai
,
Y.
Chang
,
Y.
Chen
,
Y.
Lu
,
H.
Zeng
, et al
2019
.
Lactate is a natural suppressor of RLR signaling by targeting MAVS.
Cell
178
:
176
189.e15
.
45.
Gack
M. U.
,
Y. C.
Shin
,
C. H.
Joo
,
T.
Urano
,
C.
Liang
,
L.
Sun
,
O.
Takeuchi
,
S.
Akira
,
Z.
Chen
,
S.
Inoue
,
J. U.
Jung
.
2007
.
TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity.
Nature
446
:
916
920
.
46.
Zhu
J.
,
Y.
Zhang
,
A.
Ghosh
,
R. A.
Cuevas
,
A.
Forero
,
J.
Dhar
,
M. S.
Ibsen
,
J. L.
Schmid-Burgk
,
T.
Schmidt
,
M. K.
Ganapathiraju
, et al
2014
.
Antiviral activity of human OASL protein is mediated by enhancing signaling of the RIG-I RNA sensor.
Immunity
40
:
936
948
.
47.
Chan
Y. K.
,
M. U.
Gack
.
2015
.
RIG-I-like receptor regulation in virus infection and immunity.
Curr. Opin. Virol.
12
:
7
14
.
48.
Jiang
M.
,
S.
Zhang
,
Z.
Yang
,
H.
Lin
,
J.
Zhu
,
L.
Liu
,
W.
Wang
,
S.
Liu
,
W.
Liu
,
Y.
Ma
, et al
2018
.
Self-recognition of an inducible host lncRNA by RIG-I feedback restricts innate immune response.
Cell
173
:
906
919.e13
.
49.
Jung
S.
,
T.
von Thülen
,
I.
Yang
,
V.
Laukemper
,
B.
Rupf
,
H.
Janga
,
G. D.
Panagiotidis
,
A.
Schoen
,
M.
Nicolai
,
L. N.
Schulte
, et al
2020
.
A ribosomal RNA fragment with 2′,3′-cyclic phosphate and GTP-binding activity acts as RIG-I ligand.
Nucleic Acids Res.
48
:
10397
10412
.
50.
Chiang
J. J.
,
K. M. J.
Sparrer
,
M.
van Gent
,
C.
Lässig
,
T.
Huang
,
N.
Osterrieder
,
K. P.
Hopfner
,
M. U.
Gack
.
2018
.
Viral unmasking of cellular 5S rRNA pseudogene transcripts induces RIG-I-mediated immunity.
Nat. Immunol.
19
:
53
62
.
51.
Malathi
K.
,
B.
Dong
,
M.
Gale
Jr.
,
R. H.
Silverman
.
2007
.
Small self-RNA generated by RNase L amplifies antiviral innate immunity.
Nature
448
:
816
819
.
52.
Stok
J. E.
,
M. E.
Vega Quiroz
,
A. G.
van der Veen
.
2020
.
Self RNA sensing by RIG-I-like receptors in viral infection and sterile inflammation.
J. Immunol.
205
:
883
891
.
53.
Kell
A. M.
,
M.
Gale
Jr
.
2015
.
RIG-I in RNA virus recognition.
Virology
479-480
:
110
121
.
54.
Ablasser
A.
,
S.
Hur
.
2020
.
Regulation of cGAS- and RLR-mediated immunity to nucleic acids.
Nat. Immunol.
21
:
17
29
.
55.
Iwasaki
A.
,
R.
Medzhitov
.
2015
.
Control of adaptive immunity by the innate immune system.
Nat. Immunol.
16
:
343
353
.
56.
Wu
X.
,
F.
Zang
,
M.
Liu
,
L.
Zhuo
,
J.
Wu
,
X.
Xia
,
Y.
Feng
,
R.
Yu
,
P.
Huang
,
S.
Yang
.
2019
.
Genetic variants in RIG-I-like receptor influences HCV clearance in Chinese Han population.
Epidemiol. Infect.
147
:
e195
.
57.
Yao
Y.
,
Y.
Shen
,
H.
Shao
,
Y.
Liu
,
Y.
Ji
,
G.
Du
,
X.
Ye
,
P.
Huang
,
H.
Chen
.
2021
.
Polymorphisms of RIG-I-like receptor influence HBV clearance in Chinese Han population.
J. Med. Virol.
93
:
4957
4965
.
58.
