contribute to the early response against L. monocytogenes (12). Thus, it is highly plausible that other important cell types are also being targeted by L. monocytogenes–induced type I IFNs, resulting in apoptosis. Macrophage cells have been shown to undergo type I IFN–dependent apoptosis when incubated with L. monocytogenes in vitro (16). Consis- tent with these observations, we found type I IFN–depen- dent up-regulation of a subset of proapoptotic genes in L. monocytogenes–infected macrophage cells, similar to the ex- pression profile observed in the L. monocytogenes–infected spleen. Furthermore, there were approximately twice as many macrophages and neutrophils in IRF3- and IFNAR1-deficient spleens 2 d after L. monocytogenes inocu- lation (unpublished data). Previous reports have shown that depletion of macrophages or neutrophils results in en- hanced L. monocytogenes infection during the early stages of the infection (12). Hence, the reduction of these cell types in wild-type mice relative to IRF3- and IFNAR1-deficient animals may explain why wild-type mice exhibit decreased immunity against L. monocytogenes. Both type I and II IFNs play important roles in combating viral infections through the up-regulation of overlapping and nonoverlapping gene subsets (25). In response to bacterial infections, only type II IFN has been shown to play a pro- tective role through the induction of a Th1 cell immune re- sponse (25). As type II IFN production and subsequent sig- naling are not disrupted in IFNAR1 / mice (Fig. 4), this particular cytokine appears to be sufficient for induction of IFN target genes necessary to mount an effective response to L. monocytogenes. Conversely, type I IFN–specific target genes such as Mx1, PKR, Daxx, and TRAIL have been shown to inhibit viral replication and regulate cellular apop- tosis (25). Thus, although type I IFN target genes play an imperative role in antiviral defense, they might be detrimen- tal when mounting an immune response to L. monocytogenes. This study raises an open question as to why phagocytic cells would respond to a pathogen by secreting factors that potently inhibit host immunity. One attractive possibility is that L. monocytogenes has evolved the ability to activate type I IFNs to overcome host defenses. The L. monocytogenes protein listeriolysin O (LLO) has recently been shown to be required for L. monocytogenes induction of IFN- in macrophage cells (15). Furthermore, L. monocytogenes defi- cient in LLO exhibit a drastic reduction in both virulence and splenic apoptosis compared with wild-type L. monocy- togenes in vivo (29), whereas the LLO protein is alone suffi- cient to induce apoptosis in lymph nodes (31). Further studies are needed to determine if the LLO protein, or some other L. monocytogenes–produced ligand, is sufficient to induce expression of type I IFNs. Type I IFNs may also play a different biological role in other genetic backgrounds or during later stages of the in- fection. For example, type I IFNs might contribute to the adaptive response to L. monocytogenes by regulating the ex- pression of MHC and costimulatory molecules required for developing antigen-specific CTLs, as it has been shown to do during viral infections (4). However, Auerbuch et al. (32) have not found a significant defect in immunological memory during a secondary challenge in L. monocytogenes– immunized IFNAR / mice compared with wild-type controls. Further investigation is also required to character- ize whether type I IFNs play harmful or protective roles against other bacteria or nonviral pathogens in general. A recent study has found that the administration of type I IFNs results in increased loads of Mycobacterium tuberculosis in the lungs (33), lending further evidence that other infec- tious pathogens may also benefit from these cytokines. Consequently, patients suffering from viral infections might be more susceptible to certain bacteria due to the effects of virally induced type I IFNs. Thus, our results highlight the importance of proper regulation of the IFN pathway in re- sponse to specific pathogens due to the disparate roles these cytokines play during bacterial versus viral infection. The MyD88 / mouse line was a gift from Dr. S. Akira (Osaka University, Osaka, Japan). S.A. Vaidya and S.K. Saha are supported by the UCLA Medical Scientist Training Program training grant (GM 08042). R.M. O’Connell and K.W. Bruhn are supported by the U.S. Public Health Service National Research Service Award (GM 07185 and GM 07104, respectively). A.K. Perry is supported by the Howard Hughes Medical Institute predoctoral fellowship (59003787). T.F. Lane is supported by the National Institutes of Health (NIH) re- search grant S10 RR15862-01 and Stop Cancer II, while G.A. Miranda is supported by the Department of Defense grant OC 98- 0006. G. Cheng is a Lymphoma and Leukemia Society Scholar and part of this work was also supported by NIH research grants R01 AI056154, R01 CA87924, and R37 AI47868. The authors have no conflicting financial interests. Submitted: 12 April 2004 Accepted: 6 July 2004 References 1. Isaacs, A., and J. Lindenmann. 1957. Virus interference. I. The interferon. Proc. R. Soc. Lond. B. Biol. Sci. 147:258–267. 2. Taniguchi, T., and A. Takaoka. 2002. The interferon-alpha/ beta system in antiviral responses: a multimodal machinery of gene regulation by the IRF family of transcription factors. Curr. Opin. Immunol. 14:111–116. 3. Le Bon, A., and D.F. Tough. 2002. Links between innate and adaptive immunity via type I interferon. Curr. Opin. Im- munol. 14:432–436. 4. Biron, C.A. 2001. Interferons alpha and beta as immune reg- ulators–a new look. Immunity. 14:661–664. 5. Taniguchi, T., K. Ogasawara, A. Takaoka, and N. Tanaka. 2001. IRF family of transcription factors as regulators of host defense. Annu. Rev. Immunol. 19:623–655. 6. Doyle, S., S. Vaidya, R. O’Connell, H. Dadgostar, P. Demp- sey, T. Wu, G. Rao, R. Sun, M. Haberland, R. Modlin, et al. 2002. IRF3 mediates a TLR3/TLR4-specific antiviral gene program. Immunity. 17:251–263. 7. Doyle, S.E., R. O’Connell, S.A. Vaidya, E.K. Chow, K. Yee, and G. Cheng. 2003. Toll-like receptor 3 mediates a more potent antiviral response than Toll-like receptor 4. J. Immunol. 170:3565–3571. 8. Kawai, T., O. Takeuchi, T. Fujita, J. Inoue, P.F. Muhlradt, S. 444 Type I Interferons Enhance Listeria monocytogenes Infection