Genetic Lesions of Type I Interferon Signalling in Human Antiviral Immunity
Authors: Christopher J.A. Duncan, Richard E. Randall, Sophie Hambleton
Journal: Trends in Genetics (2020)

Inborn errors of immunity affecting all key molecular components of the interferon (IFN)-I signalling pathway [IFN-alpha/beta receptor (IFNAR)1, IFNAR2, Janus kinase 1 (JAK1), tyrosine kinase 2 (TYK2), signal transducer and activator of transcription (STAT)1, STAT2, and interferon regulatory factor 9 (IRF9)] have been identified in humans.Deficiency of IFNAR results in potentially fatal susceptibility to live-attenuated viral vaccines, but without general susceptibility to common childhood viral diseases. Clinically evident vulnerability to a broader spectrum of viral diseases, including respiratory viruses such as influenza as well as live-attenuated viral vaccines, often accompanies deficiency of STAT2 and IRF9. These molecules transduce signals downstream of IFN-I and IFN-III, suggesting that the latter provides compensatory antiviral defence in IFNAR-deficient patients.Children with defects in IFN-I and IFN-III signalling are not particularly susceptible to viruses such as cytomegalovirus (CMV), suggesting that this virus has successfully evolved mechanisms to overcome IFN-I/III restriction.STAT1-deficient patients, who lack signalling in response to all types of IFN (I, II, and III), show the widest viral susceptibility of all.Pathological dissemination of parenterally delivered live-viral vaccines in otherwise healthy children should signify an inborn error of IFN-I immunity until proved otherwise. The concept that type I interferons (IFN-I) are essential to antiviral immunity derives from studies on animal models and cell lines. Virtually all pathogenic viruses have evolved countermeasures to IFN-I restriction, and genetic loss of viral IFN-I antagonists leads to virus attenuation. But just how important is IFN-I to antiviral defence in humans? The recent discovery of genetic defects of IFN-I signalling illuminates this and other questions of IFN biology, including the role of the mucosa-restricted type III IFNs (IFN-III), informing our understanding of the place of the IFN system within the concerted antiviral response. Here we review monogenic lesions of IFN-I signalling pathways and summarise the organising principles which emerge. The concept that type I interferons (IFN-I) are essential to antiviral immunity derives from studies on animal models and cell lines. Virtually all pathogenic viruses have evolved countermeasures to IFN-I restriction, and genetic loss of viral IFN-I antagonists leads to virus attenuation. But just how important is IFN-I to antiviral defence in humans? The recent discovery of genetic defects of IFN-I signalling illuminates this and other questions of IFN biology, including the role of the mucosa-restricted type III IFNs (IFN-III), informing our understanding of the place of the IFN system within the concerted antiviral response. Here we review monogenic lesions of IFN-I signalling pathways and summarise the organising principles which emerge. Interferon (IFN, see Glossary) was discovered more than 60 years ago by Isaacs and Lindemann [1.Isaacs A. Lindenmann J. Virus interference. I. The interferon.Proc. Biol. Sci. 1957; 147: 258-267Crossref PubMed Google Scholar]. This soluble factor, produced by virally infected cells in culture, conferred an antiviral state when applied to uninfected naïve cells prior to infection. Its discovery led to the clinical application of IFN-I (IFNα) as the first host-directed antiviral therapy [2.Friedman R.M. Clinical uses of interferons.Br. J. Clin. Pharmacol. 2008; 65: 158-162Crossref PubMed Scopus (80) Google Scholar]. Over the intervening six decades, the molecular basis of IFN-I activity has been carefully dissected (Box 1) and its essential function in antiviral defence has been confirmed in model organisms [3.McNab F. et al.Type I interferons in infectious disease.Nat. Rev. Immunol. 