Li
Y. P.
,
C. R.
Liu
,
H. L.
Deng
,
M. Q.
Wang
,
Y.
Tian
,
Y.
Chen
,
Y. F.
Zhang
,
S. S.
Dang
,
S.
Zhai
.
2022
.
DNA methylation and single-nucleotide polymorphisms in DDX58 are associated with hand, foot and mouth disease caused by enterovirus 71.
PLoS Negl. Trop. Dis.
16
:
e0010090
.
59.
Erazo Luna
E. V.
,
C. J.
Echavarría Sierra
,
D. M.
Cornejo-Sánchez
,
G.
Sanclemente
,
N. G.
Pineda Trujillo
.
2021
.
Protective association exhibited by a single nucleotide polymorphism of the IFIH1 gene in patients with psoriasis: a case-control study.
Medwave
21
:
e8492
.
60.
Jang
M. A.
,
E. K.
Kim
,
H.
Now
,
N. T.
Nguyen
,
W. J.
Kim
,
J. Y.
Yoo
,
J.
Lee
,
Y. M.
Jeong
,
C. H.
Kim
,
O. H.
Kim
, et al
2015
.
Mutations in DDX58, which encodes RIG-I, cause atypical Singleton-Merten syndrome.
Am. J. Hum. Genet.
96
:
266
274
.
61.
Zhang
J.
,
X.
Liu
,
Y.
Meng
,
H.
Wu
,
Y.
Wu
,
B.
Yang
,
L.
Wang
.
2018
.
Autoimmune disease associated IFIH1 single nucleotide polymorphism related with IL-18 serum levels in Chinese systemic lupus erythematosus patients.
Sci. Rep.
8
:
9442
.
62.
Gorman
J. A.
,
C.
Hundhausen
,
J. S.
Errett
,
A. E.
Stone
,
E. J.
Allenspach
,
Y.
Ge
,
T.
Arkatkar
,
C.
Clough
,
X.
Dai
,
S.
Khim
, et al
2017
.
The A946T variant of the RNA sensor IFIH1 mediates an interferon program that limits viral infection but increases the risk for autoimmunity.
Nat. Immunol.
18
:
744
752
.
63.
Molineros
J. E.
,
A. K.
Maiti
,
C.
Sun
,
L. L.
Looger
,
S.
Han
,
X.
Kim-Howard
,
S.
Glenn
,
A.
Adler
,
J. A.
Kelly
,
T. B.
Niewold
, et al
BIOLUPUS Network
.
2013
.
Admixture mapping in lupus identifies multiple functional variants within IFIH1 associated with apoptosis, inflammation, and autoantibody production.
PLoS Genet.
9
:
e1003222
.
64.
Liu
S.
,
H.
Wang
,
Y.
Jin
,
R.
Podolsky
,
M. V.
Reddy
,
J.
Pedersen
,
B.
Bode
,
J.
Reed
,
D.
Steed
,
S.
Anderson
, et al
2009
.
IFIH1 polymorphisms are significantly associated with type 1 diabetes and IFIH1 gene expression in peripheral blood mononuclear cells.
Hum. Mol. Genet.
18
:
358
365
.
65.
Hebbar
P.
,
M.
Abu-Farha
,
F.
Alkayal
,
R.
Nizam
,
N.
Elkum
,
M.
Melhem
,
S. E.
John
,
A.
Channanath
,
J.
Abubaker
,
A.
Bennakhi
, et al
2020
.
Genome-wide association study identifies novel risk variants from RPS6KA1, CADPS, VARS, and DHX58 for fasting plasma glucose in Arab population.
Sci. Rep.
10
:
152
.
66.
Li
Y.
,
W.
Liao
,
M.
Cargill
,
M.
Chang
,
N.
Matsunami
,
B. J.
Feng
,
A.
Poon
,
K. P.
Callis-Duffin
,
J. J.
Catanese
,
A. M.
Bowcock
, et al
2010
.
Carriers of rare missense variants in IFIH1 are protected from psoriasis.
J. Invest. Dermatol.
130
:
2768
2772
.
67.
Chistiakov
D. A.
,
N. V.
Voronova
,
K. V.
Savost’Anov
,
R. I.
Turakulov
.
2010
.
Loss-of-function mutations E6 27X and I923V of IFIH1 are associated with lower poly(I:C)-induced interferon-β production in peripheral blood mononuclear cells of type 1 diabetes patients.
