Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2020 Dec 1.
Published in final edited form as: Curr Opin Pediatr. 2019 Dec;31(6):815–820. doi: 10.1097/MOP.0000000000000827

New Immunodeficiency syndromes that help us understand the IFN-mediated antiviral immune response

Huie Jing 1, Helen C Su 1,*
PMCID: PMC6993897  NIHMSID: NIHMS1549374  PMID: 31693592

Abstract

Purpose of review:

Studying primary immunodeficiencies (PIDs) provides insights into human antiviral immunity in the natural infectious environment. This review describes new PIDs with genetic defects that impair innate antiviral responses.

Recent findings:

New genetic defects in the interferon (IFN) signaling pathway include 1) IFNAR1 deficiency, which causes uncontrolled infections with measles-mumps-rubella or yellow fever vaccines, and possibly also cytomegalovirus (CMV), and 2) IRF9 deficiency, which results in influenza virus susceptibility. Genetic defects in several pattern recognition receptors include 1) MDA5 deficiency, which impairs viral RNA sensing and confers human rhinovirus susceptibility, 2) RNA polymerase III haploinsufficiency, which impairs sensing of A:T-rich virus DNA and confers VZV susceptibility, and 3) TLR3 deficiency, which causes HSV-1 encephalitis (HSE) or influenza virus pneumonitis. Defects in RNA metabolism, such as that due to DBR1 deficiency, can cause virus meningoencephalitis. Finally, defects in host restriction factors for virus replication, such as in CIB1 deficiency, contribute to uncontrolled β-HPV infections.

Summary:

Several new PIDs highlight the role of type I/III IFN signaling pathway, virus sensors, and host viral restriction factors in human antiviral immunity.

Keywords: primary immunodeficiency, virus susceptibility, type I IFN signaling, virus sensors, host restriction factors

Introduction:

Virus infections induce innate immune responses to limit virus replication and spread to nearby cells. Depending on the viruses and cell types, host cells utilize several pattern recognition receptors (PRRs) to sense viral RNA or DNA by detecting characteristic virus structural features and/or inappropriate subcellular localization of such nucleic acids [1, 2]. Cytosolic RIG-I-like receptors (RLRs) or endosomal Toll-like receptors (TLR3,7,8) sense viral RNA, whereas intracellular DNA sensors such as cGAS and TLR9 sense viral DNA [1, 2]. Activating PRRs trigger downstream signaling cascades, leading to production of proinflammatory cytokines and type I/III interferons (IFNs) that exert antiviral activity. IRF3 and IRF7 are key transcription factors for IFN induction [3]. IRF3 is ubiquitously expressed and activates early transcribed genes following PRR recognition. By contrast, except for high basal expression in plasmacytoid dendritic cells, IRF7 is expressed at very low levels in most cells, but is induced by type I IFNs, resulting in a positive loop that amplifies type I/III responses [3].

Type I IFNs bind the ubiquitously expressed heterodimeric IFN-α/β receptors 1 and 2 (IFNAR1, IFNAR2). Receptor ligation activates the associated JAK1 and TYK2 kinases. These kinases phosphorylate STAT1 and STAT2, then the p-STAT1-p-STAT2 heterodimer assembles along with IRF9 to form the ISGF3 complex. The ISGF3 complex binds to IFN-stimulated regulatory elements (ISRE) in the promoter regions of IFNs or IFN-inducible genes (ISGs), to turn on the transcription of genes having diverse antiviral effects [4]. Type III IFNs exhibit similar antiviral activity via binding to the type III IFN receptor composed of IFNLR1 and IL10RB subunits [5].

The importance of PRRs and IFN signaling pathways in antiviral immunity were largely established through studies in mice or in vitro using human cells, but the roles of these molecules in the course of natural infections in humans remain unclear. Various genetic defects in innate antiviral immunity have already been identified in patients with susceptibility to a broad range of viruses, for example patients with STAT1- or TYK2- deficiency [6, 7]. In contrast, IFNAR2- and STAT2- deficient patients have susceptibility seemingly only to the live attenuated measles-mumps-rubella (MMR) vaccine [8–10]. In this review we summarize several new PIDs discovered in the past 2 years that have illuminated further the physiological role in humans of IFN signaling intermediates, virus sensors, and host restriction factors for virus replication (listed in Table 1).

Table 1.

