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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

IFN-γ reduces the fraction of germinated spores in the lung.Mice were infected with B.anthracis (108)±IFN. A. Lungs were harvested at 24 hrs and the fraction of germinated spores determined by the formula (CFU B.anthracis in lung-CFU B.anthracis lung after heat treatment{dormant spores})/CFU B.anthracis lung. B. Quantitative culture from spleen harvested at 24 hrs. Serial dilutions were made of whole splenic homogenate. * p<0.05 compared to WT. N = 5/group.
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pone-0000736-g005: IFN-γ reduces the fraction of germinated spores in the lung.Mice were infected with B.anthracis (108)±IFN. A. Lungs were harvested at 24 hrs and the fraction of germinated spores determined by the formula (CFU B.anthracis in lung-CFU B.anthracis lung after heat treatment{dormant spores})/CFU B.anthracis lung. B. Quantitative culture from spleen harvested at 24 hrs. Serial dilutions were made of whole splenic homogenate. * p<0.05 compared to WT. N = 5/group.

Mentions: We next wished to assess the effect of exogenous IFN on control of B.anthracis germination. Neither IFN-α nor IFN-γ had any effect on the total number of viable bacteria and spores recovered from the lung at 24 hrs. However, consistent with previously reported in vitro data, both IFN-γ and IFN-α significantly reduced the fraction of germinated spores obtained from the lung (Figure 5A) [18]. In addition, exogenous IFN-γ and to a lesser extent IFN-α, significantly increased extrapulmonary dissemination of B.anthracis as determined by quantitative cultures from splenic homogenates (Figure 5B). These changes we not due to alteration in lung PMN content, as WT, IFN-α and IFN-γ treated mice had similar amounts of MPO activity in whole lung (8.1±8.5 vs. 10.2±6.1 vs. 7.2±4.6 pg MPO/Lung; p = NS) and BALF (Not shown).


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)

IFN-γ reduces the fraction of germinated spores in the lung.Mice were infected with B.anthracis (108)±IFN. A. Lungs were harvested at 24 hrs and the fraction of germinated spores determined by the formula (CFU B.anthracis in lung-CFU B.anthracis lung after heat treatment{dormant spores})/CFU B.anthracis lung. B. Quantitative culture from spleen harvested at 24 hrs. Serial dilutions were made of whole splenic homogenate. * p<0.05 compared to WT. N = 5/group.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0000736-g005: IFN-γ reduces the fraction of germinated spores in the lung.Mice were infected with B.anthracis (108)±IFN. A. Lungs were harvested at 24 hrs and the fraction of germinated spores determined by the formula (CFU B.anthracis in lung-CFU B.anthracis lung after heat treatment{dormant spores})/CFU B.anthracis lung. B. Quantitative culture from spleen harvested at 24 hrs. Serial dilutions were made of whole splenic homogenate. * p<0.05 compared to WT. N = 5/group.
Mentions: We next wished to assess the effect of exogenous IFN on control of B.anthracis germination. Neither IFN-α nor IFN-γ had any effect on the total number of viable bacteria and spores recovered from the lung at 24 hrs. However, consistent with previously reported in vitro data, both IFN-γ and IFN-α significantly reduced the fraction of germinated spores obtained from the lung (Figure 5A) [18]. In addition, exogenous IFN-γ and to a lesser extent IFN-α, significantly increased extrapulmonary dissemination of B.anthracis as determined by quantitative cultures from splenic homogenates (Figure 5B). These changes we not due to alteration in lung PMN content, as WT, IFN-α and IFN-γ treated mice had similar amounts of MPO activity in whole lung (8.1±8.5 vs. 10.2±6.1 vs. 7.2±4.6 pg MPO/Lung; p = NS) and BALF (Not shown).

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