Hum. Immunol.
71
:
1128
1134
.
68.
Budu-Aggrey
A.
,
J.
Bowes
,
P. E.
Stuart
,
M.
Zawistowski
,
L. C.
Tsoi
,
R.
Nair
,
D. R.
Jadon
,
N.
McHugh
,
E.
Korendowych
,
J. T.
Elder
, et al
2017
.
A rare coding allele in IFIH1 is protective for psoriatic arthritis.
Ann. Rheum. Dis.
76
:
1321
1324
.
69.
Miya
T. V.
,
M. J.
Groome
,
D.
de Assis Rosa
.
2021
.
TLR genetic variation is associated with rotavirus-specific IgA seroconversion in South African Black infants after two doses of Rotarix vaccine.
Vaccine
39
:
7028
7035
.
70.
Nikitina
E.
,
I.
Larionova
,
E.
Choinzonov
,
J.
Kzhyshkowska
.
2018
.
Monocytes and macrophages as viral targets and reservoirs.
Int. J. Mol. Sci.
19
:
2821
.
71.
Reniewicz
P.
,
A.
Kula
,
E.
Makuch
,
M.
Ochnik
,
T.
Lipiński
,
J.
Siednienko
.
2021
.
Ligase pellino3 regulates macrophage action and survival in response to VSV infection in RIG-I-dependent path.
Oxid. Med. Cell. Longev.
2021
:
6668463
.
72.
Zhao
X.
,
H.
Chu
,
B. H.
Wong
,
M. C.
Chiu
,
D.
Wang
,
C.
Li
,
X.
Liu
,
D.
Yang
,
V. K.
Poon
,
J.
Cai
, et al
2020
.
Activation of C-type lectin receptor and (RIG)-I-like receptors contributes to proinflammatory response in Middle East respiratory syndrome coronavirus-infected macrophages.
J. Infect. Dis.
221
:
647
659
.
73.
Li
S.
,
Q.
Shao
,
Y.
Zhu
,
X.
Ji
,
J.
Luo
,
Y.
Xu
,
X.
Liu
,
W.
Zheng
,
N.
Chen
,
F.
Meurens
,
J.
Zhu
.
2021
.
Porcine RIG-I and MDA5 signaling CARD domains exert similar antiviral function against different viruses.
Front. Microbiol.
12
:
677634
.
74.
Yang
B.
,
C.
Shen
,
D.
Zhang
,
T.
Zhang
,
X.
Shi
,
J.
Yang
,
Y.
Hao
,
D.
Zhao
,
H.
Cui
,
X.
Yuan
, et al
2021
.
Mechanism of interaction between virus and host is inferred from the changes of gene expression in macrophages infected with African swine fever virus CN/GS/2018 strain. [Published erratum appears in 2021 Virol. J. 18: 186.]
Virol. J.
18
:
170
.
75.
Dutta
M.
,
S. J.
Robertson
,
A.
Okumura
,
D. P.
Scott
,
J.
Chang
,
J. M.
Weiss
,
G. L.
Sturdevant
,
F.
Feldmann
,
E.
Haddock
,
A. I.
Chiramel
, et al
2017
.
A systems approach reveals MAVS signaling in myeloid cells as critical for resistance to Ebola virus in murine models of infection.
Cell Rep.
18
:
816
829
.
76.
Li
S.
,
J.
Yang
,
Y.
Zhu
,
H.
Wang
,
X.
Ji
,
J.
Luo
,
Q.
Shao
,
Y.
Xu
,
X.
Liu
,
W.
Zheng
, et al
2021
.
Analysis of porcine RIG-I like receptors revealed the positive regulation of RIG-I and MDA5 by LGP2.
Front. Immunol.
12
:
609543
.
77.
Satoh
T.
,
H.
Kato
,
Y.
Kumagai
,
M.
Yoneyama
,
S.
Sato
,
K.
Matsushita
,
T.
Tsujimura
,
T.
Fujita
,
S.
Akira
,
O.
Takeuchi
.
2010
.
LGP2 is a positive regulator of RIG-I- and MDA5-mediated antiviral responses.
Proc. Natl. Acad. Sci. USA
107
:
1512
1517
.
78.
Hui
K. P.
,
S. M.
Lee
,
C. Y.
Cheung
,
H.
Mao
,
A. K.
Lai
,
R. W.
Chan
,
M. C.
Chan
,
W.
Tu
,
Y.