2015; 15: 87-103Crossref PubMed Scopus (1471) Google Scholar]. In parallel with these discoveries has come the realisation that virtually all human viral pathogens encode strategies to evade and/or subvert the antiviral activity of IFN-I [4.Randall R.E. Goodbourn S. Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures.J. Gen. 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Virol. 2008; 89: 1-47Crossref PubMed Scopus (1264) Google Scholar,5.Hoffmann H.H. et al.Interferons and viruses: an evolutionary arms race of molecular interactions.Trends Immunol. 2015; 36: 124-138Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar].Box 1Canonical IFN-I SignallingIn the current paradigm, the type I IFNs (IFN-Is) – comprising 13 subtypes of IFNα and one of IFNβ, IFNε, IFNκ, and IFNω – all signal at the single heterodimeric IFN alpha/beta receptor (IFNAR) expressed by all nucleated cells. By contrast, responses to the type III IFNs (IFNλ1–4, IFN-III), identified first in 2003 [8.Kotenko S.V. et al.IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex.Nat. Immunol. 2003; 4: 69-77Crossref PubMed Scopus (1569) Google Scholar, 9.Sheppard P. et al.IL-28, IL-29 and their class II cytokine receptor IL-28R.Nat. Immunol. 2003; 4: 63-68Crossref PubMed Scopus (1340) Google Scholar, 10.Prokunina-Olsson L. et al.A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus.Nat. Genet. 2013; 45: 164-171Crossref PubMed Scopus (754) Google Scholar], are constrained by the restricted expression of the IFN lambda receptor (IFNLR) on epithelial cells, (human) hepatocytes, and some immune cell subsets [11.Sommereyns C. et al.IFN-lambda (IFN-λ) is expressed in a tissue-dependent fashion and primarily acts on epithelial cells in vivo.PLoS Pathog. 2008; 4e1000017Crossref PubMed Scopus (636) Google Scholar,16.Klinkhammer J. et al.IFN-λ prevents influenza virus spread from the upper airways to the lungs and limits virus transmission.Elife. 2018; 7e33354Crossref PubMed Scopus (157) Google Scholar,60.Kreins A.Y. et al.Human TYK2 deficiency: mycobacterial and viral infections without hyper-IgE syndrome.J. Exp. 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In the canonical IFN-I pathway, IFN-I binding initiates an intracellular signalling cascade in which reciprocal transphosphorylation of the receptor-associated kinases JAK1 and TYK2 is accompanied by phosphorylation of the signal transducers and activators of transcription STAT1 and STAT2 [59.Velazquez L. et al.A protein tyrosine kinase in the interferon alpha/beta signaling pathway.Cell. 1992; 70: 313-322Abstract Full Text PDF PubMed Scopus (718) Google Scholar,83.Hwang S.Y. et al.A null mutation in the gene encoding a type I interferon receptor component eliminates antiproliferative and antiviral responses to interferons alpha and beta and alters macrophage responses.Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 11284-11288Crossref PubMed Scopus (332) Google Scholar,95.Muller M. et al.Complementation of a mutant cell line: central role of the 91 kDa polypeptide of ISGF3 in the interferon-α and -γ signal transduction pathways.EMBO J. 1993; 12: 4221-4228Crossref PubMed Scopus (374) Google Scholar]. The majority of the transcriptional response to IFN-I is attributable to the heterotrimer comprising phosphorylated STAT1 and 2 together with IRF9 [56.John J. et al.Isolation and characterization of a new mutant human cell line unresponsive to alpha and beta interferons.Mol. Cell. Biol. 1991; 11: 4189-4195Crossref PubMed Scopus (119) Google Scholar,95.Muller M. et al.Complementation of a mutant cell line: central role of the 91 kDa polypeptide of ISGF3 in the interferon-α and -γ signal transduction