New virus susceptibility diseases caused by inborn errors of innate immunity

Gene or protein Disease inheritance (penetrance) Function Infection phenotype
IRF9 AR (incomplete) Type I/III IFN responses Influenza virus
IFNAR1 AR (complete) Type I IFN responses Measles-Mumps-Rubella (MMR) or yellow fever vaccines
IFIH1 (MDA5) AR (complete); AD (incomplete) RNA virus sensor Rhinovirus (HRV)
DDX58 (RIG-I) AD (incomplete) RNA virus sensor Influenza virus
RNA polymerase III complex AD (incomplete) DNA virus sensor Varicella zoster virus (VZV)
TLR3 AR, AD (incomplete) RNA virus sensor Herpes simplex encephalitis (HSE), influenza virus
DBR1 AR (complete) RNA metabolism Brainstem encephalitis (HSV1, influenza B virus, norovirus)
CIB1 AR (complete) Host restriction factor for virus replication β-HPV
Open in a new tab

AR, autosomal recessive; AD, autosomal dominant.

1. IFN pathway

Influenza virus infection usually causes self-limiting respiratory disease but can also cause life-threatening pneumonitis in patients with preexisting medical conditions or occasionally in previously healthy individuals [11]. One patient with IRF7 deficiency was reported in this latter group due to lack of IRF7-dependent type I/III IFN amplification in the respiratory tract [12]. More recently, two children who presented similarly were discovered to have autosomal recessive IRF9 deficiency [13**, 14*]. They had other viral illnesses besides severe influenza A virus (IAV), including biliary perforation following MMR vaccination and disseminated chickenpox with pneumonitis, but a third patient was healthy, indicating variable disease penetrance. Their homozygous splicing mutations caused loss of IRF9 expression, plus abnormal expression in one child of a truncated protein that could not bind the STAT1-STAT2 heterodimer. Overexpression of the truncated protein abolished reporter activity from an ISRE promoter driven by the ISGF3 complex, but not from a gamma activation sequence (GAS) promoter driven by STAT1-STAT1 homodimers. Furthermore, upon IFN-α stimulation, this patient’s cells phosphorylated STAT1 and STAT2 and formed GAS complexes normally, but did not form a functional ISGF3 complex. Patients’ cells had impaired induction of ISGs and failed to control replication in vitro of IAV and several other viruses [13**, 14*]. Importantly, introducing wild-type IRF9 into patients’ cells restricted virus replication, whereas virus replication was increased upon siRNA-mediated gene silencing of IRF9 expression in healthy control fibroblasts [13**]. These studies revealed that human IRF9- and ISGF3-dependent type I/III IFN responsive pathways are essential for host immunity against IAV.

A single IFNAR2-deficient patient presenting with a fatal meningoencephalitis due to uncontrolled replication of vaccine-strain MMR was previously reported [9]. In contrast, three autosomal recessive IFNAR1-deficient patients were recently described [15, 16*]. In one report of two unrelated patients, both had problems with disseminated virus infections following immunization with attenuated live virus, i.e., MMR and the yellow-fever (YF) vaccines. In vitro, the patients’ cells did not restrict the replication of measles, YF, and several other viruses. The mutations caused loss of IFNAR1 protein expression and loss of responsiveness to type I IFN; overexpression of wild-type IFNAR1 restored ability of the patients’ cells to restrict the replication of measles and YF viruses in vitro [16*].

In an additional report of a third patient with disseminated cytomegalovirus (CMV) and mycobacterial disease, the patient had a homozygous small deletion in IFNAR1 that rendered the protein non-functional, along with a homozygous loss-of-function mutation in IFNGR2 [15]. Although IFNGR2 deficiency has been associated with CMV disease [17], it should be noted that at least in vitro, the failure of the patient’s cells to control CMV replication could be overcome by overexpressing wild-type IFNAR1. Nevertheless, the digenic inheritance involving both type I and type II IFN pathways makes it difficult to distinguish the exact role of each gene in antiviral defense in this patient.

