Abstract
The receptors for interferon-α/β (IFN-α/β) and IFN-γ activate components of the Janus kinase–signal transducer and activator of transcription (JAK–STAT) signaling pathway, leading to the formation of at least two transcription factor complexes1. STAT1 interacts with STAT2 and p48/IRF-9 to form the transcription factor IFN-stimulated gene factor 3 (ISGF3). STAT1 dimers form γ-activated factor (GAF). ISGF3 is induced mainly by IFN-α/β, and GAF by IFN-γ, although both factors can be activated by both types of IFN. Individuals with mutations in either chain of the IFN-γ receptor (IFN-γR) are susceptible to infection with mycobacteria2,3,4,5. A heterozygous STAT1 mutation that impairs GAF but not ISGF3 activation has been found in other individuals with mycobacterial disease6. No individuals with deleterious mutations in the IFN-α/β signaling pathway have been described. We report here two unrelated infants homozygous with respect to mutated STAT1 alleles. Neither IFN-α/β nor IFN-γ activated STAT1-containing transcription factors. Like individuals with IFN-γR deficiency, both infants suffered from mycobacterial disease, but unlike individuals with IFN-γR deficiency, both died of viral disease. Viral multiplication was not inhibited by recombinant IFN-α/β in cell lines from the two individuals. Inherited impairment of the STAT1-dependent response to human IFN-α/β thus results in susceptibility to viral disease.
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References
Stark, G.R., Kerr, I.M., Williams, B.R., Silverman, R.H. & Schreiber, R.D. How cells respond to interferons. Annu. Rev. Biochem. 67, 227–264 (1998).
Newport, M.J. et al. A mutation in the interferon-γ-receptor gene and susceptibility to mycobacterial infection. N. Engl. J. Med. 335, 1941–1949 (1996).
Jouanguy, E. et al. Interferon-γ-receptor deficiency in an infant with fatal bacille Calmette-Guerin infection. N. Engl. J. Med. 335, 1956–1961 (1996).
Dorman, S.E. & Holland, S.M. Mutation in the signal-transducing chain of the interferon-γ receptor and susceptibility to mycobacterial infection. J. Clin. Invest. 101, 2364–2369 (1998).
Casanova, J.L. & Abel, L. Genetic dissection of immunity to mycobacteria: the human model. Annu. Rev. Immunol. 20, 581–620 (2002).
Dupuis, S. et al. Impairment of mycobacterial but not viral immunity by a germline human STAT1 mutation. Science 293, 300–303 (2001).
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. 12, 4221–4228 (1993).
Chen, X. et al. Crystal structure of a tyrosine phosphorylated STAT-1 dimer bound to DNA. Cell. 93, 827–839 (1998).
Yang, C.H. et al. Direct association of STAT3 with the IFNAR-1 chain of the human type I interferon receptor. J. Biol. Chem. 271, 8057–8061 (1996).
Ramana, C.V., Gil, M.P., Schreiber, R.D. & Stark, G.R. Stat1-dependent and -independent pathways in IFN-γ-dependent signaling. Trends Immunol. 23, 96–101 (2002).
McKendry, R. et al. High-frequency mutagenesis of human cells and characterization of a mutant unresponsive to both α and γ interferons. Proc. Natl. Acad. Sci. USA 88, 11455–11459 (1991).
Horvath, C.M. & Darnell, J.E. Jr. The antiviral state induced by α interferon and γ interferon requires transcriptionally active Stat1 protein. J. Virol. 70, 647–650 (1996).
Improta, T. & Pine, R. Susceptibility to virus infection is determined by a Stat-mediated response to the autocrine effect of virus-induced type I interferon. Cytokine 9, 383–393 (1997).
Shen, Y. & Darnell, J.E. Jr. Antiviral response in cells containing Stat1 with heterologous transactivation domains. J. Virol. 75, 2627–2633 (2001).
Dorman, S.E. et al. Viral infections in interferon-γ receptor deficiency. J. Pediatr. 135, 640–643 (1999).
Lee, C.K. et al. Distinct requirements for IFNs and STAT1 in NK cell function. J. Immunol. 165, 3571–3577 (2000).
Nguyen, K.B. et al. Critical role for STAT4 activation by type 1 interferons in the interferon-γ response to viral infection. Science 297, 2063–2066 (2002).
Isaacs, A. & Lindenmann, J. Virus interference. I. The interferon. Proc. R. Soc. London Ser. B 147, 258–267 (1957).
Gresser, I. Role of interferon in resistance to viral infection in vivo. in Interferons and the Immune System (eds. Vilcek, J. & De Maeyer, E.) 221–247 (Elsevier Science Publishers B.V., Amsterdam, 1984).
Muller, U. et al. Functional role of type I and type II interferons in antiviral defense. Science 264, 1918–1921 (1994).
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 α and β and alters macrophage responses. Proc. Natl. Acad. Sci. USA 92, 11284–11288 (1995).
Fiette, L. et al. Theiler's virus infection of 129Sv mice that lack the interferon α/β or interferon γ receptors. J. Exp. Med. 181, 2069–2076 (1995).
Garcia-Sastre, A. et al. The role of interferon in influenza virus tissue tropism. J. Virol. 72, 8550–8558 (1998).
Leib, D.A. et al. Interferons regulate the phenotype of wild-type and mutant herpes simplex viruses in vivo. J. Exp. Med. 189, 663–672 (1999).
Steinhoff, U. et al. Antiviral protection by vesicular stomatitis virus-specific antibodies in α/β interferon receptor-deficient mice. J. Virol. 69, 2153–2158 (1995).
van den Broek, M.F., Muller, U., Huang, S., Aguet, M. & Zinkernagel, R.M. Antiviral defense in mice lacking both α/β and γ interferon receptors. J. Virol. 69, 4792–4796 (1995).
Hefti, H.P. et al. Human MxA protein protects mice lacking a functional α/βinterferon system against La crosse virus and other lethal viral infections. J. Virol. 73, 6984–6991 (1999).
Durbin, J.E., Hackenmiller, R., Simon, M.C. & Levy, D.E. Targeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease. Cell 84, 443–450 (1996).
Meraz, M.A. et al. Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell 84, 431–442 (1996).
Park, C., Li, S., Cha, E. & Schindler, C. Immune response in Stat2 knockout mice. Immunity 13, 795–804 (2000).
Acknowledgements
We thank L. Abel, C. Dargemont, C. Picard and C. Soudais for discussions and critical reading; S. Pellegrini, P. Lebon and E. Meurs for providing viruses; and J. Feinberg and M.T. Bandu for technical assistance. This work was supported by grants from Banque Nationale de Paris-Paribas, Fondation Schlumberger and Sequella Foundation.
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Dupuis, S., Jouanguy, E., Al-Hajjar, S. et al. Impaired response to interferon-α/β and lethal viral disease in human STAT1 deficiency. Nat Genet 33, 388–391 (2003). https://doi.org/10.1038/ng1097
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DOI: https://doi.org/10.1038/ng1097
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