Mice lacking the type I interferon receptor are resistant to Listeria monocytogenes - PubMed (original) (raw)

Comparative Study

. 2004 Aug 16;200(4):527-33.

doi: 10.1084/jem.20040976. Epub 2004 Aug 9.

Affiliations

Comparative Study

Mice lacking the type I interferon receptor are resistant to Listeria monocytogenes

Victoria Auerbuch et al. J Exp Med. 2004.

Abstract

Listeria monocytogenes is a facultative intracellular pathogen that induces a cytosolic signaling cascade resulting in expression of interferon (IFN)-beta. Although type I IFNs are critical in viral defense, their role in immunity to bacterial pathogens is much less clear. In this study, we addressed the role of type I IFNs by examining the infection of L. monocytogenes in BALB/c mice lacking the type I IFN receptor (IFN-alpha/betaR-/-). During the first 24 h of infection in vivo, IFN-alpha/betaR-/- and wild-type mice were similar in terms of L. monocytogenes survival. In addition, the intracellular fate of L. monocytogenes in macrophages cultured from IFN-alpha/betaR-/- and wild-type mice was indistinguishable. However, by 72 h after inoculation in vivo, IFN-alpha/betaR-/- mice were approximately 1,000-fold more resistant to a high dose L. monocytogenes infection. Resistance was correlated with elevated levels of interleukin 12p70 in the blood and increased numbers of CD11b+ macrophages producing tumor necrosis factor alpha in the spleen of IFN-alpha/betaR-/- mice. The results of this study suggest that L. monocytogenes might be exploiting an innate antiviral response to promote its pathogenesis.

PubMed Disclaimer

Figures

Figure 1.

Figure 1.

L. monocytogenes infection of BALB/c and IFN-α/βR−/− mice. Naive BALB/c and IFN-α/βR−/− mice (three per group) were infected with 2 × 104 wild-type L. monocytogenes and bacterial growth in the spleen (A) and liver (B) was followed over 3 d. (C) BALB/c and IFN-α/βR−/− mice were immunized with 2 × 103 L. monocytogenes 3–4 wk before challenge with 4 × 104 bacteria. Naive animals were infected with 4 × 104 bacteria. Dashed line denotes limit of detection. CFUs from the spleen 48 h after inoculation are shown. Data represents two separate experiments.

Figure 2.

Figure 2.

IFN-α/βR−/− BMDMs support normal L. monocytogenes growth. BALB/c and IFN-α/βR−/− BMDMs were (A) infected with wild-type L. monocytogenes and bacterial growth was monitored in the presence of 50 μg/ml gentamicin. Black diamonds, BALB/c; gray diamonds, IFN-α/βR−/−. BMDMs were infected with an MOI of 10:1 wild-type or 100:1 Δ_hly L. monocytogenes_, which does not enter the host cytosol and does not grow intracellularly, and ifnb (B) or tnfa (C) mRNA levels (normalized to β actin) and TNF-α supernatant protein levels (D) were quantified 6 h after inoculation. All experiments were performed at least twice.

Figure 3.

Figure 3.

Elevated IL-12p70 and TNF-α, but not IFN-γ, in the absence of type I IFN signaling. (A) BALB/c and IFN-α/βR−/− mice were infected with 2.5 × 104 wild-type L. monocytogenes, bled 24 h after inoculation, and serum was assayed for cytokine levels. Data represents the average from seven mice per group over two separate experiments ± SEM. Splenocytes from uninfected BALB/c and IFN-α/βR−/− mice (B) or from mice infected 48 h previously with 2 × 104 L. monocytogenes (C) were cultured ± 4 × 106 HKLM/ml for 18 h. Culture supernatants were assayed for TNF-α. Data represent the average from six mice per group over two separate experiments ± SEM.

Figure 4.

Figure 4.

Increased number of CD11b+ TNF-α–producing cells in IFN-α/βR−/− mice. Splenocytes from uninfected (uninf) or _L. monocytogenes_–infected (inf) BALB/c and IFN-α/βR−/− mice were cultured ± 4 × 106 HKLM/ml for 4 h. The absolute number of splenocytes was similar between BALB/c and IFN-α/βR−/− mice. Cells were stained for cell surface markers and intracellular TNF-α and Mac-3. (A–C) Cells were stained for CD11b, CD3e, and TNF-α, gated on CD3e− events, and expression of CD11b and TNF-α was analyzed. Data represents results from six mice per group over two separate experiments. (A) Representative dot plots from infected mouse splenocytes. Average percentage of total splenocytes ± SEM that are TNF-α–producing CD11b− (top left) and CD11b+ (top right) cells are shown. (B) Average percentage of total splenocytes that are CD11b+/CD3e−. (C) Average percentage of total splenocytes stimulated with 4 × 106 HKLM/ml that are CD11b+/TNF-α+ or CD11b−/TNF-α+. (D and E) Cells stimulated with 4 × 106 HKLM/ml were stained for CD11b, Mac-3, and TNF-α. (D) Representative dot plots from one of three mice per group. Values shown are average percentage of total splenocytes ± SEM residing within the R1 and R2 populations. (E) Cells within the R1 and R2 gates were analyzed for intracellular TNF-α staining. Average percentage of total splenocytes ± SEM that are CD11bint/Mac-3high/TNF-α+ (R1) or CD11bhigh/Mac-3int/high/TNF-α+ (R2). Statistical significance was determined by using the Mann-Whitney nonparametric test. *, P = 0.081; **, P = 0.005.

Similar articles

Cited by

References

    1. Taki, S. 2002. Type I interferons and autoimmunity: lessons from the clinic and from IRF-2-deficient mice. Cytokine Growth Factor Rev. 13:379–391. - PubMed
    1. Toshchakov, V., B.W. Jones, A. Lentschat, A. Silva, P.Y. Perera, K. Thomas, M.J. Cody, S. Zhang, B.R. Williams, J. Major, et al. 2003. TLR2 and TLR4 agonists stimulate unique repertoires of host resistance genes in murine macrophages: interferon-beta-dependent signaling in TLR4-mediated responses. J. Endotoxin Res. 9:169–175. - PubMed
    1. O'Riordan, M., C.H. Yi, R. Gonzales, K.D. Lee, and D.A. Portnoy. 2002. Innate recognition of bacteria by a macrophage cytosolic surveillance pathway. Proc. Natl. Acad. Sci. USA. 99:13861–13866. - PMC - PubMed
    1. van den Broek, M.F., U. Müller, S. Huang, R.M. Zinkernagel, and M. Aguet. 1995. Immune defence in mice lacking type I and/or type II interferon receptors. Immunol. Rev. 148:5–18. - PubMed
    1. Deonarain, R., A. Alcami, M. Alexiou, M.J. Dallman, D.R. Gewert, and A.C. Porter. 2000. Impaired antiviral response and alpha/beta interferon induction in mice lacking beta interferon. J. Virol. 74:3404–3409. - PMC - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources