e n i c i d e M l a t n e m i r e p x E f o l a n r u o J e h T Type I Interferon Production Enhances Susceptibility to Listeria monocytogenes Infection Ryan M. O’Connell,1 Supriya K. Saha,1,2 Sagar A.Vaidya,1,2 Kevin W. Bruhn,1 Gustavo A. Miranda,4,5 Brian Zarnegar,1 Andrea K. Perry,1 Bidong O. Nguyen,1 Timothy F. Lane,4,5 Tadatsugu Taniguchi,6 Jeff F. Miller,1,3 and Genhong Cheng1,3,4 1Department of Microbiology, Immunology and Molecular Genetics, 2Medical Scientist Training Program, 3Molecular Biology Institute, 4Jonsson Comprehensive Cancer Center, and 5Department of Obstetrics and Gynecology and Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095 6Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo,Tokyo 113-0033, Japan Abstract Numerous bacterial products such as lipopolysaccharide potently induce type I interferons (IFNs); however, the contribution of this innate response to host defense against bacterial in- fection remains unclear. Although mice deficient in either IFN regulatory factor (IRF)3 or the type I IFN receptor (IFNAR)1 are highly susceptible to viral infection, we show that these mice exhibit a profound resistance to infection caused by the Gram-positive intracellular bacte- rium Listeria monocytogenes compared with wild-type controls. Furthermore, this enhanced bac- terial clearance is accompanied by a block in L. monocytogenes–induced splenic apoptosis in IRF3- and IFNAR1-deficient mice. Thus, our results highlight the disparate roles of type I IFNs during bacterial versus viral infections and stress the importance of proper IFN modula- tion in host defense. Key words: IRF3 • IFNAR • apoptosis • intracellular bacteria • IFN target gene Introduction Type I IFNs (IFN- / ) were the first cytokines to be dis- covered, being named for their potent effects on viral “inter- ference” (1). These cytokines play a critical role in the innate antiviral response by inhibiting cellular proliferation, pro- moting apoptosis, activating the microbicidal function of macrophages and NK cells, and by linking innate and adap- tive immune responses (2–4). Induction of type I IFN gene expression in response to viral infection is accomplished by a sophisticated interplay of transcription factors of the IFN regulatory factor (IRF) family (5). Upon detection of viral entry into the cytoplasm, IRF3 becomes phosphorylated and translocates to the nucleus to drive transcription of the IFN- gene. Binding of IFN- to the type I IFN receptor (IFNAR), composed of subunits IFNAR1 and IFNAR2, results in the phosphorylation of the transcription factor STAT1 / , leading to induction of IFN target genes (2). R.M. O’Connell, S.K. Saha, and S.A. Vaidya contributed equally to this work. Address correspondence to Genhong Cheng, Dept. of Microbiology, Im- munology and Molecular Genetics, University of California, Los Angeles, 8-240 Factor Bldg., 10833 Le Conte Ave., Los Angeles, CA 90095. Phone: (310) 825-8896; Fax: (310) 206-5553; email: genhongc@microbio.ucla.edu Studies have also found that bacterial products, such as LPS, can induce IRF3-dependent type I IFN gene expression through interaction with Toll-like receptors (6–9). Although the molecular mechanisms by which bacterial products in- duce type I IFNs have been studied extensively (10), little is known of the functional significance of type I IFN induc- tion during a bacterial infection. Listeria monocytogenes is a Gram-positive intracellular bac- terium that causes sepsis and meningitis in immunocom- promised individuals and severe fetal infections in pregnant women (11–13). Furthermore, L. monocytogenes has been used widely as a laboratory model for intracellular bacterial infections (12). Recent studies have indicated that L. mono- cytogenes can induce high levels of IFN- once inside the cytoplasm of infected macrophage cells (14–17). To better understand the functional consequences of type I IFN sig- naling during a bacterial infection, we have analyzed mice Abbreviations used in this paper: BHI, brain heart infusion; BMM, bone marrow–derived macrophage; IFNAR, type I IFN receptor; IRF, IFN regulatory factor; LLO, listeriolysin O; Q-PCR, quantitative real-time PCR; TUNEL, TdT-mediated dUTP nick-end labeling; USF, upstream stimulating factor. 437 J. Exp. Med. © The Rockefeller University Press • 0022-1007/2004/08/437/9 $8.00 Volume 200, Number 4, August 16, 2004 437–445 http://www.jem.org/cgi/doi/10.1084/jem.20040712