Type I interferon production enhances susceptibility to Listeria monocytogenes infection - PubMed (original) (raw)

Comparative Study

. 2004 Aug 16;200(4):437-45.

doi: 10.1084/jem.20040712. Epub 2004 Aug 9.

Supriya K Saha, Sagar A Vaidya, Kevin W Bruhn, Gustavo A Miranda, Brian Zarnegar, Andrea K Perry, Bidong O Nguyen, Timothy F Lane, Tadatsugu Taniguchi, Jeff F Miller, Genhong Cheng

Affiliations

Comparative Study

Type I interferon production enhances susceptibility to Listeria monocytogenes infection

Ryan M O'Connell et al. J Exp Med. 2004.

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 infection 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 bacterium Listeria monocytogenes compared with wild-type controls. Furthermore, this enhanced bacterial 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 modulation in host defense.

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Figures

Figure 1.

Figure 1.

Induction of IFN-β by L. monocytogenes requires IRF3. (A) BMMs from C57BL/6 wild-type mice were infected with L. monocytogenes at a multiplicity of infection of 1 and IRF3 and p65 nuclear translocation were assayed at the indicated times by immunoblotting using nuclear extract. USF-2 was also assayed as a loading control. (B) MyD88 − / −, IRF3 − / −, IFNAR1 −/−, and wild-type BMMs were infected with L. monocytogenes as described above and assayed at the indicated time points for _IFN-_β gene expression by Q-PCR and (C) phospho-STAT1α/β, or total STAT1α/β by immunoblotting. Results shown are representative of at least two independent experiments, and Q-PCR results are expressed in relative expression units and have been normalized to L32 mRNA levels.

Figure 2.

Figure 2.

Mice deficient in IRF3 have an enhanced ability to clear infection by L. monocytogenes. (A) IRF3 −/− (n = 8) and wild-type control mice (n = 8) were infected intravenously with 1.5 × 106 L. monocytogenes and viability was assayed daily for 9 d. (B) IRF3 −/− (n = 4) and wild-type mice (n = 4) were infected intravenously with 5 × 105 L. monocytogenes for 3 d, at which time the L. monocytogenes titer in the spleen and liver was assayed and presented as CFUs. (C) A portion of the IRF3 −/− and wild-type livers from B were fixed, sectioned, and subjected to a histological analysis after hematoxylin and eosin staining. All data are representative of at least two independent experiments.

Figure 3.

Figure 3.

Type I IFNs sensitize mice to L. monocytogenes infection. (A) IFNAR1 −/− (n = 13), IFNAR1 +/− (n = 8), and IFNAR1 +/+ (n = 14) mice were infected intravenously with 1.5 × 106 L. monocytogenes and viability was assayed daily for 9 d. (B) Wild-type mice were challenged with 5 × 105 L. monocytogenes (n = 6), 200 μg poly I:C (n = 6), or the combination of the two (n = 6), and viability was assayed daily for 9 d. (C) IFNAR1 − / − and wild-type control mice were infected intravenously with 5 × 105 L. monocytogenes either in the absence or presence of 200 μg poly I:C. After 3 d, the mice were killed and the L. monocytogenes titer was determined in the liver (n = 4) and spleen (n = 4), and presented as CFUs. (D) A portion of the livers from C were fixed, sectioned, and subjected to a histological analysis after hematoxylin and eosin staining. All data are representative of at least two independent experiments.

Figure 4.

Figure 4.

Type I, but not Type II, IFN signaling is inhibited in _L. monocytogenes_–infected _IFNAR1−/−_mice. (A) The spleens and serum from IFNAR1 − / − and wild-type mice infected with 1.5 × 106 L. monocytogenes were removed 24 h after infection and serum IFN-γ and IL-6 levels were assayed by ELISA. (B) The splenocyte mRNA was subjected to a Q-PCR analysis to assay IP10, IRF1, TGTP, IL-6, Mx1, TRAIL, PKR, and Daxx expression. (C) IFNAR1 −/− and wild-type BMMs were infected with L. monocytogenes at a multiplicity of infection of 1 and assayed at the indicated time points for _IL-1_β, Mx1, PKR, Daxx, TRAIL, and PML gene expression by Q-PCR. Results shown are representative of at least two independent experiments. Q-PCR data are presented in relative expression units and have been normalized to L32 mRNA levels.

Figure 5.

Figure 5.

_L. monocytogenes_–induced splenic apoptosis is dependent on type I IFNs. (A) Spleens from IFNAR1 − / −, IRF3 −/−, and wild-type mice that had been infected with 1.5 × 106 L. monocytogenes 48 h previously were removed and subjected to a TUNEL assay followed by DAPI staining of the nuclei. Pictures were taken using a 10× lens. (B) Portions of the spleens from wild-type (n = 3), IRF3 − / − (n = 3), and IFNAR1 − / − (n = 4) mice used for TUNEL assays in A were assayed and presented as CFUs 2 d after infection with 1.5 × 106 L. monocytogenes. All data represent three independent experiments.

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