2. RNA sensors/MDA5/RIG-I:

RIG-I-like receptors (RLRs) such as melanoma differentiation-associated gene 5 (MDA5, encoded by IFIH1) and retinoic acid-inducible gene I (RIG-I, encoded by DDX58), function as intracellular cytosolic sensors of double-stranded dsRNA [1, 2]. dsRNA is normally absent within uninfected cells, but is generated as virus genomes or intermediates during replication of RNA viruses. Studies in mice and in vitro using human cells revealed that MDA5 recognizes and controls picornavirus and rotavirus, whereas RIG-I serves as the major sensor for the orthomyxoviridae, Flaviviridae, and paramyxoviridae virus families [18, 19]. MDA5 recognizes long dsRNA, whereas RIG-I recognizes short dsRNA as well as single-stranded RNA having a 5’- triphosphorylated (ppp) or 5’- diphosphorylated (pp). Upon binding of viral dsRNA, MDA5 or RIG-I assemble a signaling platform that activates the transcription factors NF-κB and IRF3 for production of proinflammatory cytokines and type I IFNs [2].

Several patients with severe, life-threatening respiratory virus infections have recently been identified with mutations in IFIH1 [20–22]. Three had rare autosomal recessive mutations that resulted in expression of a non-functional protein or loss of protein expression, leading to impaired downstream signaling through the IFN pathway [20–22]. Several patients had rare heterozygous loss-of-function mutations, which might act through a dominant-negative effect with incomplete disease penetrance [21]. Intact MDA5 function is required to restrict rhinovirus (HRV) replication, as convincingly shown using different experimental approaches [20, 21]. However, MDA5 and RIG-I probably have redundant roles against some viruses such as respiratory syncytial virus (RSV), as an intact RIG-I pathway in epithelial cells or primary fibroblasts effectively restricts RSV infection even in the absence of MDA5 [20]. Thus, depending upon the virus, treatment with IFN-α/β might potentially bypass the molecular defect in such genetically susceptible patients.

Finally, a patient with severe IAV infection was recently reported to have two heterozygous missense mutations in DDX58 carried in cis [23]. These mutations impaired the signaling activity of RIG-I as measured in an IFN-β reporter assay. Cells from the patient also expressed less IFN-β when stimulated by the synthetic agonist 5’ppp-dsRNA. However, upon in vitro infection with IAV, the patient’s cells transcribed normal levels of IFN, but increased levels of IL-6 and TNF-α. These results suggest that RIG-I haploinsufficiency could contribute to exaggerated immunopathology, perhaps associated with increased virus replication. These variants by themselves are unlikely to account for disease, since apparently healthy individuals with heterozygous loss-of-function DDX58 mutations exist in large genetic databases. Thus, the infection outcome may depend upon other factors such as the cell type, virus, and other host genetic variants in RNA sensors besides RIG-I, such as MDA5 and TLR3, having compensatory sensing function.

3. DNA sensor/RNA Polymerase III (POL III):

DNA is normally located within the nucleus or mitochondria of an uninfected cell, but can accumulate in the cytosol as virus genomes of DNA viruses or intermediates during replication of retroviruses. This accumulation is recognized by intracellular cytosolic sensors of DNA, either through the cGAS /STING pathway or through a STING-independent pathway [1]. RNA polymerase III (POL III) is a cytosolic DNA sensor that induces antiviral innate immune responses in a cGAS/STING- independent but RIG-I dependent pathway. POL III does this by transcribing A:T-rich virus DNA to generate 5’-ppp RNA, which binds to the RNA sensor RIG-I to activate type I IFN responses. POL III is a multi-subunit protein complex consisting of 17 subunits, and novel or rare heterozygous missense mutations in subunits A, C, E, and F have been reported in patients with severe varicella zoster virus (VZV) infections of the central nervous system (CNS) or lungs [24*, 25–26]. The mutations are inherited in an autosomal dominant manner with incomplete penetrance. Impaired induction of type I IFN transcripts was seen in patients’ cells in response to A:T-rich synthetic poly(dA:dT), VZV-derived-A:T-rich DNA, or actual VZV infection, but not to the intracellular RIG-I agonist poly(I:C) that bypasses the upstream POL III defect. Furthermore, upon in vitro infection with VZV, patients’ cells showed increased levels of an early VZV transcript, which were decreased after introducing wild type versions of the mutant genes. Of note, these effects seem specific to VZV, as induction of IFN-β transcripts after HSV infection, or IAV transcripts following infection, were normal. Taken together, the support the concept that POL III normally functions to control VZV primary infection in children as well as VZV reactivation in adults. These patients might also benefit from IFN-α/β treatment as well to bypass their molecular defect.

