Abstract
Primary immunodeficiencies are often monogenic disorders characterized by vulnerability to specific infectious pathogens. Here, we performed whole-exome sequencing of a patient with disseminated Mycobacterium abscessus, Streptococcus viridians bacteremia, and cytomegalovirus (CMV) viremia and identified mutations in 2 genes that regulate distinct IFN pathways. The patient had a homozygous frameshift deletion in IFNGR2, which encodes the signal transducing chain of the IFN-γ receptor, that resulted in minimal protein expression and abolished downstream signaling. The patient also harbored a homozygous deletion in IFNAR1 (IFNAR1*557Gluext*46), which encodes the IFN-α receptor signaling subunit. The IFNAR1*557Gluext*46 resulted in replacement of the stop codon with 46 additional codons at the C-terminus. The level of IFNAR1*557Gluext*46 mutant protein expressed in patient fibroblasts was comparable to levels of WT IFNAR1 in control fibroblasts. IFN-α-induced signaling was impaired in the patient fibroblasts, as evidenced by decreased STAT1/STAT2 phosphorylation, nuclear translocation of STAT1, and expression of IFN-α-stimulated genes critical for CMV immunity. Pretreatment with IFN-α failed to suppress CMV protein expression in patient fibroblasts, whereas expression of WT IFNAR1 restored IFN-α-mediated suppression of CMV. This study identifies a human IFNAR1 mutation and describes a digenic immunodeficiency specific to type I and type II IFNs.
Keywords:
Immunology; Innate immunity; Virology.
Publication types
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Clinical Trial
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Bacteremia / genetics
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Bacteremia / immunology
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Bacteremia / microbiology
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Cytomegalovirus / immunology
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Cytomegalovirus Infections / genetics
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Cytomegalovirus Infections / immunology
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Female
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Fibroblasts / immunology
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Fibroblasts / microbiology
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Fibroblasts / virology
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Genetic Diseases, Inborn / genetics*
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Genetic Diseases, Inborn / immunology*
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Genetic Diseases, Inborn / microbiology
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Genetic Diseases, Inborn / virology
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Humans
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Immunologic Deficiency Syndromes / genetics*
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Immunologic Deficiency Syndromes / immunology*
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Immunologic Deficiency Syndromes / microbiology
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Immunologic Deficiency Syndromes / virology
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Male
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Mutation*
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Mycobacterium Infections, Nontuberculous / genetics
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Mycobacterium Infections, Nontuberculous / immunology
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Mycobacterium abscessus / immunology
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Phosphorylation / genetics
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Phosphorylation / immunology
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Receptor, Interferon alpha-beta* / genetics
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Receptor, Interferon alpha-beta* / immunology
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Receptors, Interferon* / genetics
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Receptors, Interferon* / immunology
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STAT1 Transcription Factor / genetics
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STAT1 Transcription Factor / immunology
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STAT2 Transcription Factor / genetics
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STAT2 Transcription Factor / immunology
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Streptococcal Infections / genetics
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Streptococcal Infections / immunology
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Viremia / genetics
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Viremia / immunology
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Viremia / virology
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Viridans Streptococci / immunology
Substances
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IFNAR1 protein, human
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IFNGR2 protein, human
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Receptors, Interferon
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STAT1 Transcription Factor
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STAT1 protein, human
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STAT2 Transcription Factor
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STAT2 protein, human
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Receptor, Interferon alpha-beta