Guan
,
Y. L.
Lau
,
J. S.
Peiris
.
2011
.
H5N1 influenza virus-induced mediators upregulate RIG-I in uninfected cells by paracrine effects contributing to amplified cytokine cascades.
J. Infect. Dis.
204
:
1866
1878
.
79.
Roth-Cross
J. K.
,
S. J.
Bender
,
S. R.
Weiss
.
2008
.
Murine coronavirus mouse hepatitis virus is recognized by MDA5 and induces type I interferon in brain macrophages/microglia.
J. Virol.
82
:
9829
9838
.
80.
Errett
J. S.
,
M. S.
Suthar
,
A.
McMillan
,
M. S.
Diamond
,
M.
Gale
Jr
.
2013
.
The essential, nonredundant roles of RIG-I and MDA5 in detecting and controlling West Nile virus infection.
J. Virol.
87
:
11416
11425
.
81.
Stone
A. E. L.
,
R.
Green
,
C.
Wilkins
,
E. A.
Hemann
,
M.
Gale
Jr
.
2019
.
RIG-I-like receptors direct inflammatory macrophage polarization against West Nile virus infection.
Nat. Commun.
10
:
3649
.
82.
Faul
E. J.
,
C. N.
Wanjalla
,
M. S.
Suthar
,
M.
Gale
,
C.
Wirblich
,
M. J.
Schnell
.
2010
.
Rabies virus infection induces type I interferon production in an IPS-1 dependent manner while dendritic cell activation relies on IFNAR signaling.
PLoS Pathog.
6
:
e1001016
.
83.
Mesman
A. W.
,
E. M.
Zijlstra-Willems
,
T. M.
Kaptein
,
R. L.
de Swart
,
M. E.
Davis
,
M.
Ludlow
,
W. P.
Duprex
,
M. U.
Gack
,
S. I.
Gringhuis
,
T. B.
Geijtenbeek
.
2014
.
Measles virus suppresses RIG-I-like receptor activation in dendritic cells via DC-SIGN-mediated inhibition of PP1 phosphatases.
Cell Host Microbe
16
:
31
42
.
84.
Szabo
A.
,
K.
Bene
,
P.
Gogolák
,
B.
Réthi
,
Á.
Lányi
,
I.
Jankovich
,
B.
Dezső
,
E.
Rajnavölgyi
.
2012
.
RLR-mediated production of interferon-β by a human dendritic cell subset and its role in virus-specific immunity.
J. Leukoc. Biol.
92
:
159
169
.
85.
McCartney
S. A.
,
L. B.
Thackray
,
L.
Gitlin
,
S.
Gilfillan
,
H. W.
Virgin
,
M.
Colonna
.
2008
.
MDA-5 recognition of a murine norovirus. [Published erratum appears in 2008 PLoS Pathog. 4: 10.]
PLoS Pathog.
4
:
e1000108
.
86.
Gitlin
L.
,
W.
Barchet
,
S.
Gilfillan
,
M.
Cella
,
B.
Beutler
,
R. A.
Flavell
,
M. S.
Diamond
,
M.
Colonna
.
2006
.
Essential role of mda-5 in type I IFN responses to polyriboinosinic:polyribocytidylic acid and encephalomyocarditis picornavirus.
Proc. Natl. Acad. Sci. USA
103
:
8459
8464
.
87.
Kato
H.
,
S.
Sato
,
M.
Yoneyama
,
M.
Yamamoto
,
S.
Uematsu
,
K.
Matsui
,
T.
Tsujimura
,
K.
Takeda
,
T.
Fujita
,
O.
Takeuchi
,
S.
Akira
.
2005
.
Cell type-specific involvement of RIG-I in antiviral response.
Immunity
23
:
19
28
.
88.
Stone
A. E.
,
S.
Giugliano
,
G.
Schnell
,
L.
Cheng
,
K. F.
Leahy
,
L.
Golden-Mason
,
M.
Gale
Jr.
,
H. R.
Rosen
.
2013
.
Hepatitis C virus pathogen associated molecular pattern (PAMP) triggers production of lambda-interferons by human plasmacytoid dendritic cells. [Published erratum appears in 2013 PLoS Pathog. 9: 6.]
PLoS Pathog.
9
:
e1003316
.
89.
Luber
C. A.
,
J.
Cox
,
H.
Lauterbach
,
B.
Fancke
,
M.
Selbach
,
J.