pathways.EMBO J. 1993; 12: 4221-4228Crossref PubMed Scopus (374) Google Scholar,96.Leung S. et al.Role of STAT2 in the alpha interferon signaling pathway.Mol. Cell. Biol. 1995; 15: 1312-1317Crossref PubMed Google Scholar]. This complex, known as ISGF3, translocates to the nucleus where it interacts with an ISRE [97.Levy D.E. et al.Interferon-induced nuclear factors that bind a shared promoter element correlate with positive and negative transcriptional control.Genes Dev. 1988; 2: 383-393Crossref PubMed Scopus (392) Google Scholar] in the promoter of multiple ISGs [97.Levy D.E. et al.Interferon-induced nuclear factors that bind a shared promoter element correlate with positive and negative transcriptional control.Genes Dev. 1988; 2: 383-393Crossref PubMed Scopus (392) Google Scholar]. A fraction of the phosphorylated STAT1 also homodimerises to form the GAF [98.Decker T. et al.Cytoplasmic activation of GAF, an IFN-γ-regulated DNA-binding factor.EMBO J. 1991; 10: 927-932Crossref PubMed Scopus (297) Google Scholar], agonising a distinct but overlapping set of genes bearing GAS elements, typically associated with type II IFN (IFNγ) signalling [98.Decker T. et al.Cytoplasmic activation of GAF, an IFN-γ-regulated DNA-binding factor.EMBO J. 1991; 10: 927-932Crossref PubMed Scopus (297) Google Scholar]. A broadly similar pathway is activated in response to IFN-III [8.Kotenko S.V. et al.IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex.Nat. Immunol. 2003; 4: 69-77Crossref PubMed Scopus (1569) Google Scholar, 9.Sheppard P. et al.IL-28, IL-29 and their class II cytokine receptor IL-28R.Nat. Immunol. 2003; 4: 63-68Crossref PubMed Scopus (1340) Google Scholar, 10.Prokunina-Olsson L. et al.A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus.Nat. Genet. 2013; 45: 164-171Crossref PubMed Scopus (754) Google Scholar]. This simplified model omits multiple STAT-dependent and STAT-independent signalling pathways activated downstream of IFNAR, some of which involve unphosphorylated ISGF3 components assembled in distinct transcriptional complexes (e.g., STAT2:IRF9, U-ISGF3) [99.Cheon H. et al.IFNβ-dependent increases in STAT1, STAT2, and IRF9 mediate resistance to viruses and DNA damage.EMBO J. 2013; 32: 2751-2763Crossref PubMed Scopus (222) Google Scholar]. In the current paradigm, the type I IFNs (IFN-Is) – comprising 13 subtypes of IFNα and one of IFNβ, IFNε, IFNκ, and IFNω – all signal at the single heterodimeric IFN alpha/beta receptor (IFNAR) expressed by all nucleated cells. By contrast, responses to the type III IFNs (IFNλ1–4, IFN-III), identified first in 2003 [8.Kotenko S.V. et al.IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex.Nat. Immunol. 2003; 4: 69-77Crossref PubMed Scopus (1569) Google Scholar, 9.Sheppard P. et al.IL-28, IL-29 and their class II cytokine receptor IL-28R.Nat. Immunol. 2003; 4: 63-68Crossref PubMed Scopus (1340) Google Scholar, 10.Prokunina-Olsson L. et al.A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus.Nat. Genet. 2013; 45: 164-171Crossref PubMed Scopus (754) Google Scholar], are constrained by the restricted expression of the IFN lambda receptor (IFNLR) on epithelial cells, (human) hepatocytes, and some immune cell subsets [11.Sommereyns C. et al.IFN-lambda (IFN-λ) is expressed in a tissue-dependent fashion and primarily acts on epithelial cells in vivo.PLoS Pathog. 2008; 4e1000017Crossref PubMed Scopus (636) Google Scholar,16.Klinkhammer J. et al.IFN-λ prevents influenza virus spread from the upper airways to the lungs and limits virus transmission.Elife. 2018; 7e33354Crossref PubMed Scopus (157) Google Scholar,60.Kreins A.Y. et al.Human TYK2 deficiency: mycobacterial and viral infections without hyper-IgE syndrome.J. Exp. Med. 2015; 212: 1641-1662Crossref PubMed Scopus (250) Google Scholar,61.Fuchs S. et al.Tyrosine kinase 2 is not limiting human antiviral type III interferon responses.Eur. J. Immunol. 