4. RNA sensor/TLR3

Other PRRs besides the RLRs, such as Toll-like receptors (TLR3/7/8), can sense RNA when virions are internalized through the endosomes [1, 2]. TLR3 recognizes dsRNA and TLR7/8 recognize ssRNA in the endosomal compartment. Upon recognition of dsRNA, TLR3 activates the IRF3 and NF-κB transcription factors for production of antiviral type I/III IFN responses.

The importance physiologically of TLR in human antiviral immunity was initially revealed in studies of an unusual presentation of herpes simplex virus (HSV) infection. HSV-1, which causes gingivostomatitis, orolabial or anogenital rash in the general population, can sometimes infect the forebrain in otherwise healthy individuals. This HSV encephalitis (HSE) can be caused by mutations in genes that participate in the TLR3 signaling pathway (TLR3, UNC93B1, TRIF, TRAF3, TBK1, or IRF3) [27–29]. However, incompletely penetrant heterozygous TLR3 mutations, including one previously associated with HSE, were more recently identified in three patients with severe IAV pneumonitis without HSE [30*]. Cells from these patients showed either impaired IFN responses and increased IAV replication, or normal responses depending upon tissue origin, suggesting a non-redundant role of TLR3 in parenchymal vs. hematopoietic cells. Importantly, the compromised responses in parenchymal cells were rescued by introducing wild-type TLR3 or pretreating with IFN-α to bypass the sensing defect. Taken together, these studies indicate that TLR3-dependent type I/III IFN immunity is critical for host defense against HSV-1 in the CNS and against IAV in the lung.

5. DBR1

Although HSE can result from defects in the TLR3 pathway, defects in host factors that directly impact virus transcription and replication can also contribute to susceptibility. Recently five patients from three unrelated kindreds, who suffered from brainstem encephalitis caused by different viruses (HSV1, influenza B virus, norovirus), were studied [31**]. The patients had an autosomal recessive disease with complete penetrance, caused by biallelic hypomorphic DBR1 mutations. DBR1 is highly expressed in human spinal cord and brainstem. As the only known lariat-debranching enzyme in humans, DBR1 normally linearizes lariat-intron RNA that is generated by the spliceosome during pre-mRNA splicing [32]. The mutant DBR1 proteins had decreased stability and impaired debranching of a synthetic RNA lariat mimic [31**]. Interestingly, having a nonsense mutation allele was associated with a more severe biochemical defect and additional clinical manifestations including intrauterine growth retardation, mental retardation, and congenital neutropenia. In the patients’ primary fibroblasts, DRB1 protein levels and intronic lariat RNA levels were inversely correlated. Whereas HSV-1 infection normally increased both host and viral intronic lariat RNA in healthy control cells, lariat RNA was markedly increased in patient cells. Finally, the patients’ fibroblasts did not control HSV-1 replication in vitro unless wild-type DBR1 was transduced. This study clearly shows that DBR1 is critical to prevent brainstem viral encephalitis but its molecular pathogenesis remains elusive. Interestingly, DBR1 deficiency did not disrupt TLR3- and IFN-responsive pathways, which are important for preventing HSE of the forebrain. Whether accumulation of RNA lariats interferes with virus recognition to impair host cell-intrinsic defenses is unknown.

