Limits...
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.

Show MeSH

Related in: MedlinePlus

IFN-γ increases mortality in mice with inhalational anthrax.C57BL/6 mice were given 108 spores 34F2 intratracheally in 100 µl saline. IFN-γ or IFN-α at described doses was added to saline and administered with B.anthracis spores. Mice were subsequently monitored for survival. N = 5–7 mice/group.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC1937023&req=5

pone-0000736-g004: IFN-γ increases mortality in mice with inhalational anthrax.C57BL/6 mice were given 108 spores 34F2 intratracheally in 100 µl saline. IFN-γ or IFN-α at described doses was added to saline and administered with B.anthracis spores. Mice were subsequently monitored for survival. N = 5–7 mice/group.

Mentions: Given the requirement of endogenous IFN signaling for optimal control of germination and inflammatory cytokine production in vivo, we next wished to assess whether administration of exogenous IFN-α or IFN-γ would improve bacterial control and lethality in our model. Co-administration of IFN-α (104 U) intratracheally with spores slightly increased mortality of B.anthracis infection compared to spores alone (38% vs. 18%). However, administration of 1 µg IFN-γ with B.anthracis spores resulted in a 100% lethality at 3 days with similar results obtained with 0.2 µg IFN−γ (Figure 4). These effects were specific for the interaction of IFN and B.anthracis as mice treated with IFN alone had a 100% survival (data 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 increases mortality in mice with inhalational anthrax.C57BL/6 mice were given 108 spores 34F2 intratracheally in 100 µl saline. IFN-γ or IFN-α at described doses was added to saline and administered with B.anthracis spores. Mice were subsequently monitored for survival. N = 5–7 mice/group.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0000736-g004: IFN-γ increases mortality in mice with inhalational anthrax.C57BL/6 mice were given 108 spores 34F2 intratracheally in 100 µl saline. IFN-γ or IFN-α at described doses was added to saline and administered with B.anthracis spores. Mice were subsequently monitored for survival. N = 5–7 mice/group.
Mentions: Given the requirement of endogenous IFN signaling for optimal control of germination and inflammatory cytokine production in vivo, we next wished to assess whether administration of exogenous IFN-α or IFN-γ would improve bacterial control and lethality in our model. Co-administration of IFN-α (104 U) intratracheally with spores slightly increased mortality of B.anthracis infection compared to spores alone (38% vs. 18%). However, administration of 1 µg IFN-γ with B.anthracis spores resulted in a 100% lethality at 3 days with similar results obtained with 0.2 µg IFN−γ (Figure 4). These effects were specific for the interaction of IFN and B.anthracis as mice treated with IFN alone had a 100% survival (data 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