2016; 46: 2639-2649Crossref PubMed Scopus (44) Google Scholar,71.Doyle S.E. et al.Interleukin-29 uses a type 1 interferon-like program to promote antiviral responses in human hepatocytes.Hepatology. 2006; 44: 896-906Crossref PubMed Scopus (321) Google Scholar]. In the canonical IFN-I pathway, IFN-I binding initiates an intracellular signalling cascade in which reciprocal transphosphorylation of the receptor-associated kinases JAK1 and TYK2 is accompanied by phosphorylation of the signal transducers and activators of transcription STAT1 and STAT2 [59.Velazquez L. et al.A protein tyrosine kinase in the interferon alpha/beta signaling pathway.Cell. 1992; 70: 313-322Abstract Full Text PDF PubMed Scopus (718) Google Scholar,83.Hwang S.Y. et al.A null mutation in the gene encoding a type I interferon receptor component eliminates antiproliferative and antiviral responses to interferons alpha and beta and alters macrophage responses.Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 11284-11288Crossref PubMed Scopus (332) Google Scholar,95.Muller M. et al.Complementation of a mutant cell line: central role of the 91 kDa polypeptide of ISGF3 in the interferon-α and -γ signal transduction pathways.EMBO J. 1993; 12: 4221-4228Crossref PubMed Scopus (374) Google Scholar]. The majority of the transcriptional response to IFN-I is attributable to the heterotrimer comprising phosphorylated STAT1 and 2 together with IRF9 [56.John J. et al.Isolation and characterization of a new mutant human cell line unresponsive to alpha and beta interferons.Mol. Cell. Biol. 1991; 11: 4189-4195Crossref PubMed Scopus (119) Google Scholar,95.Muller M. et al.Complementation of a mutant cell line: central role of the 91 kDa polypeptide of ISGF3 in the interferon-α and -γ signal transduction pathways.EMBO J. 1993; 12: 4221-4228Crossref PubMed Scopus (374) Google Scholar,96.Leung S. et al.Role of STAT2 in the alpha interferon signaling pathway.Mol. Cell. Biol. 1995; 15: 1312-1317Crossref PubMed Google Scholar]. This complex, known as ISGF3, translocates to the nucleus where it interacts with an ISRE [97.Levy D.E. et al.Interferon-induced nuclear factors that bind a shared promoter element correlate with positive and negative transcriptional control.Genes Dev. 1988; 2: 383-393Crossref PubMed Scopus (392) Google Scholar] in the promoter of multiple ISGs [97.Levy D.E. et al.Interferon-induced nuclear factors that bind a shared promoter element correlate with positive and negative transcriptional control.Genes Dev. 1988; 2: 383-393Crossref PubMed Scopus (392) Google Scholar]. A fraction of the phosphorylated STAT1 also homodimerises to form the GAF [98.Decker T. et al.Cytoplasmic activation of GAF, an IFN-γ-regulated DNA-binding factor.EMBO J. 1991; 10: 927-932Crossref PubMed Scopus (297) Google Scholar], agonising a distinct but overlapping set of genes bearing GAS elements, typically associated with type II IFN (IFNγ) signalling [98.Decker T. et al.Cytoplasmic activation of GAF, an IFN-γ-regulated DNA-binding factor.EMBO J. 1991; 10: 927-932Crossref PubMed Scopus (297) Google Scholar]. A broadly similar pathway is activated in response to IFN-III [8.Kotenko S.V. et al.IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex.Nat. Immunol. 2003; 4: 69-77Crossref PubMed Scopus (1569) Google Scholar, 9.Sheppard P. et al.IL-28, IL-29 and their class II cytokine receptor IL-28R.Nat. Immunol. 2003; 4: 63-68Crossref PubMed Scopus (1340) Google Scholar, 10.Prokunina-Olsson L. et al.A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus.Nat. Genet. 