6. Virus restriction factors CIB1-EVER1-EVER2

β-HPV infections are very common and self-resolve in the general population, but in some people can cause a condition called epidermodysplasia verruciformis (EV) characterized by multiple polymorphic skin lesions having a high risk of transformation to nonmelanoma skin cancer (NMSC) [33]. Patients with classical EV have an isolated susceptibility to β-HPV infections, without defects in adaptive immunity, suggesting a defect in keratinocyte-intrinsic immunity to β-HPV. EV is inherited in an autosomal recessive pattern, and biallelic loss-of-function mutations in TMC6 or TMC8 (encoding EVER1 or EVER 2 proteins, respectively) account for ~50% of all known cases with full clinical penetrance [33, 34]. Recently, autosomal recessive mutations in CIB1 (for calcium- and integrin-binding protein 1), were identified as a third cause of EV [35**, 36]. de Jong et al used genome wide linkage and whole-exome sequencing to identify CIB1 as the only gene mutated among 24 patients from six families [35**]. CIB1 protein, which is normally expressed ubiquitously, was absent in patients’ skin biopsy tissues, keratinocytes, or immune cells. Human CIB1 deficiency did not recapitulate previously reported functions of murine CIB1 such as keratinocyte adhesion and migration, nor did it phenocopy previously reported functions of EVER1 and EVER2 proteins in regulating intracellular free zinc and NF-κB signaling. Interestingly, CIB1 protein expression is very low in either EVER1- or EVER2- deficient patient cells, but can be restored upon introduction of EVER1 in EVER1-deficient cells or of EVER2 in EVER2-deficient cells. The authors demonstrated that CIB1 interacts with EVER1 and EVER2 to form a multimeric complex that stabilizes CIB1 protein, and that loss of this complex probably accounts for the indistinguishable clinical and virological phenotypes of EVER1-, EVER2-, and CIB1-deficient patients. In a human keratinocyte cell line, CIB1 normally interacted with the HPV virus proteins E8 and E5, which are expressed in other HPV but not in β-HPV to which EV patients are susceptible. Thus, the CIB1-EVER1-EVER2 complex was proposed to function as a restriction factor for β-HPV through an unknown mechanism, with loss of the complex due to loss-of-function mutations in EVER1, EVER2 or CIB1 leading to disease upon β-HPV infection. Since the authors also showed that the E5 and E8 proteins from other groups of HPVs can interact with the CIB1-EVER1-EVER2 complex, they speculated that those non-β-HPVs are able to escape the restriction activity of the CIB1-EVER1-EVER2 complex, and that this is why α-HPV universally cause clinical disease in the general population. Uncovering exactly how this complex exerts its ability to restrict HPV replication will be important to clarify whether this model is correct.

Conclusions:

Progress has been made in identifying new PIDs characterized by susceptibility to virus infections. These are caused by mutations in genes participating in innate antiviral defenses, including type I/III IFN responses, virus sensors, and host restriction factors for virus replication. In some cases, susceptibilities seem restricted to a narrow range of virus infections, or even one particular virus. This property can be explained by the specific antiviral activities of the affected genes which function as sensors to detect physical properties characteristic of certain viruses, or restriction factors that are directed to specific virus proteins. By contrast, defects in adaptive immunity as seen in combined immunodeficiencies generally predispose patients to a very broad range of virus and other infections, although certain exceptions are observed, e.g., in the case of EBV susceptibility where EBV control is exquisitely dependent upon T cell functions as shown by defects in the CD70/CD27/ITK pathway [37]. However, a cautionary note should be sounded when conclusions are based upon a few patients, since ascertainment bias might incorrectly lead to premature conclusions that a particular gene mutation results in a limited infection susceptibility. Moreover, the genotype-phenotype relationships of a given inborn error could be influenced by other factors such as virus strain, virus load, and host genetic background. Clarification of the potential contribution of these other factors in modulating monogenic susceptibility to infection will require future research.

Key points:

  • Inborn errors of innate immunity that affect type I/III IFN signaling, virus sensors, and host restriction factors for virus replication, may predispose individuals to severe virus infections.

  • Defects in innate immunity can confer susceptibilities to a relative narrow range of virus infections.

  • Genotype-phenotype relationships in a given inborn error are probably influenced by factors such as virus strain, virus load, and host genetic background.

Acknowledgements

Financial support and sponsorship: This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Footnotes

Conflicts of interest: none

References:

