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-Responsive Mice1
* Integrated Department of Immunology, National Jewish Medical and Research Center; and
Denver Health Sciences Center, University of Colorado, Denver, CO 80206
Both peptidoglycan and muropeptides potently modulate inflammatory and innate immune responses. The secreted Listeria monocytogenes p60 autolysin digests peptidoglycan and promotes bacterial infection in vivo. Here, we report that p60 contributes to bacterial subversion of NK cell activation and innate IFN-
production. L. monocytogenes deficient for p60 (
p60) competed well for expansion in mice doubly deficient for IFNAR1 and IFN-R1 or singly deficient for IFN-R1, but not in wild-type, IFNAR1–/–, or TLR2–/– mice. The restored competitiveness of p60-deficient bacteria suggested a specific role for p60 in bacterial subversion of IFN--mediated immune responses, since in vivo expansion of three other mutant L. monocytogenes strains (ActA, NamA, and PlcB) was not complemented in IFN-R1–/– mice. Bacterial expression of p60 was not required to induce socs1, socs3, and il10 expression in infected mouse bone marrow macrophages but did correlate with enhanced production of IL-6, IL-12p70, and most strikingly IFN-. The primary source of p60-dependent innate IFN- was NK cells, whereas bacterial p60 expression did not significantly alter innate IFN- production by T cells. The mechanism for p60-dependent NK cell stimulation was also indirect, given that treatment with purified p60 protein failed to directly activate NK cells for IFN- production. These data suggest that p60 may act on infected cells to indirectly enhance NK cell activation and increase innate IFN- production, which presumably promotes early bacterial expansion through its immunoregulatory effects on bystander cells. Thus, the simultaneous induction of IFN- production and factors that inhibit IFN- signaling may be a common strategy for misdirection of early antibacterial immunity.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by startup funds from National Jewish Medical and Research Center and by National Institutes of Health Grant R01AI065638 (to L.L.L.). J.H. is supported by National Institutes of Health Training Grant T32AI07405.
2 Address correspondence and reprint requests to Dr. Laurel L. Lenz, Integrated Department of Immunology, National Jewish Medical and Research Center, Denver, CO 80206. E-mail address: lenzl{at}njc.org
3 Abbreviations used in this paper: SOCS, suppressor of cytokine signaling; CI, competitive index; NOD, nucleotide oligomerization domain; CARD, caspase activation and recruitment domain; PlcB, phospholipase B; PGN, peptidoglycan; wt, wild type; Erm, erythromycin; ErmR, Erm resistant; BMM, bone marrow-derived macrophages; NWNA, nylon wool-nonadherent.
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