2013; 45: 164-171Crossref PubMed Scopus (754) Google Scholar]. This simplified model omits multiple STAT-dependent and STAT-independent signalling pathways activated downstream of IFNAR, some of which involve unphosphorylated ISGF3 components assembled in distinct transcriptional complexes (e.g., STAT2:IRF9, U-ISGF3) [99.Cheon H. et al.IFNβ-dependent increases in STAT1, STAT2, and IRF9 mediate resistance to viruses and DNA damage.EMBO J. 2013; 32: 2751-2763Crossref PubMed Scopus (222) Google Scholar]. IFN-I does not operate in isolation. Additional IFNs have been identified; namely, IFNγ (type II IFN) [7.Wheelock E.F. Interferon-like virus-inhibitor induced in human leukocytes by phytohemagglutinin.Science. 1965; 149: 310-311Crossref Scopus (471) Google Scholar] and the mucosa-restricted IFNs (IFNλ1–4, or type III IFNs) [8.Kotenko S.V. et al.IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex.Nat. Immunol. 2003; 4: 69-77Crossref PubMed Scopus (1569) Google Scholar, 9.Sheppard P. et al.IL-28, IL-29 and their class II cytokine receptor IL-28R.Nat. Immunol. 2003; 4: 63-68Crossref PubMed Scopus (1340) Google Scholar, 10.Prokunina-Olsson L. et al.A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus.Nat. Genet. 2013; 45: 164-171Crossref PubMed Scopus (754) Google Scholar]. These IFN types differ in their range of activity in tissues and their tendency to cause immunopathology and can be considered part of an integrated 'IFN system'. IFN-III is produced by most cells but acts mainly at epithelial surfaces, due to constrained receptor expression [11.Sommereyns C. et al.IFN-lambda (IFN-λ) is expressed in a tissue-dependent fashion and primarily acts on epithelial cells in vivo.PLoS Pathog. 2008; 4e1000017Crossref PubMed Scopus (636) Google Scholar]. IFN-III restricts virus replication at the point of initial encounter without inducing systemic immune activation or immunopathology [10.Prokunina-Olsson L. et al.A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus.Nat. 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By contrast, most tissues respond to IFN-I, which assumes greater importance when viruses breach epithelial barriers (e.g., invading into the lymphatics, bloodstream, or brain), but with an inherently greater risk of toxicity, particularly for the brain [17.Duncan C.J.A. et al.Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2.Sci. Immunol. 2019; 4eaav7501Crossref PubMed Scopus (62) Google Scholar]. Finally, type II IFN (IFN-II) (IFNγ) is an extremely potent immunostimulatory cytokine, with the greatest potential for immunopathology. While expression of the IFNγ receptor (IFNGR) is, like that of the IFN-I receptor (IFNAR), widespread, the production of IFNγ is tightly controlled and restricted to specialised immune cells [18.Schroder K. et al.Interferon-γ: an overview of signals, mechanisms and functions.J. Leukoc. Biol. 2004; 75: 163-189Crossref PubMed Scopus (3035) Google Scholar]. 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Within this group of autosomal recessive (AR) diseases are loss-of-expression variants negating the response to IFN-I alone (IFNAR1 or IFNAR2), responses to both IFN-I and IFN-III (i.e., STAT2, IRF9), and STAT1 variants, which negate responses to all IFNs (Figure 1). These inborn errors of immunity produce a phenotype of vulnerability to severe and/or recurrent viral disease (Table 1), the clinical significance of which depends on the extent of compromise to the IFN system as a whole. However, variable expressivity is also recognised; for example, ranging from death in infancy to survival into adulthood with no apparent phenotype in some signal transducer and activator of transcription (STAT)2-deficient patients [31.Hambleton S. et al.STAT2 deficiency and susceptibility to viral illness in humans.Proc. Natl. Acad. Sci. U. S. A. 2013; 110: 3053-3058Crossref PubMed Scopus (179) Google Scholar]. This may, among other factors, be due to environmental differences in the range and dose of viruses encountered by individual patients and/or the effectiveness of compensatory immune pathways against specific pathogens [32.Nish S. Medzhitov R. Host defense pathways: role of redundancy and compensation in infectious disease phenotypes.Immunity. 