  • 1.Matz KM, Guzman RM, Goodman AG. The Role of Nucleic Acid Sensing in Controlling Microbial and Autoimmune Disorders. Int Rev Cell Mol Biol. 2019;345:35–136. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Chow KT, Gale M Jr, Loo YM. RIG-I and Other RNA Sensors in Antiviral Immunity. Annu Rev Immunol. 2018;36:667–94. [DOI] [PubMed] [Google Scholar]
  • 3.Honda K, Taniguchi T. IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors. Nat Rev Immunol. 2006;6(9):644–58. [DOI] [PubMed] [Google Scholar]
  • 4.Lukhele S, Boukhaled GM, Brooks DG. Type I interferon signaling, regulation and gene stimulation in chronic virus infection. Semin Immunol. 2019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Lazear HM, Schoggins JW, Diamond MS. Shared and Distinct Functions of Type I and Type III Interferons. Immunity. 2019;50(4):907–23. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Dupuis S, Jouanguy E, Al-Hajjar S, et al. Impaired response to interferon-alpha/beta and lethal viral disease in human STAT1 deficiency. Nat Genet. 2003;33(3):388–91. [DOI] [PubMed] [Google Scholar]
  • 7.Kreins AY, Ciancanelli MJ, Okada S, et al. Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome. J Exp Med. 2015;212(10):1641–62. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Hambleton S, Goodbourn S, Young DF, et al. STAT2 deficiency and susceptibility to viral illness in humans. Proc Natl Acad Sci U S A. 2013;110(8):3053–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Duncan CJ, Mohamad SM, Young DF, et al. Human IFNAR2 deficiency: Lessons for antiviral immunity. Sci Transl Med. 2015;7(307):307ra154. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Moens L, Van Eyck L, Jochmans D, et al. A novel kindred with inherited STAT2 deficiency and severe viral illness. J Allergy Clin Immunol. 2017;139(6):1995–7.e9. [DOI] [PubMed] [Google Scholar]
  • 11.Short KR, Kroeze E, Fouchier RAM, Kuiken T. Pathogenesis of influenza-induced acute respiratory distress syndrome. Lancet Infect Dis. 2014;14(1):57–69. [DOI] [PubMed] [Google Scholar]
  • 12.Ciancanelli MJ, Huang SX, Luthra P, et al. Infectious disease. Life-threatening influenza and impaired interferon amplification in human IRF7 deficiency. Science. 2015;348(6233):448–53. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.**.Hernandez N, Melki I, Jing H, et al. Life-threatening influenza pneumonitis in a child with inherited IRF9 deficiency. J Exp Med. 2018;215(10):2567–85. [DOI] [PMC free article] [PubMed] [Google Scholar]; This paper studies autosomal recessive IRF9 deficiency in a patient with severe influenza and suggests that human ISGF3-dependent type I/III IFN responsive pathways have an essential role in host immunity against influenza A virus infection.
  • 14.*.Bravo Garcia-Morato M, Calvo Apalategi A, Bravo-Gallego LY, et al. Impaired control of multiple viral infections in a family with complete IRF9 deficiency. J Allergy Clin Immunol. 2019;144(1):309–12.e10. [DOI] [PubMed] [Google Scholar]; The paper identifies a second IRF9-deficient patient with similar viral infections and further reveals the important role of IRF9- and ISGF3-dependent type I/III IFN immunity in host antiviral response.
  • 15.Hoyos-Bachiloglu R, Chou J, Sodroski CN, et al. A digenic human immunodeficiency characterized by IFNAR1 and IFNGR2 mutations. J Clin Invest. 2017;127(12):4415–20. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.*.Hernandez N, Bucciol G, Moens L, et al. Inherited IFNAR1 deficiency in otherwise healthy patients with adverse reaction to measles and yellow fever live vaccines. J Exp Med. 2019. [DOI] [PMC free article] [PubMed] [Google Scholar]; This paper identifies two additional IFNAR1 deficient patients with severe infections due to live-attenuated MMR or YF vaccines, similar to previously reported IFNAR2-or STAT2-deficient patients, and reveals that type I IFN responsive pathway is crucial for host immunity against such live-attenuated vaccines.
  • 17.Rosenzweig SD, Dorman SE, Uzel G, et al. A novel mutation in IFN-gamma receptor 2 with dominant negative activity: biological consequences of homozygous and heterozygous states. J Immunol. 2004;173(6):4000–8. [DOI] [PubMed] [Google Scholar]
