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Exogenous interferon-alpha and interferon-gamma increase lethality of murine inhalational anthrax.

Gold JA, Hoshino Y, Jones MB, Hoshino S, Nolan A, Weiden MD - PLoS ONE (2007)

Bottom Line: This was associated with impaired IL-6, IL-10 and IL-12 production.This was associated with an increase in extrapulmonary dissemination.In conclusion, while endogenous IFNs are essential for control of B.anthracis germination and lethality, administration of exogenous IFNs appear to increase the local inflammatory response, thereby increasing mortality.

View Article: PubMed Central - PubMed

Affiliation: Division of Pulmonary and Critical Care Medicine, Oregon Health and Sciences University, Portland, Oregon, United States of America. goldje@ohsu.edu

ABSTRACT

Background: Bacillus anthracis, the etiologic agent of inhalational anthrax, is a facultative intracellular pathogen. Despite appropriate antimicrobial therapy, the mortality from inhalational anthrax approaches 45%, underscoring the need for better adjuvant therapies. The variable latency between exposure and development of disease suggests an important role for the host's innate immune response. Type I and Type II Interferons (IFN) are prominent members of the host innate immune response and are required for control of intracellular pathogens. We have previously described a protective role for exogenous Type I and Type II IFNs in attenuating intracellular B.anthracis germination and macrophage cell death in vitro.

Methodology and principal findings: We sought to extend these findings in an in vivo model of inhalational anthrax, utilizing the Sterne strain (34F2) of B.anthracis. Mice devoid of STAT1, a component of IFN-alpha and IFN-gamma signaling, had a trend towards increased mortality, bacterial germination and extrapulmonary spread of B.anthracis at 24 hrs. This was associated with impaired IL-6, IL-10 and IL-12 production. However, administration of exogenous IFN-gamma, and to a lesser extent IFN-alpha, at the time of infection, markedly increased lethality. While IFNs were able to reduce the fraction of germinated spores within the lung, they increased both the local and systemic inflammatory response manifest by increases in IL-12 and reductions in IL-10. This was associated with an increase in extrapulmonary dissemination. The mechanism of IFN mediated inflammation appears to be in part due to STAT1 independent signaling.

Conclusions: In conclusion, while endogenous IFNs are essential for control of B.anthracis germination and lethality, administration of exogenous IFNs appear to increase the local inflammatory response, thereby increasing mortality.

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Related in: MedlinePlus

STAT1−/− mice have impaired cytokine induction during infection with B.anthracis.Mice were administered B.anthracis 108 spores/mouse and plasma harvested at 24 hrs. IL-6/10/12p40 determined by ELISA. N = 5/group.
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pone-0000736-g003: STAT1−/− mice have impaired cytokine induction during infection with B.anthracis.Mice were administered B.anthracis 108 spores/mouse and plasma harvested at 24 hrs. IL-6/10/12p40 determined by ELISA. N = 5/group.

Mentions: We first wished to establish an in vivo model for pulmonary anthrax. C57BL/6 mice were administered 108 spores 34F2 intratracheally. This resulted in significant pulmonary infiltration and PMN recruitment into the alveolar space (data not shown) and an approximate 20% mortality. Saline administration had no effect on mortality or PMN recruitment (Data not shown). Quantitative cultures from whole lung performed 30 min after administration resulted in>90% yield of original inoculums. We next wished to test the role of endogenous IFN in our model. We chose STAT1−/− mice, as STAT1 is required for IFN-α and IFN-γ signaling. STAT1−/− mice had a 2-fold increase in mortality compared to WT mice (37% vs. 19%) with B.anthracis infection (Figure 1). This was associated with an increase in the fraction germinated spores within the lung (Figure 2A) as well as extrapulmonary spread as assessed by splenic cultures (Figure 2B). Interestingly, in contrast to WT mice, STAT1−/− mice had marked attenuation in systemic levels of IL-6, IL-10 and IL-12 (Figure 3) suggesting endogenous IFN are required for maximal innate immune activation and cytokine production during inhalational anthrax. Finally, STAT1−/− mice had no difference in total lung Myeloperoxidase activity (MPO) (12.5±30 vs. 8.1±8 pg MPO/Lung; p = NS) compared to WT mice, suggesting little role for STAT1 in controlling PMN recruitment.