Tschopp
,
S.
Akira
,
M.
Wiegand
,
H.
Hochrein
,
M.
O’Keeffe
,
M.
Mann
.
2010
.
Quantitative proteomics reveals subset-specific viral recognition in dendritic cells.
Immunity
32
:
279
289
.
90.
Wang
Y.
,
G.
Huang
,
P.
Vogel
,
G.
Neale
,
B.
Reizis
,
H.
Chi
.
2012
.
Transforming growth factor beta-activated kinase 1 (TAK1)-dependent checkpoint in the survival of dendritic cells promotes immune homeostasis and function.
Proc. Natl. Acad. Sci. USA
109
:
E343
E352
.
91.
Zhou
S.
,
A. M.
Cerny
,
A.
Zacharia
,
K. A.
Fitzgerald
,
E. A.
Kurt-Jones
,
R. W.
Finberg
.
2010
.
Induction and inhibition of type I interferon responses by distinct components of lymphocytic choriomeningitis virus.
J. Virol.
84
:
9452
9462
.
92.
Bowen
J. R.
,
K. M.
Quicke
,
M. S.
Maddur
,
J. T.
O’Neal
,
C. E.
McDonald
,
N. B.
Fedorova
,
V.
Puri
,
R. S.
Shabman
,
B.
Pulendran
,
M. S.
Suthar
.
2017
.
Zika virus antagonizes type I interferon responses during infection of human dendritic cells.
PLoS Pathog.
13
:
e1006164
.
93.
Kandasamy
M.
,
A.
Suryawanshi
,
S.
Tundup
,
J. T.
Perez
,
M.
Schmolke
,
S.
Manicassamy
,
B.
Manicassamy
.
2016
.
RIG-I signaling is critical for efficient polyfunctional T cell responses during influenza virus infection.
PLoS Pathog.
12
:
e1005754
.
94.
Sprokholt
J. K.
,
T. M.
Kaptein
,
J. L.
van Hamme
,
R. J.
Overmars
,
S. I.
Gringhuis
,
T. B. H.
Geijtenbeek
.
2017
.
RIG-I-like receptor triggering by dengue virus drives dendritic cell immune activation and TH1 differentiation.
J. Immunol.
198
:
4764
4771
.
95.
Sprokholt
J. K.
,
T. M.
Kaptein
,
J. L.
van Hamme
,
R. J.
Overmars
,
S. I.
Gringhuis
,
T. B. H.
Geijtenbeek
.
2017
.
RIG-I-like receptor activation by dengue virus drives follicular T helper cell formation and antibody production.
PLoS Pathog.
13
:
e1006738
.
96.
Roe
K.
,
D.
Giordano
,
L. B.
Young
,
K. E.
Draves
,
U.
Holder
,
M. S.
Suthar
,
M.
Gale
Jr.
,
E. A.
Clark
.
2019
.
Dendritic cell-associated MAVS is required to control West Nile virus replication and ensuing humoral immune responses.
PLoS One
14
:
e0218928
.
97.
Beljanski
V.
,
C.
Chiang
,
G. A.
Kirchenbaum
,
D.
Olagnier
,
C. E.
Bloom
,
T.
Wong
,
E. K.
Haddad
,
L.
Trautmann
,
T. M.
Ross
,
J.
Hiscott
.
2015
.
Enhanced influenza virus-like particle vaccination with a structurally optimized RIG-I agonist as adjuvant.
J. Virol.
89
:
10612
10624
.
98.
Zalinger
Z. B.
,
R.
Elliott
,
K. M.
Rose
,
S. R.
Weiss
.
2015
.
MDA5 is critical to host defense during infection with murine coronavirus.
J. Virol.
89
:
12330
12340
.
99.
Lazear
H. M.
,
A. K.
Pinto
,
H. J.
Ramos
,
S. C.
Vick
,
B.
Shrestha
,
M. S.
Suthar
,
M.
Gale
Jr.
,
M. S.
Diamond
.
2013
.
Pattern recognition receptor MDA5 modulates CD8+ T cell-dependent clearance of West Nile virus from the central nervous system.
J. Virol.
87
:
11401
11415
.
100.
Wang
Y.
,
M.
Swiecki
,
M.
Cella
,
G.
Alber
,
R. D.
Schreiber
,
S.
Gilfillan
,
M.
Colonna
.
2012
.
Timing and magnitude of type I interferon responses by distinct sensors impact CD8 T cell exhaustion and chronic viral infection.
Cell Host Microbe
11
:
631
642
.
101.
Wang
Y.
,
M.
Cella
,
S.
Gilfillan
,
M.
Colonna
.
2010
.
Cutting edge: polyinosinic:polycytidylic acid boosts the generation of memory CD8 T cells through melanoma differentiation-associated protein 5 expressed in stromal cells.
J. Immunol.
184
:
2751
2755
.
102.
Suthar
M. S.
,
H. J.
Ramos
,
M. M.
Brassil
,
J.
Netland
,
C. P.
Chappell
,
G.
Blahnik
,
A.
McMillan
,
M. S.
Diamond
,
E. A.
Clark
,
M. J.
Bevan
,
M.
Gale
Jr
.
2012
.
The RIG-I-like receptor LGP2 controls CD8(+) T cell survival and fitness.
Immunity
37
:
235
248
.
103.
Kato
H.
,
O.
Takeuchi
,
S.
Sato
,
M.
Yoneyama
,
M.
Yamamoto
,
K.
Matsui
,
S.
Uematsu
,
A.
Jung
,
T.
Kawai
,
K. J.
Ishii
, et al
2006
.
Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses.
Nature
441
:
101
105
.
104.
Wang
Y.
,
H. X.
Zhang
,
Y. P.
Sun
,
Z. X.
Liu
,
X. S.
Liu
,
L.
Wang
,
S. Y.
Lu
,
H.
Kong
,
Q. L.
Liu
,
X. H.
Li
, et al
2007
.
Rig-I-/- mice develop colitis associated with downregulation of G alpha i2.
Cell Res.
17
:
858
868
.
105.
Elion
D. L.
,
R. S.
Cook
.
2018
.
Harnessing RIG-I and intrinsic immunity in the tumor microenvironment for therapeutic cancer treatment.
Oncotarget
9
:
29007
29017
.
106.
Kasumba
D. M.
,
N.
Grandvaux
.
2019
.
Therapeutic targeting of RIG-I and MDA5 might not lead to the same Rome.
Trends Pharmacol. Sci.
40
:
116
127
.
107.
Luke
J. M.
,
G. G.
Simon
,
J.
Söderholm
,
J. S.
Errett
,
J. T.
August
,
M.
Gale
Jr.
,
C. P.
Hodgson
,
J. A.
Williams
.
2011
.
Coexpressed RIG-I agonist enhances humoral immune response to influenza virus DNA vaccine.
J. Virol.
85
:
1370
1383
.
108.
Martínez-Gil
L.
,
P. H.
Goff
,
R.
Hai
,
A.
García-Sastre
,
M. L.
Shaw
,
P.
Palese
.
2013
.
A Sendai virus-derived RNA agonist of RIG-I as a virus vaccine adjuvant.
J. Virol.
87
:
1290
1300
.
109.
Kulkarni
R. R.
,
M. A.
Rasheed
,
S. K.
Bhaumik
,
P.
Ranjan
,
W.
Cao
,
C.
Davis
,
K.
Marisetti
,
S.
Thomas
,
S.
Gangappa
,
S.
Sambhara
,
K.
Murali-Krishna
.
2014
.
Activation of the RIG-I pathway during influenza vaccination enhances the germinal center reaction, promotes T follicular helper cell induction, and provides a dose-sparing effect and protective immunity.
J. Virol.
88
:
13990
14001
.
110.
Masumi
A.
,
M.
Ito
,
K.
Mochida
,
I.
Hamaguchi
,
T.
Mizukami
,
H.
Momose
,
M.
Kuramitsu
,
M.
Tsuruhara
,
K.
Takizawa
,
A.
Kato
,
K.
Yamaguchi
.
2010
.
Enhanced RIG-I expression is mediated by interferon regulatory factor-2 in peripheral blood B cells from hepatitis C virus-infected patients.
Biochem. Biophys. Res. Commun.
391
:
1623
1628
.
111.
Perrot
I.
,
F.
Deauvieau
,
C.
Massacrier
,
N.
Hughes
,
P.
Garrone
,
I.
Durand
,
O.
Demaria
,
N.
Viaud
,
L.
Gauthier
,
M.
Blery
, et al
2010
.
TLR3 and Rig-like receptor on myeloid dendritic cells and Rig-like receptor on human NK cells are both mandatory for production of IFN-gamma in response to double-stranded RNA.