2011; 34: 629-636Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar].Table 1Human Molecular Defects of IFN-I Signalling and Their Associated PhenotypesaAll of the variants included above are pathogenic in homozygosity or compound heterozygosity., bAdV, adenovirus; CNS, central nervous system; ECMO, extracorporeal membrane oxygenation; EV, enterovirus; HHV6, human herpesvirus 6; HPV, human papillomavirus; HRV, human rhinovirus; IAV/IBV, influenza A/B virus; LPD, lymphoproliferative disease; MuV, mumps virus; NTM, nontuberculous mycobacteria; NTS, non-typhoidal Salmonella; PIV, parainfluenza virus; RTI, respiratory tract infection; SCIG, subcutaneous immunoglobulin; SNHL, sensorineural hearing loss; TB, tuberculosis.GeneProtein expressionSevere/recurrent viral diseaseUncomplicated infectionAsymptomatic exposureOther clinical manifestationRefsIFNAR1AbsentP1: MMR encephalitisP2: disseminated 17D YFV (MMR without incident)P1: noneP2: noneP1: CMVP2: CMV, HSV1, HSV2No[35.Hernandez N. et al.Inherited IFNAR1 deficiency in otherwise healthy patients with adverse reaction to measles and yellow fever live vaccines.J. Exp. Med. 2019; 216: 2057-2070Crossref PubMed Scopus (108) Google Scholar]IFNAR2AbsentP1: MMR encephalitis (fatal)P2: none (MMR withheld)P1: HHV6P2: noneP1: CMV, EBVP2: unknown (SCIG)No[33.Duncan C.J. et al.Human IFNAR2 deficiency: lessons for antiviral immunity.Sci. Transl. Med. 2015; 7307ra154Crossref PubMed Scopus (161) Google Scholar]STAT1AbsentP1: recurrent HSV encephalitis (fatal)P2: unknown viral pathogen (fatal)UnknownUnknownBoth: disseminated BCG[43.Dupuis S. et al.Impaired response to interferon-α/β and lethal viral disease in human STAT1 deficiency.Nat. Genet. 2003; 33: 388-391Crossref PubMed Scopus (649) Google Scholar]STAT1AbsentVaccine-strain polio virus sheddingEBV-driven LPD post-HSCTHRV, PIV2, polio vaccineNoneDisseminated BCGSevere hepatitisMultiorgan failure post-HSCT (fatal)[45.Chapgier A. et al.Human complete Stat-1 deficiency is associated with defective type I and II IFN responses in vitro but immunity to some low virulence viruses in vivo.J. Immunol. 2006; 176: 5078-5083Crossref PubMed Scopus (158) Google Scholar]STAT1Reduced expression of truncated nonfunctional protein (∆Ex3)Recurrent CMV pneumonitisEncephalitis (cause not identified)Viral GI infections and RTIsCutaneous HSV1UnknownPulmonary NTM infectionSepsisRecurrent pneumonia(BCG naïve)[44.Vairo D. et al.Severe impairment of IFN-γ and IFN-α responses in cells of a patient with a novel STAT1 splicing mutation.Blood. 2011; 118: 1806-1817Crossref PubMed Scopus (77) Google Scholar]STAT1AbsentHLH, possibly related to MMR and/or HHV6Nil statedUnknown(BCG naïve)[41.Burns C. et al.A novel presentation of homozygous loss-of-function STAT-1 mutation in an infant with hyperinflammation – a case report and review of the literature.J. Allergy Clin. Immunol. Pract. 2016; 4: 777-779Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar]STAT1Splicing defect (∆Ex23) with low-level expression of WT proteinP1: None notedP2: HSV1 gingivostomatitis, hospitalisation for CMV and VZV infectionUnknownUnknownP1: recurrent NTS infection (BCG naïve)P2: Salmonella meningitis (BCG naïve)[46.Chapgier A. et al.A partial form of recessive STAT1 deficiency in humans.J. Clin. Invest. 2009; 119: 1502-1514Crossref PubMed Scopus (151) Google Scholar]STAT1Splicing defect (∆Ex8) with low-level expression of WT proteinP1: severe varicellaP2: none notedUnknownP1: CMV, EBVP2: unknownP1: disseminated NTM infection (BCG naïve), Candida line infectionP2: disseminated BCGSeptic shock (fatal)[47.Kong X.F. et al.A novel form of human