Table 1. Common characteristics of... | Rockefeller University Press

Table 1.

Common characteristics of IE-IRFs

Gene		IRF1	IRF3		IRF4				IRF6		IRF7		IRF8		IRF9
Inheritance pattern		AR	AD (HSE)	AD	AD (T95R)	AD (F359L)	AD (R98W)	AR (V405Gfs Ter127)	AD (VWS)	AD (PPS)	AR	AD	AR	AD	AR
Mechanism		LOF	HI	HI	MM	MM	HI	UPD	HI	DN	LOF	?	LOF	DN	LOF
Bacterial susceptibility		✔			✔	✔	✔	?					✔	✔
Viral susceptibility			✔	✔	✔	✔		✔			✔	✔	✔	✔	✔
Known pathogen range		Weakly virulent mycobacteria + Histoplasma capsulatum	HSV	Respiratory viral infections: Severe SARS-CoV-2 and influenza	P. jirovecii, vaccine strain BCG, M. bovis, CMV, EBV, … (see Table 2)	CMV, HSV, VZV, oral mycosis, G. lamblia, onychomycosis, … (see Table 2)	Tw	Rotavirus, C. albicans, HSV, respiratory infections (unknown cause)	No known infection susceptibility	No known infection susceptibility	Respiratory viral infections: severe SARS-CoV-2 and influenza + RSV, TBE virus, and adenovirus	Respiratory viral infections: severe SARS-CoV-2 and influenza	Weakly virulent mycobacteria		Respiratory viral infections: severe SARS-CoV-2 and influenza + eight other viruses (see Table 2)
Known pathogen range		Weakly virulent mycobacteria + Histoplasma capsulatum	HSV				Tw		No known infection susceptibility	No known infection susceptibility			+ EBV, influenza, C. albicans, rhinovirus, HPV, CMV, and mycoplasma	+ EBV, HPV, recurrent Clostridium difficile
Cellular abnormalities	CD4⁺ T cells	↑↓			↓	↑↓		↑↓					↓	↑	↓
	CD8⁺ T cells	↑↓				↑↓		↓					↓
	NK cells	↓↓											↓		↓
	B cells	↑			↓↓	↓		↓					↓	↓	↓
	DCs	↓						↑↓					↓↓/↓↓↓	↓
	Monocytes							↑↓					↓↓/↓↓↓	↑
IFN impairment		IFN-γ	IFN-α/β	IFN-α/β	IFN-γ		IFN-γ	IFN-γ			IFN-α/β/λ1	IFN-α/β	IFN-γ	IFN-α	IFN-α
Gene expression defect		↓	↓	↓	↑↓	↑↓	↓	↓	Likely ↓		↓	↓	↓	↓	↓
Other defects		Reduced innate lymphoid precursors			Hypogammaglobulinemia	Hypogammaglobulinemia, premature hair graying		Agammaglobulinemia, hypereosinophilia, and hemophagocytosis	Lip pits and CLP	Lip pits, CLP, popliteal webbing, syndactyly, hypodontia, and deformities of the limbs and genitals	Impaired viral control in fibroblasts and pulmonary epithelia	Impaired IAV control in macrophages	Increased hypofunctional granulocytes. Intracerebral calcification and developmental delay	Mild neutrophilia	Impaired IAV control in fibroblasts, hypogammaglobulinemia

Gene		IRF1	IRF3		IRF4				IRF6		IRF7		IRF8		IRF9
Inheritance pattern		AR	AD (HSE)	AD	AD (T95R)	AD (F359L)	AD (R98W)	AR (V405GfsTer127)	AD (VWS)	AD (PPS)	AR	AD	AR	AD	AR
Mechanism		LOF	HI	HI	MM	MM	HI	UPD	HI	DN	LOF	?	LOF	DN	LOF
Bacterial susceptibility		✔			✔	✔	✔	?					✔	✔
Viral susceptibility			✔	✔	✔	✔		✔			✔	✔	✔	✔	✔
Known pathogen range		Weakly virulent mycobacteria+ Histoplasma capsulatum	HSV	Respiratory viral infections: Severe SARS-CoV-2 and influenza	P. jirovecii, vaccine strain BCG, M. bovis, CMV, EBV, … (see Table 2)	CMV, HSV, VZV, oral mycosis, G. lamblia, onychomycosis, … (see Table 2)	Tw	Rotavirus, C. albicans, HSV, respiratory infections (unknown cause)	No known infection susceptibility	No known infection susceptibility	Respiratory viral infections: severe SARS-CoV-2 and influenza+ RSV, TBE virus, and adenovirus	Respiratory viral infections: severe SARS-CoV-2 and influenza	Weakly virulent mycobacteria		Respiratory viral infections: severe SARS-CoV-2 and influenza+ eight other viruses (see Table 2)
Known pathogen range		Weakly virulent mycobacteria+ Histoplasma capsulatum	HSV				Tw		No known infection susceptibility	No known infection susceptibility			+ EBV, influenza, C. albicans, rhinovirus, HPV, CMV, and mycoplasma	+ EBV, HPV, recurrent Clostridium difficile
Cellular abnormalities	CD4⁺ T cells	↑↓			↓	↑↓		↑↓					↓	↑	↓
	CD8⁺ T cells	↑↓				↑↓		↓					↓
	NK cells	↓↓											↓		↓
	B cells	↑			↓↓	↓		↓					↓	↓	↓
	DCs	↓						↑↓					↓↓/↓↓↓	↓
	Monocytes							↑↓					↓↓/↓↓↓	↑
IFN impairment		IFN-γ	IFN-α/β	IFN-α/β	IFN-γ		IFN-γ	IFN-γ			IFN-α/β/λ1	IFN-α/β	IFN-γ	IFN-α	IFN-α
Gene expression defect		↓	↓	↓	↑↓	↑↓	↓	↓	Likely ↓		↓	↓	↓	↓	↓
Other defects		Reduced innate lymphoid precursors			Hypogammaglobulinemia	Hypogammaglobulinemia, premature hair graying		Agammaglobulinemia, hypereosinophilia, and hemophagocytosis	Lip pits and CLP	Lip pits, CLP, popliteal webbing, syndactyly, hypodontia, and deformities of the limbs and genitals	Impaired viral control in fibroblasts and pulmonary epithelia	Impaired IAV control in macrophages	Increased hypofunctional granulocytes. Intracerebral calcification and developmental delay	Mild neutrophilia	Impaired IAV control in fibroblasts, hypogammaglobulinemia

HI, haploinsufficiency; DN, dominant negative; MM, multimorphic; HSE, herpes simplex encephalitis; LOF, loss of function; TBE, tick-borne encephalitis; cellular abnormalities, abnormal count/function; IFN impairment, abnormal production/response; ↑, elevated; ↓, reduced; ↑↓, mixed effect or variable by genotype. See Table 2 for a detailed characterization of each IE-IRF.

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