J. Immunol.
185
:
2080
2088
.
112.
McCartney
S.
,
W.
Vermi
,
S.
Gilfillan
,
M.
Cella
,
T. L.
Murphy
,
R. D.
Schreiber
,
K. M.
Murphy
,
M.
Colonna
.
2009
.
Distinct and complementary functions of MDA5 and TLR3 in poly(I:C)-mediated activation of mouse NK cells.
J. Exp. Med.
206
:
2967
2976
.
113.
Yang
Y.
,
Q.
Han
,
Z.
Hou
,
C.
Zhang
,
Z.
Tian
,
J.
Zhang
.
2017
.
Exosomes mediate hepatitis B virus (HBV) transmission and NK-cell dysfunction.
Cell. Mol. Immunol.
14
:
465
475
.
114.
Daßler-Plenker
J.
,
A.
Paschen
,
B.
Putschli
,
S.
Rattay
,
S.
Schmitz
,
M.
Goldeck
,
E.
Bartok
,
G.
Hartmann
,
C.
Coch
.
2019
.
Direct RIG-I activation in human NK cells induces TRAIL-dependent cytotoxicity toward autologous melanoma cells.
Int. J. Cancer
144
:
1645
1656
.
115.
Tsutsui-Takeuchi
M.
,
H.
Ushio
,
M.
Fukuda
,
T.
Yamada
,
F.
Niyonsaba
,
K.
Okumura
,
H.
Ogawa
,
S.
Ikeda
.
2015
.
Roles of retinoic acid-inducible gene-I-like receptors (RLRs), Toll-like receptor (TLR) 3 and 2′-5′ oligoadenylate synthetase as viral recognition receptors on human mast cells in response to viral infection.
Immunol. Res.
61
:
240
249
.
116.
Fukuda
M.
,
H.
Ushio
,
J.
Kawasaki
,
F.
Niyonsaba
,
M.
Takeuchi
,
T.
Baba
,
K.
Hiramatsu
,
K.
Okumura
,
H.
Ogawa
.
2013
.
Expression and functional characterization of retinoic acid-inducible gene-I-like receptors of mast cells in response to viral infection.
J. Innate Immun.
5
:
163
173
.
117.
Brown
M. G.
,
S. M.
McAlpine
,
Y. Y.
Huang
,
I. D.
Haidl
,
A.
Al-Afif
,
J. S.
Marshall
,
R.
Anderson
.
2012
.
RNA sensors enable human mast cell anti-viral chemokine production and IFN-mediated protection in response to antibody-enhanced dengue virus infection.
PLoS One
7
:
e34055
.
118.
Simon
H. U.
,
S.
Yousefi
,
N.
Germic
,
I. C.
Arnold
,
A.
Haczku
,
A. V.
Karaulov
,
D.
Simon
,
H. F.
Rosenberg
.
2020
.
The cellular functions of eosinophils: Collegium Internationale Allergologicum (CIA) update 2020.
Int. Arch. Allergy Immunol.
181
:
11
23
.
119.
Samarasinghe
A. E.
,
R. C.
Melo
,
S.
Duan
,
K. S.
LeMessurier
,
S.
Liedmann
,
S. L.
Surman
,
J. J.
Lee
,
J. L.
Hurwitz
,
P. G.
Thomas
,
J. A.
McCullers
.
2017
.
Eosinophils promote antiviral immunity in mice infected with influenza A virus.
J. Immunol.
198
:
3214
3226
.
120.
Kvarnhammar
A. M.
,
T.
Petterson
,
L. O.
Cardell
.
2011
.
NOD-like receptors and RIG-I-like receptors in human eosinophils: activation by NOD1 and NOD2 agonists.
Immunology
134
:
314
325
.
121.
Wong
C. K.
,
S.
Hu
,
K. M.
Leung
,
J.
Dong
,
L.
He
,
Y. J.
Chu
,
I. M.
Chu
,
H. N.
Qiu
,
K. Y.
Liu
,
C. W.
Lam
.
2013
.
NOD-like receptors mediated activation of eosinophils interacting with bronchial epithelial cells: a link between innate immunity and allergic asthma.
Cell. Mol. Immunol.
10
:
317
329
.
122.
Flores-Torres
A. S.
,
A.
Rendon
,
M. C.
Salinas-Carmona
,
E.
Salinas
,
A. G.
Rosas-Taraco
.