Exogenous interferon-alpha and interferon-gamma increase lethality of murine inhalational anthrax.

Gold JA, Hoshino Y, Jones MB, Hoshino S, Nolan A, Weiden MD - PLoS ONE (2007)

STAT1−/− mice have impaired cytokine induction during infection with B.anthracis.Mice were administered B.anthracis 108 spores/mouse and plasma harvested at 24 hrs. IL-6/10/12p40 determined by ELISA. N = 5/group.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1937023&req=5

pone-0000736-g003: STAT1−/− mice have impaired cytokine induction during infection with B.anthracis.Mice were administered B.anthracis 108 spores/mouse and plasma harvested at 24 hrs. IL-6/10/12p40 determined by ELISA. N = 5/group.
Mentions: We first wished to establish an in vivo model for pulmonary anthrax. C57BL/6 mice were administered 108 spores 34F2 intratracheally. This resulted in significant pulmonary infiltration and PMN recruitment into the alveolar space (data not shown) and an approximate 20% mortality. Saline administration had no effect on mortality or PMN recruitment (Data not shown). Quantitative cultures from whole lung performed 30 min after administration resulted in>90% yield of original inoculums. We next wished to test the role of endogenous IFN in our model. We chose STAT1−/− mice, as STAT1 is required for IFN-α and IFN-γ signaling. STAT1−/− mice had a 2-fold increase in mortality compared to WT mice (37% vs. 19%) with B.anthracis infection (Figure 1). This was associated with an increase in the fraction germinated spores within the lung (Figure 2A) as well as extrapulmonary spread as assessed by splenic cultures (Figure 2B). Interestingly, in contrast to WT mice, STAT1−/− mice had marked attenuation in systemic levels of IL-6, IL-10 and IL-12 (Figure 3) suggesting endogenous IFN are required for maximal innate immune activation and cytokine production during inhalational anthrax. Finally, STAT1−/− mice had no difference in total lung Myeloperoxidase activity (MPO) (12.5±30 vs. 8.1±8 pg MPO/Lung; p = NS) compared to WT mice, suggesting little role for STAT1 in controlling PMN recruitment.

Bottom Line: This was associated with impaired IL-6, IL-10 and IL-12 production.This was associated with an increase in extrapulmonary dissemination.In conclusion, while endogenous IFNs are essential for control of B.anthracis germination and lethality, administration of exogenous IFNs appear to increase the local inflammatory response, thereby increasing mortality.

View Article: PubMed Central - PubMed

Affiliation: Division of Pulmonary and Critical Care Medicine, Oregon Health and Sciences University, Portland, Oregon, United States of America. goldje@ohsu.edu

ABSTRACT

Background: Bacillus anthracis, the etiologic agent of inhalational anthrax, is a facultative intracellular pathogen. Despite appropriate antimicrobial therapy, the mortality from inhalational anthrax approaches 45%, underscoring the need for better adjuvant therapies. The variable latency between exposure and development of disease suggests an important role for the host's innate immune response. Type I and Type II Interferons (IFN) are prominent members of the host innate immune response and are required for control of intracellular pathogens. We have previously described a protective role for exogenous Type I and Type II IFNs in attenuating intracellular B.anthracis germination and macrophage cell death in vitro.

Methodology and principal findings: We sought to extend these findings in an in vivo model of inhalational anthrax, utilizing the Sterne strain (34F2) of B.anthracis. Mice devoid of STAT1, a component of IFN-alpha and IFN-gamma signaling, had a trend towards increased mortality, bacterial germination and extrapulmonary spread of B.anthracis at 24 hrs. This was associated with impaired IL-6, IL-10 and IL-12 production. However, administration of exogenous IFN-gamma, and to a lesser extent IFN-alpha, at the time of infection, markedly increased lethality. While IFNs were able to reduce the fraction of germinated spores within the lung, they increased both the local and systemic inflammatory response manifest by increases in IL-12 and reductions in IL-10. This was associated with an increase in extrapulmonary dissemination. The mechanism of IFN mediated inflammation appears to be in part due to STAT1 independent signaling.

Conclusions: In conclusion, while endogenous IFNs are essential for control of B.anthracis germination and lethality, administration of exogenous IFNs appear to increase the local inflammatory response, thereby increasing mortality.

Show MeSH
Related in: MedlinePlus