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Characterization of the interferon-producing cell in mice infected with Listeria monocytogenes.

Stockinger S, Kastner R, Kernbauer E, Pilz A, Westermayer S, Reutterer B, Soulat D, Stengl G, Vogl C, Frenz T, Waibler Z, Taniguchi T, Rülicke T, Kalinke U, Müller M, Decker T - PLoS Pathog. (2009)

Bottom Line: Synthesis of serum IFN-I did not require TLR9.In contrast, in vitro-differentiated pDC infected with L. monocytogenes needed TLR9 to transcribe IFN-I mRNA.Based on these data, we propose that the engagement of pDC, the mode of IFN-I mobilization, as well as the shaping of the antimicrobial innate immune response by IFN-I differ between intracellular pathogens.

View Article: PubMed Central - PubMed

Affiliation: Max F. Perutz Laboratories, Department of Microbiology and Immunobiology, University of Vienna, Vienna, Austria.

ABSTRACT
Production of type I interferons (IFN-I, mainly IFNalpha and IFNbeta) is a hallmark of innate immune responses to all classes of pathogens. When viral infection spreads to lymphoid organs, the majority of systemic IFN-I is produced by a specialized "interferon-producing cell" (IPC) that has been shown to belong to the lineage of plasmacytoid dendritic cells (pDC). It is unclear whether production of systemic IFN-I is generally attributable to pDC irrespective of the nature of the infecting pathogen. We have addressed this question by studying infections of mice with the intracellular bacterium Listeria monocytogenes. Protective innate immunity against this pathogen is weakened by IFN-I activity. In mice infected with L. monocytogenes, systemic IFN-I was amplified via IFN-beta, the IFN-I receptor (IFNAR), and transcription factor interferon regulatory factor 7 (IRF7), a molecular circuitry usually characteristic of non-pDC producers. Synthesis of serum IFN-I did not require TLR9. In contrast, in vitro-differentiated pDC infected with L. monocytogenes needed TLR9 to transcribe IFN-I mRNA. Consistent with the assumption that pDC are not the producers of systemic IFN-I, conditional ablation of the IFN-I receptor in mice showed that most systemic IFN-I is produced by myeloid cells. Furthermore, results obtained with FACS-purified splenic cell populations from infected mice confirmed the assumption that a cell type with surface antigens characteristic of macrophages and not of pDC is responsible for bulk IFN-I synthesis. The amount of IFN-I produced in the investigated mouse lines was inversely correlated to the resistance to lethal infection. Based on these data, we propose that the engagement of pDC, the mode of IFN-I mobilization, as well as the shaping of the antimicrobial innate immune response by IFN-I differ between intracellular pathogens.

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Prerequisites for the increase in resistance to lethal infection caused by IFN-I.(A) Mice of the indicated genotypes were infected with 5×106 L. monocytogenes, and survival was monitored for ten days. The data presented here are a summary of several individual experiments with groups of 4–6 mice per genotype and treatment. Total number of mice analysed are: C57BL/6 wt n = 34, IFNAR1−/− n = 23, IFNβ−/− n = 23, IRF3−/− n = 24, IRF7−/− n = 29. (B) Groups of ten (C57BL/6 wt and IFNβ−/−) or eight (IRF7−/−) mice were infected with 1×106 L. monocytogenes. After three days, mice were killed and the L. monocytogenes titre was determined in the liver and spleen and presented as CFU. Data were log-transformed to achieve approximate normality. Linear models with genotype as fixed effect were fitted using SPSS. Significant values are indicated by: n.s. not significant p>0.05, *** p≤0.001.
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ppat-1000355-g004: Prerequisites for the increase in resistance to lethal infection caused by IFN-I.(A) Mice of the indicated genotypes were infected with 5×106 L. monocytogenes, and survival was monitored for ten days. The data presented here are a summary of several individual experiments with groups of 4–6 mice per genotype and treatment. Total number of mice analysed are: C57BL/6 wt n = 34, IFNAR1−/− n = 23, IFNβ−/− n = 23, IRF3−/− n = 24, IRF7−/− n = 29. (B) Groups of ten (C57BL/6 wt and IFNβ−/−) or eight (IRF7−/−) mice were infected with 1×106 L. monocytogenes. After three days, mice were killed and the L. monocytogenes titre was determined in the liver and spleen and presented as CFU. Data were log-transformed to achieve approximate normality. Linear models with genotype as fixed effect were fitted using SPSS. Significant values are indicated by: n.s. not significant p>0.05, *** p≤0.001.

Mentions: To investigate the contribution of IFNβ and IRF7 to the IFN-I-dependent increase in mortality, we monitored the survival of animals infected with L. monocytogenes. In accordance with previous findings [22]–[24], IFNAR deficiency caused a strong resistance to lethal infection, particularly during the innate phase of the anti-Listeria immune response (up to day 6, Figure 4A). By comparison, the increase caused by IFNβ deficiency was less pronounced. Lack of IRF7 had a greater impact on survival than absence of IRF3. This difference became smaller if survival was monitored beyond the period of the innate immune response (up to day 10). Lower pathogen burdens in liver and spleens from IRF7 or IFNβ-deficient mice reflected the increase in survival on day 3 (Figure 4B). Similar findings have been reported for IFNAR1 and IRF3-deficient mice [22]–[24]. Since differences in the bacterial load between wt animals and those with defects in IFN-I synthesis and/or response are not present 24 h after infection (Figure S1) the inhibitory effect of IFN-I on bacterial clearance must develop between day 1 and 3 post infection. Together, the data emphasize the importance of the early IFNAR, IFNβ and IRF7-mediated amplification of IFN-I production for adverse IFN-I action during the early, innate immune response.