2021
.
Human eosinophils reduce viral titer, secrete IL-8, and increase RIG-I expression in response to influenza A H1N1 pdm09.
Viral Immunol.
34
:
573
578
.
123.
Tamassia
N.
,
V.
Le Moigne
,
M.
Rossato
,
M.
Donini
,
S.
McCartney
,
F.
Calzetti
,
M.
Colonna
,
F.
Bazzoni
,
M. A.
Cassatella
.
2008
.
Activation of an immunoregulatory and antiviral gene expression program in poly(I:C)-transfected human neutrophils.
J. Immunol.
181
:
6563
6573
.
124.
Giraldo
D. M.
,
J. C.
Hernandez
,
S.
Urcuqui-Inchima
.
2016
.
HIV-1-derived single-stranded RNA acts as activator of human neutrophils.
Immunol. Res.
64
:
1185
1194
.
125.
Hernandez
J. C.
,
D. M.
Giraldo
,
S.
Paul
,
S.
Urcuqui-Inchima
.
2015
.
Involvement of neutrophil hyporesponse and the role of Toll-like receptors in human immunodeficiency virus 1 protection.
PLoS One
10
:
e0119844
.
126.
Berger
M.
,
C. Y.
Hsieh
,
M.
Bakele
,
V.
Marcos
,
N.
Rieber
,
M.
Kormann
,
L.
Mays
,
L.
Hofer
,
O.
Neth
,
L.
Vitkov
, et al
2012
.
Neutrophils express distinct RNA receptors in a non-canonical way.
J. Biol. Chem.
287
:
19409
19417
.
127.
Duewell
P.
,
A.
Steger
,
H.
Lohr
,
H.
Bourhis
,
H.
Hoelz
,
S. V.
Kirchleitner
,
M. R.
Stieg
,
S.
Grassmann
,
S.
Kobold
,
J. T.
Siveke
, et al
2014
.
RIG-I-like helicases induce immunogenic cell death of pancreatic cancer cells and sensitize tumors toward killing by CD8(+) T cells. [Published erratum appears in 2014 Cell Death Differ. 21: 161.]
Cell Death Differ.
21
:
1825
1837
.
128.
Linehan
M. M.
,
T. H.
Dickey
,
E. S.
Molinari
,
M. E.
Fitzgerald
,
O.
Potapova
,
A.
Iwasaki
,
A. M.
Pyle
.
2018
.
A minimal RNA ligand for potent RIG-I activation in living mice.
Sci. Adv.
4
:
e1701854
.
129.
Elion
D. L.
,
M. E.
Jacobson
,
D. J.
Hicks
,
B.
Rahman
,
V.
Sanchez
,
P. I.
Gonzales-Ericsson
,
O.
Fedorova
,
A. M.
Pyle
,
J. T.
Wilson
,
R. S.
Cook
.
2018
.
Therapeutically active RIG-I agonist induces immunogenic tumor cell killing in breast cancers.
Cancer Res.
78
:
6183
6195
.
130.
Jiang
X.
,
V.
Muthusamy
,
O.
Fedorova
,
Y.
Kong
,
D. J.
Kim
,
M.
Bosenberg
,
A. M.
Pyle
,
A.
Iwasaki
.
2019
.
Intratumoral delivery of RIG-I agonist SLR14 induces robust antitumor responses.
J. Exp. Med.
216
:
2854
2868
.
131.
Mao
T.
,
B.
Israelow
,
C.
Lucas
,
C. B. F.
Vogels
,
M. L.
Gomez-Calvo
,
O.
Fedorova
,
M. I.
Breban
,
B. L.
Menasche
,
H.
Dong
,
M.
Linehan
, et al
Yale SARS-CoV-2 Genome Surveillance Initiative
.
2022
.
A stem-loop RNA RIG-I agonist protects against acute and chronic SARS-CoV-2 infection in mice.
J. Exp. Med.
219
:
e20211818
.
132.
Probst
P.
,
J. B.
Grigg
,
M.
Wang
,
E.
Muñoz
,
Y. M.
Loo
,
R. C.
Ireton
,
M.
Gale
Jr.
,
S. P.
Iadonato
,
K. M.
Bedard
.
2017
.
A small-molecule IRF3 agonist functions as an influenza vaccine adjuvant by modulating the antiviral immune response.
Vaccine
35
:
1964
1971
.

The authors have no financial conflicts of interest.