  • 18.Loo YM, Fornek J, Crochet N, et al. Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity. J Virol. 2008;82(1):335–45. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Dou Y, Yim HC, Kirkwood CD, et al. The innate immune receptor MDA5 limits rotavirus infection but promotes cell death and pancreatic inflammation. Embo j. 2017;36(18):2742–57. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Lamborn IT, Jing H, Zhang Y, et al. Recurrent rhinovirus infections in a child with inherited MDA5 deficiency. J Exp Med. 2017;214(7):1949–72. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Asgari S, Schlapbach LJ, Anchisi S, et al. Severe viral respiratory infections in children with IFIH1 loss-of-function mutations. Proc Natl Acad Sci U S A. 2017;114(31):8342–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Zaki M, Thoenes M, Kawalia A, et al. Recurrent and Prolonged Infections in a Child with a Homozygous IFIH1 Nonsense Mutation. Front Genet. 2017;8:130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Jorgensen SE, Christiansen M, Ryo LB, et al. Defective RNA sensing by RIG-I in severe influenza virus infection. Clin Exp Immunol. 2018;192(3):366–76. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.*.Carter-Timofte ME, Hansen AF, Christiansen M, et al. Mutations in RNA Polymerase III genes and defective DNA sensing in adults with varicella-zoster virus CNS infection. Genes Immun. 2019;20(3):214–23. [DOI] [PubMed] [Google Scholar]; This study reports two adult POL III haploinsufficient patients with VZV meningoencephalitis, and found that patients’ cells could not sense A:T-rich VZV DNA to activate type I IFN responses. This work supports the concept that POL III functions as a DNA sensor to control VZV primary infection or reactivation.
  • 25.Carter-Timofte ME, Hansen AF, Mardahl M, et al. Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins. Neurol Neuroimmunol Neuroinflamm. 2018;5(6):e500. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Ogunjimi B, Zhang SY, Sorensen KB, et al. Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections. J Clin Invest. 2017;127(9):3543–56. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Zhang SY, Casanova JL. Inborn errors underlying herpes simplex encephalitis: From TLR3 to IRF3. J Exp Med. 2015;212(9):1342–3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Sancho-Shimizu V, Perez de Diego R, Jouanguy E, et al. Inborn errors of anti-viral interferon immunity in humans. Curr Opin Virol. 2011;1(6):487–96. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Zhang SY, Jouanguy E, Ugolini S, et al. TLR3 deficiency in patients with herpes simplex encephalitis. Science. 2007;317(5844):1522–7. [DOI] [PubMed] [Google Scholar]
  • 30.*.Lim HK, Huang SXL, Chen J, et al. Severe influenza pneumonitis in children with inherited TLR3 deficiency. J Exp Med. 2019. [DOI] [PMC free article] [PubMed] [Google Scholar]; This paper identifies heterozygous TLR3 mutations as a genetic etiology of influenza pneumonitis with incomplete clinical penetrance. This work expands the clinical disease spectrum of TLR3 deficiency beyond HSE.
  • 31.**.Zhang SY, Clark NE, Freije CA, et al. Inborn Errors of RNA Lariat Metabolism in Humans with Brainstem Viral Infection. Cell. 2018;172(5):952–65.e18. [DOI] [PMC free article] [PubMed] [Google Scholar]; This study demonstrates that defects in lariat RNA metabolism due to biallelic hypomorphic DBR1 mutations underlie HSE of the brainstem, through a mechanism that does not disrupt TLR3-responsive pathways.
  • 32.Chapman KB, Boeke JD. Isolation and characterization of the gene encoding yeast debranching enzyme. Cell. 1991;65(3):483–92. [DOI] [PubMed] [Google Scholar]
  • 33.de Jong SJ, Imahorn E, Itin P, et al. Epidermodysplasia Verruciformis: Inborn Errors of Immunity to Human Beta-Papillomaviruses. Front Microbiol. 2018;9:1222. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Ramoz N, Rueda LA, Bouadjar B, et al. Mutations in two adjacent novel genes are associated with epidermodysplasia verruciformis. Nat Genet. 2002;32(4):579–81. [DOI] [PubMed] [Google Scholar]
  • 35.**.de Jong SJ, Crequer A, Matos I, et al. The human CIB1-EVER1-EVER2 complex governs keratinocyte-intrinsic immunity to beta-papillomaviruses. J Exp Med. 2018;215(9):2289–310. [DOI] [PMC free article] [PubMed] [Google Scholar]; This paper reports autosomal recessive CIB1 deficiency as a third genetic etiology of typical epidermodysplasia verruciformis, and provides experimental evidence that CIB1-EVER1-EVER2 complex may functions as a host restriction factor for replication of β-HPV.
  • 36.Vahidnezhad H, Youssefian L, Saeidian AH, et al. A CIB1 Splice-Site Founder Mutation in Families with Typical Epidermodysplasia Verruciformis. J Invest Dermatol. 2019;139(5):1195–8. [DOI] [PubMed] [Google Scholar]
  • 37.Abolhassani H, Edwards ES, Ikinciogullari A, et al. Combined immunodeficiency and Epstein-Barr virus-induced B cell malignancy in humans with inherited CD70 deficiency. J Exp Med. 2017;214(1):91–106. [DOI] [PMC free article] [PubMed] [Google Scholar]

RESOURCES