Characterization of the interferon-producing cell in mice infected with Listeria monocytogenes.

Stockinger S, Kastner R, Kernbauer E, Pilz A, Westermayer S, Reutterer B, Soulat D, Stengl G, Vogl C, Frenz T, Waibler Z, Taniguchi T, Rülicke T, Kalinke U, Müller M, Decker T - PLoS Pathog. (2009)

Prerequisites for the increase in resistance to lethal infection caused by IFN-I.(A) Mice of the indicated genotypes were infected with 5×106 L. monocytogenes, and survival was monitored for ten days. The data presented here are a summary of several individual experiments with groups of 4–6 mice per genotype and treatment. Total number of mice analysed are: C57BL/6 wt n = 34, IFNAR1−/− n = 23, IFNβ−/− n = 23, IRF3−/− n = 24, IRF7−/− n = 29. (B) Groups of ten (C57BL/6 wt and IFNβ−/−) or eight (IRF7−/−) mice were infected with 1×106 L. monocytogenes. After three days, mice were killed and the L. monocytogenes titre was determined in the liver and spleen and presented as CFU. Data were log-transformed to achieve approximate normality. Linear models with genotype as fixed effect were fitted using SPSS. Significant values are indicated by: n.s. not significant p>0.05, *** p≤0.001.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2654726&req=5

ppat-1000355-g004: Prerequisites for the increase in resistance to lethal infection caused by IFN-I.(A) Mice of the indicated genotypes were infected with 5×106 L. monocytogenes, and survival was monitored for ten days. The data presented here are a summary of several individual experiments with groups of 4–6 mice per genotype and treatment. Total number of mice analysed are: C57BL/6 wt n = 34, IFNAR1−/− n = 23, IFNβ−/− n = 23, IRF3−/− n = 24, IRF7−/− n = 29. (B) Groups of ten (C57BL/6 wt and IFNβ−/−) or eight (IRF7−/−) mice were infected with 1×106 L. monocytogenes. After three days, mice were killed and the L. monocytogenes titre was determined in the liver and spleen and presented as CFU. Data were log-transformed to achieve approximate normality. Linear models with genotype as fixed effect were fitted using SPSS. Significant values are indicated by: n.s. not significant p>0.05, *** p≤0.001.
Mentions: To investigate the contribution of IFNβ and IRF7 to the IFN-I-dependent increase in mortality, we monitored the survival of animals infected with L. monocytogenes. In accordance with previous findings [22]–[24], IFNAR deficiency caused a strong resistance to lethal infection, particularly during the innate phase of the anti-Listeria immune response (up to day 6, Figure 4A). By comparison, the increase caused by IFNβ deficiency was less pronounced. Lack of IRF7 had a greater impact on survival than absence of IRF3. This difference became smaller if survival was monitored beyond the period of the innate immune response (up to day 10). Lower pathogen burdens in liver and spleens from IRF7 or IFNβ-deficient mice reflected the increase in survival on day 3 (Figure 4B). Similar findings have been reported for IFNAR1 and IRF3-deficient mice [22]–[24]. Since differences in the bacterial load between wt animals and those with defects in IFN-I synthesis and/or response are not present 24 h after infection (Figure S1) the inhibitory effect of IFN-I on bacterial clearance must develop between day 1 and 3 post infection. Together, the data emphasize the importance of the early IFNAR, IFNβ and IRF7-mediated amplification of IFN-I production for adverse IFN-I action during the early, innate immune response.

Bottom Line: Synthesis of serum IFN-I did not require TLR9.In contrast, in vitro-differentiated pDC infected with L. monocytogenes needed TLR9 to transcribe IFN-I mRNA.Based on these data, we propose that the engagement of pDC, the mode of IFN-I mobilization, as well as the shaping of the antimicrobial innate immune response by IFN-I differ between intracellular pathogens.

View Article: PubMed Central - PubMed

Affiliation: Max F. Perutz Laboratories, Department of Microbiology and Immunobiology, University of Vienna, Vienna, Austria.

ABSTRACT
Production of type I interferons (IFN-I, mainly IFNalpha and IFNbeta) is a hallmark of innate immune responses to all classes of pathogens. When viral infection spreads to lymphoid organs, the majority of systemic IFN-I is produced by a specialized "interferon-producing cell" (IPC) that has been shown to belong to the lineage of plasmacytoid dendritic cells (pDC). It is unclear whether production of systemic IFN-I is generally attributable to pDC irrespective of the nature of the infecting pathogen. We have addressed this question by studying infections of mice with the intracellular bacterium Listeria monocytogenes. Protective innate immunity against this pathogen is weakened by IFN-I activity. In mice infected with L. monocytogenes, systemic IFN-I was amplified via IFN-beta, the IFN-I receptor (IFNAR), and transcription factor interferon regulatory factor 7 (IRF7), a molecular circuitry usually characteristic of non-pDC producers. Synthesis of serum IFN-I did not require TLR9. In contrast, in vitro-differentiated pDC infected with L. monocytogenes needed TLR9 to transcribe IFN-I mRNA. Consistent with the assumption that pDC are not the producers of systemic IFN-I, conditional ablation of the IFN-I receptor in mice showed that most systemic IFN-I is produced by myeloid cells. Furthermore, results obtained with FACS-purified splenic cell populations from infected mice confirmed the assumption that a cell type with surface antigens characteristic of macrophages and not of pDC is responsible for bulk IFN-I synthesis. The amount of IFN-I produced in the investigated mouse lines was inversely correlated to the resistance to lethal infection. Based on these data, we propose that the engagement of pDC, the mode of IFN-I mobilization, as well as the shaping of the antimicrobial innate immune response by IFN-I differ between intracellular pathogens.

Show MeSH
Related in: MedlinePlus